건선 .. 각질세포 과증식.. 자가면역...

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• Review Article
• Open access
• Published: 24 January 2022

Advances in the pathogenesis of psoriasis: from keratinocyte perspective

• Xue Zhou, 
• Youdong Chen, 
• Lian Cui, 
• Yuling Shi & 
• Chunyuan Guo 

Cell Death & Disease volume 13, Article number: 81 (2022) Cite this article

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Abstract

Psoriasis is a complex long-lasting inflammatory skin disease with high preval‎ence and associated comorbidity. It is characterized by epidermal hyperplasia and dermal infiltration of immune cells. Here, we review the role of keratinocytes in the pathogenesis of psoriasis, focusing on factors relevant to genetics, cytokines and receptors, metabolism, cell signaling, transcription factors, non-coding RNAs, antimicrobial peptides, and proteins with other different functions. The critical role of keratinocytes in initiating and maintaining the inflammatory state suggests the great significance of targeting keratinocytes for the treatment of psoriasis.

건선은 

유병률이 높고 동반 질환이 있는 

오래 지속되는 복잡한 염증성 피부 질환입니다. 

건선은 

표피 과형성과 

면역 세포의 피부 침윤이 특징입니다. 

epidermal hyperplasia and dermal infiltration of immune cells

여기에서는 

유전학, 

사이토카인 및 수용체, 

대사, 

세포 신호, 

전사인자, 

비코딩 RNA, 

항균 펩타이드 및 기타 다양한 기능을 가진 단백질과 관련된 요인에 초점을 맞추어 

건선 발병에서 

각질 세포의 역할을 검토합니다. 

염증 상태를 시작하고 유지하는 데 있어 

각질 세포의 중요한 역할은 

건선 치료를 위해 각질 세포를 표적으로 삼는 것이 

매우 중요하다는 것을 시사합니다.

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Facts

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건선은 각질 세포의 과도한 증식과 비정상적인 분화, 그리고 여러 염증 세포의 침윤이 특징입니다.

각질 세포는 건선 발병에 매우 중요하며 건선의 시작과 유지 단계에 모두 관여합니다.

유전학, 사이토카인 및 수용체, 대사, 세포 신호, 전사 인자, 비코딩 RNA, 항균 펩타이드 등 다양한 인자가 각질 세포의 기능을 조절하고 건선에 영향을 미칩니다.

이러한 인자를 표적으로 삼는 것은 건선에 대한 유망한 치료 전략을 제공합니다.

Open questions

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건선에서 각질 세포를 조절하는 핵심 인자는 무엇인가요?

건선 재발에서 각질 세포의 역할은 무엇인가요?

각질 세포를 보다 선택적이고 효율적으로 표적으로 하는 치료를 통해 더 높은 항건선 효능을 달성할 수 있을까요?

Introduction

Psoriasis is a chronic, inflammatory autoimmune skin disease affected by genetic and various environmental factors. It has been recognized as a significant public health burden and is estimated to affect ~125 million people globally and ~2–4% of the population in western countries [1, 2]. Although the mortality rate of psoriasis is low, patients with psoriasis experience a significant impairment in life quality and a tremendous psychosocial burden.

Psoriasis is characterized by epidermal hyperplasia and dermal infiltration of immune cells. The pathogenesis of psoriasis is complicated, which involves the interplay between keratinocytes, immune cells, and other skin-resident cells. Over the last 2 decades, psoriasis has been considered as an immune cell-driven disease, and keratinocytes are just executors to perform the function of immune cells during psoriasis [3]. And the IL-23/IL-17 pathogenic axis is the key to drive psoriasis. Activation of plasmacytoid dendritic (pDCs) promotes myeloid dendritic cells (mDCs) maturation and production of TNF-α, IL-12, and IL-23, which leads to the activation of Th (T helper) 1 and Th17 and subsequent secretion of inflammatory cytokines, such as TNF-α, IL-17, IL-21, and IL-22. Keratinocytes are then activated by these cytokines (especially IL-17) and produce antimicrobial peptides, cytokines, and chemokines, contributing to the amplification of inflammation [1, 4]. Multiple biologics targeting TNF-α, IL-23, and IL-17 have shown tremendous success in the treatment of psoriasis. However, the side effects, safety, loss of efficacy and recurrence after discontinuation of these biologics encourage researchers to explore novel therapeutic strategies. Emerging evidence has shown that keratinocytes could act as a trigger in psoriasis, and would be a promising target for psoriasis treatment [3].

In this extensive review, we aim to discuss the recent advances in the pathogenesis of psoriasis from keratinocyte perspective. We will discuss multiple factors modulating keratinocytes and how keratinocytes are affected and linked to the pathogenesis of psoriasis.

건선은 

유전적 요인과 다양한 환경적 요인의 영향을 받는 

만성 염증성 자가면역 피부 질환입니다. 

전 세계적으로 약 1억 2,500만 명, 

서구 국가에서는 인구의 약 2~4%가 앓고 있는 것으로 추정되는 

심각한 공중 보건 부담으로 인식되고 있습니다[1, 2]. 

건선의 사망률은 낮지만, 

건선 환자는 삶의 질이 크게 저하되고 

심리사회적 부담이 매우 큽니다.

건선은 

표피 증식과 

면역 세포의 피부 침윤이 특징입니다. 

건선의 발병 기전은 복잡하며 

각질 세포, 

면역 세포 및 기타 피부 상주 세포 간의 상호 작용을 포함합니다. 

지난 20년 동안 건선은 

면역 세포가 주도하는 질환으로 간주되어 왔으며, 

각질 세포는 

건선 동안 면역 세포의 기능을 수행하는 실행자에 불과합니다 [3]. 

그리고 

IL-23/IL-17 병원성 축이 

건선을 유발하는 핵심입니다. 

형질 세포 수지상(pDC)의 활성화는 

골수성 수지상 세포(mDC)의 성숙과 

TNF-α, IL-12 및 IL-23의 생산을 촉진하여 

Th(T helper) 1 및 Th17의 활성화와 

그에 따른 TNF-α, IL-17, IL-21 및 IL-22와 

같은 염증성 사이토카인의 분비를 유도합니다. 

각질 세포는 

이러한 사이토카인(특히 IL-17)에 의해 활성화되고 

항균 펩타이드, 

사이토카인 및 케모카인을 생성하여 

염증을 증폭시키는 데 기여합니다[1, 4]. 

TNF-α, IL-23, IL-17을 표적으로 하는 

여러 생물학적 제제가 건선 치료에 큰 성공을 거두었습니다. 

그러나 이러한 

생물학적 제제의 

부작용, 안전성, 효능 상실 및 중단 후 재발로 인해 

연구자들은 새로운 치료 전략을 모색하고 있습니다. 

새로운 증거에 따르면 

각질 세포가 

건선의 유발 요인으로 작용할 수 있으며 

건선 치료의 유망한 표적이 될 수 있다는 사실이 밝혀졌습니다 [3].

이 광범위한 리뷰에서는 각질 세포의 관점에서 건선의 발병 기전에 대한 최근의 진전을 논의하고자 합니다. 각질 세포를 조절하는 여러 인자와 각질 세포가 건선의 발병에 어떻게 영향을 미치고 연관되어 있는지에 대해 논의할 것입니다.

The role of keratinocytes in psoriasis pathogenesis

Keratinocytes play essential roles in both the initiation and maintenance phases of psoriasis (Fig. 1). As part of the innate immune system, keratinocytes can respond to multiple triggers. Stressed keratinocytes release self-nucleotides and antimicrobial peptides, thus promoting the activation of pDCs. Then mDCs is activated and matured by producing IFN-α, IFN-γ, TNF-α, and IL-1β [5, 6].

각질 세포는 

건선의 시작과 유지 단계 모두에서 필수적인 역할을 합니다(그림 1). 

선천 면역 체계의 일부인 각질 세포는 

여러 가지 유발 요인에 반응할 수 있습니다. 

스트레스를 받은 각질 세포는 

자기 뉴클레오티드와 

항균 펩타이드를 방출하여 

pDC의 활성화를 촉진합니다. 

그런 다음 IFN-α, IFN-γ, TNF-α 및 IL-1β를 생성하여 

mDC를 활성화하고 성숙시킵니다[5, 6].

Fig. 1: The role of keratinocytes in psoriasis pathogenesis.

This figure depicts the pathological process of psoriasis mainly from the keratinocyte perspective. Keratinocytes can be stimulated by initial triggers, and stressed keratinocytes release self-nucleotides and antimicrobial peptide, activate pDCs and subsequent mDCs, involving in the initiation phase of psoriasis. After cytokines stimulation, activated keratinocytes influence psoriasis pathology from aspects of inflammatory infiltration, epidermal hyperplasia, innate immunity, tissue reorganization, etc. pDCs plasmacytoid dendritic cells, mDCs myeloid dendritic cells, IFN interferon, TNF-α tumor necrosis factor-α, IL-1β interleukin-1β, Th1 T helper 1.

