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Review
. 2024 Jun 21:15:1393799.
doi: 10.3389/fimmu.2024.1393799. eCollection 2024.

SOCS1 and SOCS3 as key checkpoint molecules in the immune responses associated to skin inflammation and malignant transformation

Martina Morelli  1 , Stefania Madonna  1 , Cristina Albanesi  1
Affiliations
Review

SOCS1 and SOCS3 as key checkpoint molecules in the immune responses associated to skin inflammation and malignant transformation

Martina Morelli et al. Front Immunol. .

Abstract

SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3-derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo.

Keywords: JAK inhibitors; Janus Activated Kinases (JAK); immunemediated skin diseases; skin cancer; skin inflammation; suppressors of cytokine signaling (SOCS).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Regulation of JAK/STAT pathways induced by IFN-γ and IL-6 cytokine by SOCS1 and SOCS3. IFN-γ and IL-6 bind their specific IFN-γ and IL-6 receptors (IFNGR and IL-6R/GP130, respectively), causing the activation of associated intracellular JAK complexes (JAK1/JAK2 for IFN-γ and TYK2/JAK2 for IL-6 signaling), which mediate phosphorylation of tyrosine residues in components of receptor complexes. Docking site formation permit binding to receptors of STAT1 or STAT3, which form STAT dimers (STAT1/STAT1 or STAT1/STAT3 dimers for IFN-γ signaling, STAT3/STAT3 dimer for IL-6 signaling) following their phosphorylation. STAT homo- or heterodimers translocate into the nucleus where they activate expression of inflammatory molecules, as well as SOCS1 and SOCS3 themselves that provide negative feedback regulation.
Figure 2
Figure 2
Schematic representation of the employment of SOCS1 and SOCS3 mimetic peptides in experimental models of skin inflammation and non-melanoma skin cancer. In IFN-γ-activated keratinocytes or skin explants, SOCS1 and its mimetic peptide PS-5 inhibit the expression of ICAM-1, HLA-DR, CXCL10, and CCL2 through the blockade of JAK2 tyrosine kinase activity, that leads to STAT1 and IRF-1 activation. In IL-22 activated keratinocytes and skin biopsies of squamous cell carcinoma murine model, KIR-ESS SOCS3 peptide inhibits the expression of p-STAT3 and p-ERK1/2, as well as keratinocyte proliferation and migration.
Figure 3
Figure 3
Inverted pyramid model illustrating the design and employment of SOCS1 and SOCS3 mimetic peptides in skin disorders, as well as the discovery and approval of JAK inhibitors, highlighting the key milestones and stages in the process.
See this image and copyright information in PMC

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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by grants obtained by IDI-IRCCS from the Italian Ministry of Health (Ricerca Corrente 2022 and 2023).