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Review
. 2024 Mar 13;13(6):505.
doi: 10.3390/cells13060505.

Inflammatory Skin Diseases: Focus on the Role of Suppressors of Cytokine Signaling (SOCS) Proteins

Antonia Cianciulli  1 , Rosa Calvello  1 , Chiara Porro  2 , Dario Domenico Lofrumento  3 , Maria Antonietta Panaro  1
Affiliations
Review

Inflammatory Skin Diseases: Focus on the Role of Suppressors of Cytokine Signaling (SOCS) Proteins

Antonia Cianciulli et al. Cells. .

Abstract

Inflammatory skin diseases include a series of disorders characterized by a strong activation of the innate and adaptive immune system in which proinflammatory cytokines play a fundamental role in supporting inflammation. Skin inflammation is a complex process influenced by various factors, including genetic and environmental factors, characterized by the dysfunction of both immune and non-immune cells. Psoriasis (PS) and atopic dermatitis (AD) are the most common chronic inflammatory conditions of the skin whose pathogeneses are very complex and multifactorial. Both diseases are characterized by an immunological dysfunction involving a predominance of Th1 and Th17 cells in PS and of Th2 cells in AD. Suppressor of cytokine signaling (SOCS) proteins are intracellular proteins that control inflammatory responses by regulating various signaling pathways activated by proinflammatory cytokines. SOCS signaling is involved in the regulation and progression of inflammatory responses in skin-resident and non-resident immune cells, and recent data suggest that these negative modulators are dysregulated in inflammatory skin diseases such as PS and AD. This review focuses on the current understanding about the role of SOCS proteins in modulating the activity of inflammatory mediators implicated in the pathogenesis of inflammatory skin diseases such as PS and AD.

Keywords: JAK/STAT signaling pathway; SOCS proteins; atopic dermatitis; inflammation; psoriasis; skin.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Inflammatory mediators implicated in the pathogenesis of PS and AD. In PS (left), a dysregulation of the crosstalk between cells of the innate and adaptive immune system and keratinocytes induces the production of proinflammatory cytokines that activate dendritic cells. Activated dendritic cells secrete cytokines (IL-12 and IL-23) that guide the differentiation and proliferation of Th-1 and Th-17 lymphocytes, in turn releasing a wide variety of inflammatory mediators and determining the hyperproliferation of keratinocytes with an increase in thickness of the epidermis and production of antimicrobial peptides, chemokines, and proinflammatory cytokines, contributing to the amplification of psoriatic inflammation. In AD (right), multiple factors cause a dysfunction of the innate and adaptive immune system of the skin barrier associated with a reduction in the structural protein filaggrin, epidermal lipids, and antimicrobial peptides and a dysbiosis of commensal bacteria determining a loss of epidermal integrity, dehydration, chronic inflammation of the skin, and increased sensitization to allergens and infections.
Figure 2
Figure 2
Possible involvement of SOCS proteins in PS. (A) In human keratinocytes, SOCS1 and its mimetic peptide PS-5 reduce the production of ICAM-1, HLA-DR, IP-10, MCP-1, CXCL10, and CCL2 through inhibition of JAK1/2 and the consequent downregulation of STAT1/3, blocking IFN-γRα-induced signal. (B) Deletion of SOCS3 in mouse keratinocytes induces increased expression of IL-20R-receptor-related proinflammatory cytokines and hyperactivation of STAT3 in response to IL-6. (C) In human psoriatic keratinocytes, the cytokines IFN-g and TNF-a induce high levels of SOCS1 and SOCS3 expression, which activates PI3K with consequent phosphorylation of AKT. The latter determines the phosphorylation of the transcription factor NF-κB, which induces the gene expression of anti-apoptotic molecules.
Figure 3
Figure 3
Mechanistic view of immune response regulation by SOCS proteins in AD. SOCS proteins are differently expressed in Th cell populations. High expression of SOCS1 leads to the Th1 responses, whereas SOCS3 drives the Th2 responses; SOCS5 promotes the Th1 responses, reducing those of Th2 cells probably through the IL-4/STAT6 pathway. SOCS7 deletion develops AD-like manifestations and an increase in the number of granular mast cells. Deletion of SOCS2 protein induces the appearance of AD-like signals.
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