이 그림은 건선의 병리학적 과정을 각질 세포의 관점에서 주로 설명합니다. 각질 세포는 초기 유발 요인에 의해 자극을 받을 수 있으며, 스트레스를 받은 각질 세포는 자기 뉴클레오티드와 항균 펩타이드를 방출하고, 건선의 시작 단계에 관여하는 pDC와 후속 mDC를 활성화합니다. 사이토카인 자극 후 활성화된 각질 세포는 염증성 침윤, 표피 증식, 선천성 면역, 조직 재구성 등의 측면에서 건선 병리에 영향을 미칩니다. pDCs 형질 세포 수지상 세포, mDCs 골수성 수지상 세포, IFN 인터페론, TNF-α 종양 괴사인자-α, IL-1β 인터루킨-1β, Th1 T 헬퍼 1.

Full size image

Besides participating in the initiation phase, keratinocytes also work as amplifiers of psoriatic inflammation during maintenance phase [7]. Once activated by proinflammatory cytokines synergistically, keratinocytes are highly proliferative and can produce copious chemokines (e.g. CXCL1/2/3, CXCL8, CXCL9/10/11, CCL2, and CCL20) to recruit leukocytes (such as neutrophils, Th17 cells, dendritic cells, and macrophages), antimicrobial peptides (e.g. S100A7/8/9/12, hBD2, and LL37) to induce innate immunity, and other inflammatory mediators to amplify inflammation. Moreover, keratinocytes, together with fibroblasts and endothelial cells, lead to tissue reorganization via activation and proliferation of endothelial cells and deposition of extracellular matrix [8,9,10]. The crosstalk between keratinocytes and immune cells especially Th17 cells results in the induction and maintenance of psoriasis with hyperproliferation and aberrant differentiation of keratinocytes, dilated and hyperplastic blood vessels, and infiltration of inflammatory cells like leukocytes [7, 11, 12].

각질 세포는 

시작 단계에 참여하는 것 외에도 

유지 단계에서 건선 염증의 증폭기 역할을 합니다 [7]. 

염증성 사이토카인에 의해 상승적으로 활성화되면 

각질 세포는 

증식력이 매우 높아져 많은 케모카인(예를 들어 백혈구(예: 호중구, Th17 세포, 수지상 세포, 대식세포), 

항균 펩타이드(예: S100A7/8/9/12, hBD2, LL37)를 모집하여 

선천성 면역을 유도하고 

기타 염증 매개 물질을 만들어 염증을 증폭시킬 수 있습니다. 

또한 각질 세포는 

섬유아세포 및 내피 세포와 함께 

내피 세포의 활성화 및 증식, 

세포 외 기질의 침착을 통해 조직 재구성을 유도합니다[8,9,10]. 

각질 세포와 면역 세포, 

특히 Th17 세포 간의 교차는 

각질 세포의 과증식 및 비정상적인 분화, 

혈관 확장 및 과형성, 

백혈구와 같은 염증 세포의 침윤으로 

건선의 유발 및 유지를 초래합니다 [7, 11, 12].

Factors regulating psoriatic keratinocytes

Genetic regulation

Epidemiologic studies indicate a strong genetic basis for psoriasis with a high heritability rate of 60–90% [13]. Over 80 psoriasis-susceptible loci have been identified, the strongest of which was the psoriasis-associated susceptibility locus 1 (PSORS1). Throughout these decades, there are at least 100 susceptibility genes for psoriasis identified, most of which are involved in adaptive immunity, innate immunity, and skin barrier function [13, 14]. Some of the candidate causal genes are keratinocyte-associated, which will be discussed below and summarized in Table 1.

역학 연구에 따르면 

건선은 60~90%의 높은 유전율로 

건선의 강력한 유전적 근거가 있는 것으로 나타났습니다[13]. 

80개 이상의 건선 감수성 유전자좌가 확인되었으며, 

그 중 가장 강력한 유전자좌는 

건선 관련 감수성 유전자좌 1(PSORS1)입니다. 

지난 수십 년 동안 최소 100개의 건선 감수성 유전자가 확인되었으며, 이들 대부분은 적응 면역, 선천성 면역, 피부 장벽 기능에 관여합니다[13, 14]. 후보 원인 유전자 중 일부는 각질 세포와 관련되어 있으며, 아래에서 설명하며 표 1에 요약되어 있습니다.

Table 1 Characteristics of mutations of gene associated with keratinocytes in psoriasis.

Full size table

Genomic studies linked the mediators of NF-κB pathway as disease susceptibility genes for psoriasis. For example, CARD14, encoding scaffold protein CARMA2 (CARD-containing MAGUK protein 2), is a NF-κB activator, which is mainly expressed in epidermal keratinocytes. Several genetic mutations of CARD14 (which maps to the psoriasis susceptibility locus 2 (PSORS2)) have been identified associated with psoriasis susceptibility [6]. To investigate the pathogenic role of CARD14 mutation in psoriasis, two groups generated two mouse models with patient-derived CARD14 gain-of-function mutations (a mutation in E138 (Card14E138A/+) or a deletion of E138 (Card14∆E138A/+)), respectively. Spontaneous psoriasis-like phenotype was developed in both models, indicating the CARD14 gain-of-function mutation is sufficient to drive the initiation of psoriasis [15, 16]. Furthermore, CARD14 deficiency protected mice from IMQ- or IL-23-induced psoriasis-like dermatitis [15, 17]. Mechanically, gain-of-function CARD14 mutations caused CARD14 aggregation and hyperactivation and enhanced CARD14-BCL10-MALT1 complex formation in keratinocytes, which results in constitutive activation of NF-κB and MAPK signaling pathway, subsequently leading to elevated expression‎ of inflammatory cytokines, chemokines, and antimicrobial peptides and enhanced activation of IL23/IL-17A axis [15, 16, 18]. Of note, CARD14 serves as a key mediator in IL-23/IL-17A axis through interaction with ACT1-TRAP6 signaling complex [15].

In addition, the NF-κB inhibitors TNFAIP3 (TNF-α induced protein 3, encoding A20) and TNIP1 (TNFAIP3-interacting protein 1, encoding ABIN1) have been identified as susceptibility loci for psoriasis and keratinocyte-associated genes. TNFAIP3/A20 is a deubiquitinase that can be linked to the IkB kinase complex by TNIP1/ABIN1, thus preventing activation of NF-κB. TNFAIP3/A20 was decreased in the epidermis of psoriatic patients, and keratinocyte-specific deletion of TNFAIP3/A20 potentiates the pro-inflammatory genes expression‎ of keratinocytes in psoriasis and other inflammatory disorders [19]. Global deletion of TNIP1/ABIN1 caused mice susceptible to the development psoriasis-like dermatitis induced by IMQ. Further investigation indicated TNIP1/ABIN1 deficiency in keratinocytes was sufficient to promote psoriasis inflammation, which disturbed IL-17-induced gene expression‎, and exaggerated chemokine and cytokine production [20]. Furthermore, the inhibitory effect of TNIP1/ABIN1 on psoriasis is mainly attributed to the suppression of inflammatory responses in keratinocytes rather than inhibiting keratinocyte proliferation [21].

Vascular endothelial growth factor A (VEGFA), the main epidermal-derived vessel-specific growth factor, is overexpressed in several inflammatory diseases, including psoriasis. The VEGFA gene is located at the PSORS1 locus, which is highly polymorphic and associated with psoriasis severity [22]. Transgenic mouse model overexpressing VEGFA in keratinocytes developed a spontaneous psoriasiform phenotype and inhibition of VEGFA reversed the psoriatic phenotype mediated by epidermal overexpression‎ of VEGFA or epidermal deletion of c-Jun/JunB [23,24,25,26]. VEGFA works through its receptors Flt1 (VEGFR1) and Flk1 (VEGFR2) and its coreceptor Neuropilin 1 (Nrp1). Keratinocyte-specific deletion of Flt1 or Nrp1 diminished VEGFA-induced psoriasis, suggesting that VEGFA/Flt1/Nrp1 axis has an essential epidermal autonomous function in the pathogenesis of psoriasis [27]. Altogether, these results indicate the epidermal VEGFA signaling as a promising therapeutic target for psoriasis.

TRAF3 interacting protein 2 (TRAF3IP2) is another psoriasis susceptibility gene associated with keratinocytes. It encodes ACT1, which is an adaptor protein with ubiquitin ligase activity, and plays an essential role in the signal transduction downstream of IL-17A receptor. TRAF3IP2 silencing in keratinocytes enhanced cell differentiation and inhibited IL-17 response [28]. In vivo, loss of ACT1 inhibited IL-17 signaling pathway and protected mice from psoriasiform dermatitis induced by IMQ and IL-23 [28, 29]. Interferon alpha-inducible protein 27 (IFI27) maps chromosome 14q32, which is located at a psoriasis susceptibility locus [30]. IFI27 was upregulated in the lesional skin of psoriatic patients and serves as a novel epidermal growth factors-stabilized protein in keratinocytes. Silencing IFI27 in keratinocytes caused cell cycle arrest and inhibited cell proliferation, and topical application of IFI27 siRNA ameliorated IMQ-induced epidermal hyperplasia in mice [31].

Except for mutations in CARD14, mutations in IL-36 receptor antagonist (IL-36RN) and adaptor-related protein complex 1 subunit sigma 3 (AP1S3) have also been identified to cause or contribute to pustular psoriasis that is a rare and severe form of psoriasis. IL-36Ra (encoded by IL-36RN) is released by keratinocytes and accumulates in the initial phase of psoriasis after inflammatory cytokines stimulation [32]. Loss of IL-36Ra in mice exacerbated IMQ-induced psoriasis-like dermatitis [33]. Mutations in IL36RN results in a reduced/loss of function of IL-36Ra and therefore enhances IL-36 and NF- κB signaling in keratinocytes [34]. AP1S3 is highly expressed in keratinocytes, with low expression‎ in neutrophils or undetectable expression‎ in CD4+ T cells. Mutations of AP1S3, such as p.Phe4Cys and p.Arg33Trp, are loss-of-function mutations and AP1S3 deficiency led to autoinflammation mediated by impaired keratinocyte autophagy and increased IL-36 signaling, finally contributing to the development of psoriasis [35].

유전체 연구를 통해 건선의 질병 감수성 유전자로 NF-κB 경로의 매개체를 연결했습니다. 예를 들어, 스캐폴드 단백질 CARMA2(CARD 함유 MAGUK 단백질 2)를 암호화하는 CARD14는 주로 표피 각질 세포에서 발현되는 NF-κB 활성화 인자입니다. 건선 감수성 유전자좌 2(PSORS2)에 매핑되는 CARD14의 여러 유전자 변이가 건선 감수성과 관련이 있는 것으로 확인되었습니다[6]. 건선에서 CARD14 돌연변이의 병원성 역할을 조사하기 위해 두 그룹에서 각각 환자 유래 CARD14 기능 획득 돌연변이(E138(Card14E138A/+) 또는 E138 결실(Card14∆E138A/+))를 가진 두 개의 마우스 모델을 생성했습니다. 두 모델 모두에서 자연 건선과 유사한 표현형이 나타났으며, 이는 CARD14 기능 향상 돌연변이가 건선 발병을 유도하기에 충분하다는 것을 나타냅니다[15, 16]. 또한, CARD14 결핍은 마우스를 IMQ 또는 IL-23으로 유발된 건선 유사 피부염으로부터 보호했습니다 [15, 17]. 기계적으로, 기능 향상 CARD14 돌연변이는 각질 세포에서 CARD14 응집 및 과활성화를 유발하고 CARD14-BCL10-MALT1 복합체 형성을 강화하여 NF-κB 및 MAPK 신호 경로의 구성적 활성화를 초래하여 염증성 사이토카인, 케모카인 및 항균 펩타이드의 발현을 증가시키고 IL23/IL-17A 축의 활성화를 강화합니다 [15, 16, 18]. 특히, CARD14는 ACT1-TRAP6 신호 복합체와의 상호작용을 통해 IL-23/IL-17A 축의 핵심 매개체 역할을 합니다 [15].



또한, 건선 및 각질 세포 관련 유전자의 감수성 유전자로는 NF-κB 억제제인 TNFAIP3(TNF-α 유도 단백질 3, 코딩 A20)와 TNIP1(TNFAIP3 상호작용 단백질 1, 코딩 ABIN1)이 확인되었습니다. TNFAIP3/A20은 TNIP1/ABIN1에 의해 IkB 키나제 복합체와 연결될 수 있는 탈유비퀴틴화 효소로서 NF-κB의 활성화를 방지합니다. 건선 환자의 표피에서 TNFAIP3/A20이 감소했으며, 각질 세포 특이적인 TNFAIP3/A20의 결실은 건선 및 기타 염증성 질환에서 각질 세포의 전 염증성 유전자 발현을 강화합니다 [19]. TNIP1/ABIN1을 전 세계적으로 결실시킨 마우스는 IMQ에 의해 유도된 건선 유사 피부염에 취약한 것으로 나타났습니다. 추가 조사에 따르면 각질 세포에서 TNIP1/ABIN1 결핍은 건선 염증을 촉진하기에 충분하여 IL-17에 의한 유전자 발현을 방해하고 케모카인과 사이토카인 생성을 과장하는 것으로 나타났습니다 [20]. 또한, 건선에 대한 TNIP1/ABIN1의 억제 효과는 주로 각질 세포 증식을 억제하기보다는 각질 세포의 염증 반응을 억제하는 데 기인합니다 [21].



주요 표피 유래 혈관 특이적 성장 인자인 혈관 내피 성장 인자 A(VEGFA)는 건선을 포함한 여러 염증성 질환에서 과발현됩니다. VEGFA 유전자는 다형성이 높고 건선 중증도와 관련이 있는 PSORS1 유전자좌에 위치합니다[22]. 각질 세포에서 VEGFA를 과발현하는 형질 전환 마우스 모델은 자연 건선 표현형이 발생했으며, VEGFA를 억제하면 VEGFA의 표피 과발현 또는 c-Jun/JunB의 표피 결실에 의해 매개되는 건선 표현형이 역전되었습니다 [23,24,25,26]. VEGFA는 수용체 Flt1(VEGFR1) 및 Flk1(VEGFR2)과 그 핵심 수용체인 뉴로필린 1(Nrp1)을 통해 작용합니다. 각질 세포 특이적으로 Flt1 또는 Nrp1을 결실시키면 VEGFA에 의한 건선이 감소하여 VEGFA/Flt1/Nrp1 축이 건선 발병에 필수적인 표피 자율 기능을 가지고 있음을 시사합니다 [27]. 이러한 결과를 종합하면 표피 VEGFA 신호가 건선의 유망한 치료 표적임을 알 수 있습니다.



TRAF3 상호 작용 단백질 2(TRAF3IP2)는 각질 세포와 관련된 또 다른 건선 감수성 유전자입니다. 유비퀴틴 리가제 활성을 가진 어댑터 단백질인 ACT1을 암호화하며 IL-17A 수용체의 하류 신호 전달에 필수적인 역할을 합니다. 각질 세포에서 TRAF3IP2를 침묵시키면 세포 분화가 향상되고 IL-17 반응이 억제됩니다 [28]. 생체 내에서 ACT1의 손실은 IL-17 신호 경로를 억제하고 IMQ 및 IL-23에 의해 유도된 건선형 피부염으로부터 마우스를 보호했습니다 [28, 29]. 인터페론 알파 유도 단백질 27(IFI27)은 건선 감수성 유전자좌에 위치한 염색체 14q32를 매핑합니다[30]. IFI27은 건선 환자의 병변 피부에서 상향 조절되었으며 각질 세포에서 새로운 표피 성장 인자 안정화 단백질로 작용합니다. 각질 세포에서 IFI27을 침묵시키면 세포주기가 정지되고 세포 증식이 억제되었으며, IFI27 siRNA를 국소 적용하면 마우스에서 IMQ에 의한 표피 증식이 개선되었습니다 [31].



CARD14의 돌연변이 외에도 IL-36 수용체 길항제(IL-36RN)와 어댑터 관련 단백질 복합체 1 서브유닛 시그마 3(AP1S3)의 돌연변이도 희귀하고 심각한 형태의 건선인 농포성 건선을 유발하거나 기여하는 것으로 확인되었습니다. IL-36Ra(IL-36RN에 의해 암호화됨)는 각질 세포에서 방출되며 염증성 사이토카인 자극 후 건선 초기 단계에 축적됩니다[32]. 마우스에서 IL-36Ra의 손실은 IMQ에 의한 건선 유사 피부염을 악화시켰습니다 [33]. IL36RN의 돌연변이는 IL-36Ra의 기능 감소/상실을 초래하여 각질 세포에서 IL-36 및 NF- κB 신호를 강화합니다 [34]. AP1S3는 각질 세포에서 높게 발현되며 호중구에서는 발현이 낮거나 CD4+ T 세포에서는 발현이 감지되지 않습니다. p.Phe4Cys 및 p.Arg33Trp와 같은 AP1S3의 돌연변이는 기능 상실 돌연변이이며 AP1S3 결핍은 각질 세포 자가포식 장애 및 IL-36 신호 증가에 의해 매개되는 자가 염증을 유발하여 결국 건선 발병에 기여합니다 [35].

Cytokines and receptors

Communication between immune cells and keratinocytes is through cytokines and their receptors, which plays a pivotal role in psoriasis pathogenesis. Mainly produced by immune cells, TNF-α, IFN-γ, IL-23/IL-17A, IL-22, etc, activate keratinocytes, triggering multiple cell signaling pathways, ultimately resulting in excessive keratinocytes proliferation and production of antimicrobial proteins, cytokines, chemokines, and growth factors. Among them, TNF-α, IL-17A, and IL-23 are of central importance in psoriasis as therapies targeting them are most efficient in the treatment of patients [10]. Recently, cytokines derived from or receptors expressed on keratinocytes have attracted more attention from researchers (Fig. 2).

면역 세포와 각질 세포 간의 통신은 

사이토카인과 그 수용체를 통해 이루어지며, 

이는 건선 발병에 중추적인 역할을 합니다. 

주로 면역 세포에서 생성되는 TNF-α, IFN-γ, IL-23/IL-17A, IL-22 등은 

각질 세포를 활성화하여 

여러 세포 신호 경로를 유발하여 

궁극적으로 각질 세포가 과도하게 증식하고 

항균 단백질, 사이토카인, 케모카인 및 성장 인자를 생성하게 합니다. 

이 중 TNF-α, IL-17A, IL-23은 

건선에서 가장 중요한 역할을 하며, 

이를 표적으로 하는 치료법이 환자 치료에 가장 효과적입니다 [10]. 

최근에는 

각질 세포에서 유래하거나 

각질 세포에서 발현되는 사이토카인이 

연구자들로부터 더 많은 관심을 받고 있습니다(그림 2).

Fig. 2: The role of cytokines derived from or receptors expressed on keratinocytes in psoriasis.

Cytokines are essential in the pathogenesis of psoriasis. Recently, cytokines derived from or receptors expressed on keratinocytes have shown great importance in psoriasis. Keratinocytes are critical cytokine responders in psoriasis, as keratinocyte-specific deletion of their receptors (such as IL-17RA and IL-36R) alleviated psoriasiform lesion in psoriatic mouse model. Keratinocyte-derived IL-17C, IL-17E, IL-36, and IL-23 could induce expression‎ of proliferative and proinflammatory genes by multiple signaling pathways, leading to epidermal hyperplasia and amplification of inflammation and leukocyte infiltration. IL-17RA IL-17 receptor A, TRAF6 TNF receptor-associated factor 6, IL-36R IL-36 receptor, IL-1RAcp IL-1 receptor accessory protein, TWEAK tumor necrosis factor (TNF)-like weak inducer of apoptosis, Fn14 factor-inducible 14, IL-22BP IL-22 binding protein.

Full size image

The IL-23/IL-17 cytokine axis is considered as a major driver of psoriasis. IL-23 expressed by immune cells is believed to be required for the maintenance and expansion of IL-17-producing immune cells [10]. However, IL-23 is also produced by keratinocytes, but the role of keratinocyte-produced IL-23 in psoriasis is unclear. Recently, using a genetic mouse model, Li and colleagues showed that keratinocyte-derived IL-23 was sufficient to activate IL-17-producing immune cells to secrete IL-17 and cause a chronic skin inflammation. Further investigation found that epigenetic regulation by H3K9 dimethylation controled IL-23 expression‎ in keratinocytes, which may contribute to psoriasis [36].

The IL-17 family cytokine contains six members: IL-17A (commonly referred to as IL-17), IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F, which acts through a IL-17 receptor heterodimer. IL-17A, the major downstream cytokine of IL-23, is most strongly implicated and well-studied in psoriasis pathogenesis [37]. Briefly, IL-17A binds to its receptors on keratinocytes, through multiple cell signaling pathways, it induces the production of keratinocyte-derived antimicrobial peptides (e.g. S100A7, LL37, and DEFB4A) to activate innate immunity, chemokines (e.g. CXCL1, CXCL8, and CCL20) to recruit leukocytes such as neutrophils, Th17 cells, mDCs and macrophage, and multiple pro-inflammatory genes (such as IL-1β, IL-6, IL-8, and TNF-α), thus amplifying the IL-23/IL-17A axis and producing the “feed forward” inflammatory circuits. On the other hand, IL-17A could indirectly induce epidermal hyperplasia via increased expression‎ of IL-19 and IL-36 by keratinocytes [11, 37]. However, there has been less attention on other IL-17 family members, despite of their upregulation in psoriatic lesions. Like IL-23, IL-17E (IL-25) is derived from both immune cells and keratinocytes, which was highly expressed in the epidermal layer of lesional skin of psoriatic patients and IMQ-induced psoriasis mouse model. IL-17E injection caused psoriasis-like pathology in mouse skin, whereas global knockout of IL-17E ameliorated IMQ-induced psoriasis. Specially, IL-17E deficiency in keratinocytes could lead to resistance to IMQ-induced psoriasis. Mechanically, epidermal IL-17E expression‎ is upregulated by IL-17A in psoriasis, and through its receptor IL-17RB on keratinocytes, it promotes keratinocyte proliferation and production of inflammatory cytokines and chemokines via STAT3 activation [38]. IL-17C is another IL-17 family member that has been identified as an epithelial cytokine predominantly produced by keratinocytes in skin [38]. IL-17C is reported to be increased in keratinocytes in a number of inflammatory skin diseases, such as psoriasis and atopic dermatitis (AD) [39]. And keratinocyte-specific IL-17C transgenic mice developed a spontaneous psoriasis-like phenotype [40]. Using MOR106, a specific anti-IL-17C antibody, it attenuated keratinocyte hyperproliferation and skin inflammation in mouse models of psoriasis and AD [41]. Of note, IL-17C builds a self-amplifying circuit, which results in enhanced production of inflammatory cytokines, chemokines, and antimicrobial peptides by keratinocytes, ultimately recruiting immune cells to the skin. It is noteworthy that IL-17C is not a specific target for psoriasis and AD but for a variety of inflammatory skin diseases.

The IL-17 receptor family contains five members, including IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE. IL-17RA is the most common co-receptor subunit of IL-17A, IL-17C, IL-17E, and IL-17F. Recently, Moos and colleagues determined the critical cell type responding to IL-17 by using different murine models with IL-17RA deficient in distinct cell types, such as keratinocytes, T cells, neutrophils, and macrophages. They found that only IL-17RA deletion in keratinocytes significantly protected mice from IMQ-induced psoriasis-like dermatitis, which is similar to full-body deficiency of IL-17RA. Importantly, mice lacking IL-17RA in keratinocytes also featured significantly decreased expression‎ of IL-1, IL-22, and CXCL2, as well as loss of neutrophil infiltration into the skin. However, deletion of IL-17RA in T cells, neutrophils or macrophages showed no impact on disease development [42]. Thus, keratinocytes are the crucial IL-17 responder in psoriasis.

The IL-36 family is a member of IL-1 superfamily and comprises three agonists (IL-36α, IL-36β, and IL-36γ) and one antagonist (IL-36 receptor antagonist (IL-36Ra)). All of the members bind to a heterodimeric receptor complexes composed of IL-36 receptor (IL-36R) and IL-1 receptor accessory protein (IL-1RAcp). Now, the IL-36 family cytokines are emerging as crucial players in the pathogenesis of psoriasis. Loss of IL-36Ra exacerbated IMQ-induced psoriasiform lesion [33]. By contrast, mice with IL-36α deficiency (but not IL-36β or IL-36γ deficiency), had significantly reduced psoriasis-like phenotype induced by IMQ [33, 43]. Similarly, IL-36R deficiency protected mice from IMQ-induced psoriasis-like dermatitis [33]. Specially, conditional deletion of IL-36R in keratinocytes showed similar protection as global deficiency of IL-36R [44], suggesting keratinocyte is the primarily responsive cell type for IL-36 signaling in psoriasis. Notably, IL-36 exerts its pathogenic role by promoting keratinocyte proliferation and enhancing the production of inflammatory cytokines and chemokines to amplify psoriatic inflammation [45,46,47,48,49,50,51]. Recently, therapies targeting IL-36 have been developed for psoriasis treatment, which are under clinical trials.

IL-22 is another major downstream cytokine of IL-23, which is mainly produced by CD4+ T cells and group 3 innate lymphoid cells (ILC3). Its receptor IL-22R is expressed on non-hematopoietic cells such as keratinocytes, epithelial cells, and hepatocytes [52]. IL-22 exerts its pathogenic role in psoriasis by inhibiting the terminal differentiation of keratinocytes, as well as inducing antimicrobial peptides and proinflammatory chemokines [53]. IL-22 binding protein (IL-22BP) is a natural inhibitor of IL-22 that specially binds to IL-22, thereby inhibiting its biological function. Both genetic IL-22BP deficiency and anti-IL-22BP neutralizing antibody exacerbated IMQ-induced psoriasis-like skin disease with increased levels of epidermal thickeness and enhanced expression‎ of inflammatory cytokines and IL-22-inducible antimicrobial peptides. Further investigation found that IL-24 is a downstream target of IL-22, regulating the terminal differentiation of keratinocytes [54].

Except for TNF-α, another member of TNF superfamily, TNF-like weak inducer of apoptosis (TWEAK) has recently been identified as a key cytokine in psoriasis. Daniel and colleagues showed that TWEAK deficiency alleviated IMQ-induced psoriatic dermatitis [55]. In addition, mice deficient in fibroblast growth factor-inducible 14 (Fn14, the receptor for TWEAK) also reduced the disease severity [56]. Most recently, using a mouse model with keratinocyte-specific deletion of Fn14, Rinkesh and colleagues have demonstrated a central role of keratinocytes in the action of TWEAK in psoriasis. Loss of Fn14 in keratinocytes protected mice from IMQ-induced psoriasiform hyperplasia and inflammation. Importantly, blocking TWEAK showed a similar reduction in epidermal thickness, skin infiltrates, and inflammation mediators as blocking TNF-α and IL-17A. However, there was no further improvement with combined treatments [57]. Altogether, blocking TWEAK may be an alternative therapeutic strategy for psoriasis.

Metabolic mechanism

One of the hallmark of psoriasis is keratinocyte hyperproliferation, which requires extensive energy, amino acids, nucleotides and lipids. In recent years, emerging evidence has implicated that metabolism is essential in the pathogenesis of psoriasis, especially in keratinocytes.

Glucose is the main source of energy for all cells, particularly for rapidly proliferating cells. Now, glucose metabolism is being recognized as a key metabolic mechanism involved in psoriasis. Glucose uptake is through glucose transporters, and glucose transporter 1(Glut1) is most widely expressed and dramatically elevated in psoriatic epidermis from the patient and IMQ-induced psoriasis mouse model [58, 59]. Keratinocyte-specific deletion of Glut1 did not affect normal skin development and homeostasis, but ameliorated IMQ- and IL-23-induced psoriasiform hyperplasia. Furthermore, topical application of GLUT inhibitor WZB117 attenuated both posriasiform hyperplasia and inflammation in mouse models of psoriasis, identifying glucose transport as a promising therapeutic target of psoriasis [59]. Also, suppressing glucose metabolism by 2-deoxy-d-glucose (2DG), a glucose analog, inhibited keratinocyte proliferation and alleviated IMQ-induced skin lesions [58, 60, 61]. Glycolysis and aerobic respiration are also related with keratinocyte function in psoriasis. Recently, a key rate-limiting enzyme of glycolysis, pyruvate kinase M2 (PKM2), was found significantly increased in the lesional skin of psoriatic patients and IMQ-induced psoriasis-like dermatitis. Overexpression‎ of PKM2 increased keratinocyte glucose metabolism, whereas silencing or inhibition of PKM2 suppressed keratinocyte cell glycolysis and proliferation. Moreover, genetic deletion of PKM2 in keratinocytes or pharmacological inhibition of PKM2 markedly reduced psoriasis-like skin lesions induced by IMQ. Importantly, EGF may contribute to the induction of PKM2 in keratinocyte through ERK1/2 pathway [61].

In addition to glucose metabolism, glutamate metabolism has been reported to be abnormal in psoriasis. Multiple metabolomics analysis revealed an elevation of glutamate metabolism in patients with psoriasis, which is positively correlated with the Psoriasis Area Severity Index (PASI) score. Glutamate metabolism serves a crucial role in psoriasis, as it may facilitate the hyperproliferating keratinocytes to meet their high metabolic demand, such as ATP or biosynthetic procurers [62,63,64,65]. Recently, Xia and colleagues found that Glutaminase 1(GLS1)-mediated glutaminolysis was aberrantly activated in psoriasis patients, as indicated by elevated mRNA and protein levels in both immune cells and keratinocytes, contributing to the pathogenesis of psoriasis. In keratinocytes, induction of GLS1 was caused by IL-17A/MALT1/c-Jun axis, and enhanced cell proliferation and chemokine production, contributing to the development of psoriasis phenotype [66].

Emerging evidence also suggests the importance of lipid metabolism in psoriasis. Studies analyzing plasma or serum showed altered lipid metabolites in psoriatic patients [67, 68]. In psoriatic skin lesions, lipid metabolism abnormalities were also observed [69, 70]. And our high-throughput transcriptome analysis of psoriatic skins identified notable differences in genes involved in lipid metabolism [71]. Sphingosine-1-phosphate (S1P), a metabolic product of sphingolipids, has been reported to be elevated in patients with psoriasis. It is a bioactivator that acts both as an intracellular second messenger and an extracellular ligand for G-protein-coupled receptors, which is involved in diverse cellular processes, including immune cell trafficking and keratinocyte proliferation and differentiation [72, 73]. To date, the role of S1P in psoriasis is controversial. Schaper and colleagues found that topical application of S1P alleviated IMQ-induced epidermal thickening and skin inflammation in the ear [74]. And using a selective S1P1 receptor agonist- Sy1930, it attenuated propranolol-induced psoriasis in pigs [75]. Furthermore, Jeon and colleagues showed that elevating S1P by inhibiting of S1P lyase ameliorated IMQ-induced psoriasis-like dermatitis, and reduced IL-17- and IL-22-induced cell proliferation and promoted keratinocyte differentiation [76]. However, blocking S1P generation by ceramidase inhibitor or sphingosine kinase 1/2 inhibitor protected mice from IMQ- induced skin lesions and inflammation, especially through inhibiting Th17 cell differentiation. Thus, it would be better to use conditional knockout mice to study the role of S1P in psoriasis, to dissect its role in immune cells and keratinocytes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a chaperone protein to the low-density lipoprotein (LDL) receptors, which promotes the degradation of LDL receptors. Induction of PCSK9 was observed in the lesional skin of both psoriatic patients and IMQ-induced psoriasis mouse model. Genetic deletion of PCSK9 or topical application of siRNA targeting PCSK9 relieved the psoriasis-like inflammation as well as the proliferation of keratinocytes. Notably, silencing PCSK9 in keratinocytes induced cell apoptosis and inhibited hyperproliferation [77].

Cellular metabolism in keratinocytes not only affects the supply of energy for keratinocyte proliferation but is also involved in a variety of inflammatory and immune response.

Cell signaling

The signaling pathway is a major regulator of psoriasis involved in diverse biological aspects we discussed in this review, which influences both immune cells and keratinocytes. Major signaling pathways altered in psoriasis include signal transducer and activator of transcription (STAT), nuclear factor-kappa B (NF-κB), MAPK, etc. In this section, only the key regulators of major signaling pathways in keratinocytes will be discussed and other factors involved in cell signaling may be discussed in other sections.

STAT signaling pathways

The JAK (Janus kinase)/STAT signaling is known to play an essential role in psoriasis. Of note, among the various STATs, STAT3 is hyperactivated in both immune cells and keratinocytes, regulating cell proliferation, differentiation, and apoptosis. In keratinocytes, STAT3 has a central role in response to various inflammatory cytokines in psoriasis, such as IL-6, IL-17, IL-21, IL-19, IL-22, etc. STAT3 activation in keratinocytes inhibited cell differentiation, promoted proliferation and production of antimicrobial peptides [78, 79]. The transgenic mouse model overexpressing STAT3 in keratinocytes led to the spontaneous development of psoriasis-like lesions with similar cytokine profiles as those of human psoriatic plaques [80, 81]. Moreover, specific deletion of STAT3 in keratinocytes rather than in T cells reduced psoriasis-like dermatitis [82]. Thus, STAT3 in keratinocytes is more important for the development of psoriasis.

NF-κB signaling pathway

Increasing evidence has shown that NF-κB signaling contributes to the pathogenesis of psoriasis by acting on immune cells and keratinocytes. NF-κB was highly activated in the lesional skin of psoriatic patients [83]. Using different mouse models, Bernd and colleagues showed that aberrant activation of NF-κB in both keratinocytes and T cells are important for the development of inflammatory skin diseases, like psoriasis. Mice with global deletion of IκBα developed psoriasis-like skin symptoms, while IκBα deficiency in keratinocytes only resulted in epidermal hyperplasia without epidermal inflammation. However, loss of IκBα in both keratinocytes and T cells led to a similar phenotype as that in global deficiency. Moreover, keratinocyte-specific deletion of RelA rescued the phenotype developed in global IκBα knockout mice [84]. And mice deficient in NF-κB alleviated IMQ-induced psoriasis-like dermatitis [85]. These indicate NF-κB activation in both keratinocytes and immune cells are essential for the development of psoriasis.

MAPK signaling pathway

MAPK kinases are involved in the pathogenesis of psoriasis, and play important roles in regulating keratinocyte proliferation and immune response. p38 was activated in psoriatic epidermis and cutaneous activation of p38 resulted in psoriasis-like dermatitis in mice. Topical application of p38 inhibitor attenuated IMQ-induced dermatitis [86]. In vitro studies showed that p38 inhibitor suppressed TNF-α or IL-17A-stimulated inflammatory response in keratinocytes [86, 87]. Like p38, ERK1/2 was also activated in the epidermis of psoriatic patients [88]. Inhibition of ERK by a specific ERK inhibitor JSI287 decreased IMQ-induced psoriasiform lesion [89]. DUSP1/MKP-1, a member of the dual-specificity phosphatase family, acts as a negative regulator of MAPK pathway. It was significantly downregulated in psoriasis patients and overexpression‎ of DUSP1 markedly inhibited keratinocyte proliferation and promoted apoptosis by targeting ERK/Elk-1/Egr-1 signaling pathway [90].

Other signaling pathways

Secreted frizzled-related protein (SFRP) 4, a negative regulator of Wnt, is pivotal for epidermal hyperplasia. SFRP4 was decreased in the skin epidermis of psoriatic patients and mouse models of psoriasis by an epigenetic regulation- DNA methylation. SFRP4 treatment or Wnt inhibition suppressed keratinocyte hyperproliferation induced by IL-6 in vitro. Administration of SFRP4 or pharmacological inhibition of Wnt alleviated psoriasis-like dermatitis induced by IMQ [91]. Recently, Hippo-Yes-associated protein (YAP) signaling has been reported to be involved in psoriasis. YAP and its downstream target amphiregulin (AREG) were dramatically induced in skin of psoriatic patients and in psoriasis-like mouse model. As an oncogene, YAP promotes cell proliferation and inhibits cell apoptosis. And silencing YAP inhibited keratinocyte proliferation, induced cell cycle arrest, and promoted cell apoptosis, which acts through an AREG-dependent pathway [92].

Transcription factor

Except for the transcription factors involved in the major signaling pathways in psoriasis discussed above, some other transcription factors expressed in keratinocytes have emerged as important regulators in psoriasis, which have appealing therapeutic potential.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in regulating cellular defenses against oxidative or toxic stresses. In psoriasis, Nrf2 was highly expressed and activated in psoriatic epidermis. Overexpression‎ of Nrf2 facilitated keratinocyte proliferation by increasing the expression‎ of hyperproliferation-associated keratins, including keratin (KRT) 6, KRT16, and KRT17. Locally silencing Nrf2 reduced IMQ-induced psoriasis-like dermatitis and inhibited KRT6, KRT16, and KRT17 expression‎ [93]. These indicate Nrf2 acts as a regulator of hyperproliferation-associated keratins, which is a potential therapeutic target for psoriasis. AP-1 transcription factor superfamily (including JUN, JUNB, JUND, FOS, FOSB, FRA1, and FRA2) is essential in the pathogenesis of psoriasis. Epidermal deletion of c-Jun and JunB led to a spontaneous psoriasiform phenotype [94]. FRA1 was evidently elevated in the lesional skin of psoriatic patients. Overexpression‎ of FRA1 in keratinocytes triggerred enhanced production of proinflammatory cytokine and chemokine and promoted keratinocyte migration and wound healing process [95]. Grainyhead-like 3 (GRHL3) is a transcription factor that plays a critical role in epidermal differentiation and barrier formation. Upregulation of GRHL3 was observed in the epidermis of both psoriatic patients and IMQ-induced psoriasis mouse model. GRHL3 deficiency in keratinocytes aggravated IMQ-induced psoriasiform phenotype [96]. Further investigation identified thymus and activation-regulated chemokine (TARC) as a downstream of GRHL3 that promoted keratinocyte proliferation after loss of GRHL3 [97].

Non-coding RNAs

Besides genetic factors, epigenetic regulation is also involved in psoriasis. Non-coding RNA regulation is one of the epigenetic regulations important for various biological processes and disease pathogenesis. The role of non-coding RNAs in psoriasis, especially the role of microRNAs has been extensively explored previously [98, 99]. Here, we will focus on the effects of non-coding RNAs (microRNA and long non-coding RNA (lncRNA)) on keratinocytes in psoriasis.

Role of microRNAs in psoriatic keratinocytes

MicroRNAs are short non-coding RNAs, which inhibit protein-coding gene expression‎ at the post-transcriptional level and their dysfunction is linked to psoriasis [100]. Early studies observed that more than 250 microRNAs were aberrantly expressed in the lesional skin of psoriatic patients, and play an essential role in modulating the functions of multiple cell types important for psoriasis pathogenesis, such as keratinocytes and leukocytes, as well as the interplay between them [98, 101]. Here, we will discuss how microRNAs affect psoriatic keratinocytes and psoriasis, and the summary of microRNAs involved in keratinocytes is shown in Table 2.

Table 2 Characteristics of microRNAs regulating keratinocytes in psoriasis.

Full size table

Some microRNAs show aberrant upregulation in psoriasis and mainly promote keratinocyte proliferation. For example, microRNA (miR)-31 is upregulated in psoriatic skin of patients or IMQ-induced mouse model, especially in the basal or superbasal cell layers of epidermis. Genetic deletion of miR-31 in keratinocytes alleviated psoriasiform hyperplasia and inflammation induced by IMQ or IL-23. Of note, miR-31 was induced by NF-κB, which in turn suppressed protein phosphatase 6 (ppp6c), and thereby promoted the G1 to S phase progression, finally resulting in increased proliferation of keratinocytes in psoriasis [102]. miR-17-92 cluster, including miR-17, miR-18a, miR-19a, miR-19b miR-20a, and miR-92a, was also induced in psoriatic lesions and positively correlated with PASI. Zhang and colleagues found that STAT1-induced miR-17-92 cluster promoted keratinocyte proliferation by suppressing cyclin-dependent kinase inhibitor 2B (CDKN2B) and increased the chemokine production via inhibition of suppressor of cytokine signaling 1 (SOCS1), suggesting miR-17-92 as a potential therapeutic target for psoriasis [103]. Moreover, miR-130a, highly expressed in psoriatic lesions, directly targeted serine/threonine kinase 40 (STK40) to activate NF-κB pathway or indirectly upregulated sex-determining region Y chromosome-box 9 (SOX9) to activate JNK/MAPK pathway, thus promoting keratinocytes viability and migration and inhibiting apoptosis of keratinocytes [104]. In addition, miR-223 targeted phosphatase and tensin homolog (PTEN), a tumor suppressor inhibiting the PI3K/AKT signaling pathway, and ultimately contributed to increased proliferation and decreased apoptosis in IL-22-stimulated HaCaT cells [105]. However, miR-146a/b, which were highly expressed in the psoriatic skin lesions, negatively regulated keratinocyte proliferation and played protective roles in psoriasis. miR-146a targeted TNF receptor-associated factor 6 (TRAF6) and epidermal growth factor receptor (EGFR), which regulated keratinocyte proliferation and inflammatory responses [106, 107]. Overexpression‎ of miR-146a inhibited epidermal proliferation, impaired neutrophil infiltration, and suppressed IL-17-driven psoriatic inflammation of mouse models via its target genes, while genetic deficiency in miR-146a exacerbated pathology of psoriasis-like skin inflammation especially in the early onset of the disease [101]. miR-146b facilitated miRNA-146a to inhibit the proliferation and psoriasis-related target gene expression‎ (such as FERM domain containing kindlin 1 (FERMT1), NUMB endocytic adaptor protein (NUMB), etc.) in cultured human keratinocytes stimulated with IFN-γ or TNF-α [108].

Besides, some microRNAs are aberrantly downregulated in psoriatic skin lesions and exert proliferation-inhibiting and differentiation-promoting effects on keratinocytes. miR-let-7b, the first known human microRNA, was dramatically reduced in psoriatic epidermis of IMQ-induced psoriasis mouse model. Using a keratinocyte-specific miR-let-7b transgenic mouse model, Wu and colleagues showed that overexpression‎ of miR-let-7b in keratinocytes ameliorated psoriasis-like dermatitis induced by IMQ. Mechanically, miR-let-7b inhibited ERK signaling pathway through targeting IL-6, resulting in the acceleration of keratinocyte differentiation in psoriasis [109]. Downregulation of miR-145-5p was observed in the lesional skin of psoriatic patients. Overexpression‎ of miR-145-5p inhibited cell proliferation and chemokine production by targeting mixed-lineage kinase 3 (MLK3)-mediated NF-κB and STAT3 activation in vitro and alleviated psoriasiform hyperplasia and inflammation in vivo. By contrast, inhibition of miR-145-5p led to the opposite effects [110]. Similarly, overexpression‎ of miR-187 suppressed keratinocyte hyperproliferation and protected mice from IMQ-induced skin lesions through inhibition of CD276-STAT3 signaling [111]. miR-486-3p was markedly decreased in the epidermis of psoriatic patients and showed a negative correlation with the disease severity. TGFβ/SMAD was identified as an upstream of miR-486-3p. In psoriasis, inactivation of TGFβ/SMAD pathway led to the loss of miR-486-3p, resulting in KRT17 (a cytoskeletal protein that play a pathogenic role in psoriasis) overexpression‎ and keratinocyte hyperproliferation [112]. In line with miR-486-3p, miR-138 is another negative regulator of KRT17 by targeting human telomerase reverse transcriptase (hTERT), subsequently inhibiting keratinocyte proliferation and increasing cell apoptosis [113]. Moreover, miR-125b-5p and miR-181b-5p shared the same target gene AKT3, which at least partly contributed to the inhibition of keratinocyte proliferation in psoriasis [114]. Besides, miR-125b-5p and miR-181b-5p may suppress keratinocyte proliferation by targeting fibroblast growth factor receptor 2 (FGFR2) and ubiquitin-specific peptidase 2 (USP2) or TLR4, respectively [115, 116]. Furthermore, miR-20a-3p and miR-330 are two IL-22 responsive microRNAs identified in psoriasis. miR-20-3p promoted keratinocyte cell apoptosis and inhibited cell proliferation by Scm like with four mbt domains 1 (SFMBT1) and subsequent TGF-β1/Survivin pathway [117]. miR-330 can directly target catenin beta 1 (CTNNB1, also known as β-catenin), leading to repression of CyclinD1 and Axin2 and subsequent suppression of keratinocyte proliferation [118]. Importantly, miR-876-5p suppressed PI3K/AKT and ERK signaling way to regulate keratinocyte proliferation by targeting Angiopoietin-1 (Ang-1) [119]. Additionally, as a well-known tumor suppressor, miR-217 targeted Grainyhead-like 2 (GRHL2), a developmental transcriptional factor with ability of influencing epithelial barrier function and keratinocyte differentiation, to inhibit keratinocyte proliferation and promote cell differentiation [120].

MicroRNAs play crucial roles in psoriasis, particularly modulating keratinocyte proliferation, differentiation, apoptosis, and inflammation. With all those important signaling pathways involved, microRNAs demonstrate such a comprehensive and potent role in the pathogenesis of psoriasis (Fig. 3).

Fig. 3: Non-coding RNAs and their involved signaling pathways in psoriasis.

Non-coding RNAs play pivotal roles in the pathogenesis of psoriasis. In keratinocytes, they can affect cell proliferation, apoptosis, differentiation, and inflammatory response through targeting multiple signaling pathways, such as NF-κB signaling, STAT3 signaling, ERK signaling, AKT signaling, etc. Also, expression‎ of some of microRNAs are found to be regulated by NF-κB, STAT, or TGFβ signaling. MEG3 maternally expressed gene 3, ppp6c protein phosphatase 6, STK40 serine/threonine kinase 40, MLK3 mixed-lineage kinase 3, SFMBT1 Scm like with four mbt domains 1, PTEN phosphatase and tensin homolog, Ang1 Angiopoietin-1, CDKN2B cyclin-dependent kinase inhibitor 2B, SOCS1 suppressor of cytokine signaling 1, K17 keratin 17.

Full size image

Role of lncRNAs in psoriatic keratinocytes

Unlike microRNAs, lncRNAs are a group of non-protein coding transcripts >200 nucleotides and regulate gene expression‎ at both transcriptional and post-transcriptional levels [121]. Increasing evidence has shown that lncRNAs are involved in the pathogenesis of psoriasis, affecting the function of keratinocytes, T cells and dendritic cells. In this review, we are specially focusing on the role of lncRNAs in keratinocytes.

Psoriasis-associated non-protein coding RNA induced by stress (PRINS), the first identified psoriasis susceptibility-associated lncRNA, was highly expressed in the epidermis of non-lesional and lesional skin of psoriatic patients. PRINS was induced in response to the stress, and silencing of it decreased keratinocyte viability under stress condition [122]. Further investigation identified G1P3 as a downstream target of PRINS, which was also upregulated in psoriatic epidermis and exerted anti-apoptotic effects in keratinocytes [123]. Besides, lncRNA-MSX2P1 was elevated in the lesional skin of psoriatic patients and IL-22-stimulated keratinocytes. It accelerated IL-22-induced keratinocyte proliferation and inhibited apoptosis by inhibition of miR-6731-5p and activation of S100A7 [124]. Similarly, upregulation of lncRNA RP6-65G23.1 has been found in psoriatic epidermis [125]. Overexpression‎ of RP6-65G23.1 promoted keratinocyte proliferation and decreased cell apoptosis, whereas silencing of it showed opposite effects. Of note, RP6-65G23.1 regulated keratinocyte proliferation via AKT and ERK1/2 pathways, and affected keratinocyte apoptosis by Bcl2 and Bcl-xl [121]. In contrast, lncRNA maternally expressed gene 3 (MEG3) was markedly downregulated in psoriatic skin. MEG3 suppressed keratinocyte proliferation and accelerated cell apoptosis by targeting miR-21 and increasing the expression‎ of Caspase 8 [126]. Furthermore, MEG3 inhibited keratinocyte inflammatory response and enhanced autophagy via PI3K/AKT/mTOR signaling pathway in vitro or in vivo [127].

Therefore, lncRNAs influence the proliferation, apoptosis and inflammatory responses of keratinocytes in psoriasis. Identifying dysregulated lncRNAs and the related networks involved in psoriasis will be an important area of research and would provide potential new clues for future diagnosis and treatment of this disease.

Antimicrobial peptides

Antimicrobial peptides, including LL37, β-defensins and S100 proteins are small proteins that activate innate immune response and are associated with psoriasis pathogenesis [128]. Studied found antimicrobial peptides could also regulate the function of keratinocytes. S100A7 is an antimicrobial peptide that is stored in differentiated keratinocytes and S100A7 was significantly elevated in psoriasis patients. Studies suggest that S100A7 expression‎ can be induced by differentiation of keratinocytes dependent on protein kinase C pathway or downregulation of Caspase 8. However, overexpression‎ of S100A7 led to aberrant keratinocyte differentiation in psoriasis [129,130,131], suggesting a negative feedback during psoriasis development. Furthermore, C10orf99 is another antimicrobial peptide identified recently that was highly expressed in psoriatic epidermis of patients or IMQ-induced mouse model. Topical application of C10orf99 shRNA effectively attenuated IMQ-induced psoriasis-like dermatitis. Notably, C10orf99 promoted keratinocyte proliferation by enhancing the G1/S transition and activating the ERK1/2 and NF-κB pathways, thus contributing to psoriasis pathogenesis [132]. Therefore, antimicrobial peptides exert important impacts on psoriatic keratinocytes.

LL37, β-디펜신 및 S100 단백질을 포함한 항균 펩타이드는 

선천성 면역 반응을 활성화하는 작은 단백질이며 

건선 발병과 관련이 있습니다 [128]. 

연구에 따르면 

항균 펩타이드는 

각질 세포의 기능도 조절할 수 있는 것으로 밝혀졌습니다. 

S100A7은 분화된 각질 세포에 저장되는 항균 펩타이드이며, 건선 환자에서 S100A7이 유의미하게 증가했습니다. 연구에 따르면 단백질 키나아제 C 경로에 의존하는 각질 세포의 분화 또는 카스파제 8의 하향 조절에 의해 S100A7 발현이 유도될 수 있다고 합니다. 그러나 S100A7의 과발현은 건선에서 비정상적인 각질 세포 분화로 이어져[129,130,131] 건선 발생 중 부정적인 피드백이 있음을 시사합니다. 또한 최근에 발견된 또 다른 항균 펩타이드인 C10orf99는 환자의 건선 표피 또는 IMQ 유도 마우스 모델에서 높게 발현되는 것으로 나타났습니다. C10orf99 shRNA를 국소 적용하면 IMQ로 유발된 건선 유사 피부염이 효과적으로 약화되었습니다. 특히, C10orf99는 G1/S 전환을 강화하고 ERK1/2 및 NF-κB 경로를 활성화하여 각질 세포 증식을 촉진함으로써 건선 발병에 기여했습니다 [132]. 따라서 항균 펩타이드는 건선 각질 세포에 중요한 영향을 미칩니다.

Proteins with other functionsProteins upregulated in psoriasis

Emerging evidence has shown that the ubiquitin-proteasome system plays a crucial role in the pathogenesis of psoriasis. Zieba and colleagues showed that the proteasome assembly chaperone POMP (proteasome maturation protein) was upregulated in psoriatic skin, resulting in an increase of proteasome levels and activities. Silencing POMP inhibited cell proliferation and differentiation, and promoted cell apoptosis via inhibition of the proteasome assembly [133]. E3 Ligase tripartite motif-containing 21 (Trim21) belongs to the Trim protein family with E3 ligase activity. In psoriatic epidermis, Trim21 was found overexpressed and induced activation of STAT3 through ubiquitylating and stabilizing KRT17 in keratinocytes, thus promoting the development of psoriasis [134]. Neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) is another E3 ligase that was downregulated in psoriatic epidermis. Suppression of NEDD4L promoted keratinocyte hyperplasia by mediating GP130 degradation and activation of STAT3 [135]. TRAF6 is a signaling adaptor and E3 ubiquitin ligase. In psoriasis, IL-17 signals through TRAF6, then activates NF-κB and MAPK pathways. Keratinocyte-specific deletion of TRAF6 diminished psoriasiform hyperplasia and IL-17-mediated inflammation [136]. Prokineticin 2 (PK2), a neuroendocrine peptide, is a psoriasis-specific factor highly expressed psoriatic skins. PK2 enhanced the production of IL-1 in keratinocytes and macrophages, thus inducing keratinocyte hyperproliferation and inflammatory cascades in psoriasis. Overexpression‎ of PK2 exacerbated psoriasis-like dermatitis in mice, whereas knockdown of PK2 ameliorated psoriasis-like dermatitis [137]. Therefore, PK2 could be a novel psoriasis-specific target in the treatment of psoriasis. Ras-related C3 botulinum toxin substrate 1 (RAC1) belongs to the small GTPases of the Rho family. RAC1 was hyperactivated in psoriatic epidermis and overexpression‎ of RAC1 in keratinocytes caused psoriasis-like skin lesions in mice. Epidermal activation of RAC1 stimulated a variety of key signaling pathways, such as STAT3, ZNF750, and NF-κB, leading to keratinocyte hyperproliferation and cytokines production, as well as cell differentiation inhibition [138]. Plexin-B2, an axon-guidance molecule, was found greatly increased in keratinocytes of psoriatic patients and IMQ-induced psoriatic mouse model. Silencing Plexin-B2 decreased IMQ-induced psoriatic dermatitis. Mechanically, binding by its ligand CD100, Plexin-B2 promoted the production of inflammatory chemokines/cytokines and the formation of the NLRP inflammasome in keratinocytes through activating NF-κB pathway, subsequently strengthening inflammatory responses of keratinocytes in psoriasis [139]. CCN1, also known as cysteine-rich protein 61 (Cyr61), is an extracellular protein elevated in psoriatic lesions. It stimulated keratinocyte proliferation and a variety of immune-related molecule expression‎ by keratinocytes, such as IL-8, IL1-β, CCL20, HLA-ABC, HLA-DR, and ICAM. Silencing or blocking CCN1 alleviated IL-23- or IMQ-induced psoriasis-like dermatitis [140,141,142,143]. High-mobility group protein B1 (HMGB1) is a nuclear protein that can be released to act as a cytokine when cells undergo stress. In psoriasis, HMGB1 can be released from keratinocytes, which potentiates the production and secretion of IL-18 by keratinocytes through an autocrine mechanism. Importantly, blocking HMGB1 or IL-8 by neutralizing antibodies not only attenuated but also accelerated the recovery from psoriasis-like dermatitis induced by IMQ [144]. Recently, a member of the epidermal differentiation complex, Cornulin (CRNN), was shown highly expressed in psoriatic epidermis from patients or IMQ-induced mouse model. Induction of CRNN in keratinocytes activated PI3K/AKT pathway, contributing to keratinocyte hyperproliferation [145].

Proteins downregulated in psoriasis

Galectin-3, which belongs to the galectin family of β-galactoside-binding lectins, is a psoriasis-specific protein downregulated in psoriatic epidermis. Galectin-3 deficient in epidermal keratinocytes resulted in a spontaneous development of psoriasis-like phenotype. Administration of recombinant Galectin-3 ameliorated IMQ-induced psoriasis-like dermatitis. Notably, downregulation of Galectin-3 altered keratinocyte differentiation and apoptosis and induced the expression‎ of antimicrobial peptides (S100A7, S100A8, and S100A9) and chemokines (CXCL1, CXCL8, and CCL20) by activation of JNK signaling, leading to neutrophil accumulation [146]. Cholecystokinin octapeptide (CCK8), a stimulatory hormone released from enteroendocrine I-cells of the intestine, was constitutively expressed in the epidermis of normal skin, but decreased in psoriatic patients. Administration of sulfated CCK8 ameliorated IMQ-induced psoriasiform hyperplasia and inflammation through an autocrine or paracrine manner with decreased expression‎ of IL-17, IL-22, and IL-6 but not IL-23. In vitro studies found that IL-17 stimulation reduced CCK8 expression‎, which may lead to the induction of IL-6 [147]. Connexin 43 (Cx43) is a member of gap junction protein, which is abundantly expressed in epidermis. Cx43 was markedly downregulated in psoriatic epidermis and IL-22-stimulated keratinocyte. Downregulation of Cx43 significantly promoted cell proliferation and decreased gap junction intercellular communication in keratinocytes, resulting from IL-22-induced JNK pathway activation [148].

Concluding remarks

In this review, we have highlighted the critical roles of keratinocytes in psoriasis. Keratinocytes participate in both the initiation and maintenance phases of psoriasis. There are various factors that can regulate keratinocytes, including genetic regulation, cytokines and receptors, metabolism, cell signaling, transcription factors, non-coding RNAs, antimicrobial peptides, and proteins with other different functions. These modulating factors are not independent, but work together to alter the biological behavior of keratinocytes via multiple mechanisms, linking keratinocytes with psoriasis.

Although our understanding of the role of keratinocytes in psoriatic pathogenesis has advanced considerably, our knowledge about how various factors regulate the detailed functions of keratinocytes are still limited. Right now, many anti-psoriatic drugs, especially the biologics have demonstrated good efficacy, however, long-term efficacy and safety are still the problems for psoriasis treatment. Therefore, it is of great need to discover better treatment targeting keratinocytes more selectively and efficiently. Investigation into the mechanisms of keratinocyte-immune cell interaction network may shed light on restoring keratinocyte homeostasis and benefiting the alleviation of psoriasis.

이 리뷰에서는 

건선에서 각질 세포의 중요한 역할을 강조했습니다. 

각질 세포는 건선의 시작과 유지 단계에 모두 관여합니다. 유전자 조절, 사이토카인 및 수용체, 대사, 세포 신호, 전사인자, 비코딩 RNA, 항균 펩타이드 및 기타 다른 기능을 가진 단백질 등 각질 세포를 조절할 수 있는 다양한 인자가 있습니다. 이러한 조절 인자들은 독립적으로 작용하는 것이 아니라 여러 메커니즘을 통해 각질 세포의 생물학적 행동을 변화시켜 각질 세포와 건선을 연결합니다.

건선 발병에서 각질 세포의 역할에 대한 이해는 상당히 발전했지만, 다양한 인자가 각질 세포의 세부 기능을 어떻게 조절하는지에 대한 지식은 아직 제한적입니다. 현재 많은 건선 치료제, 특히 생물학적 제제가 우수한 효능을 입증했지만 장기적인 효능과 안전성은 여전히 건선 치료의 과제로 남아 있습니다. 따라서 각질 세포를 보다 선택적이고 효율적으로 표적하는 더 나은 치료제를 발굴하는 것이 절실히 필요합니다. 각질세포-면역세포 상호작용 네트워크의 메커니즘에 대한 연구는 각질세포 항상성을 회복하고 건선 완화에 도움이 될 수 있는 방법을 밝혀낼 수 있습니다.

Data availability

All data generated during and/or analyzed during the current study are available.

References

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