SOCS1-derived mimetic peptides attenuate cytokine-induced Microglial Activation via Jak2 inhibition 2308895

Abstract

Abstract Introduction Recent evidence suggests that microglia can initiate autoimmune uveitis (AU). Notably, the JAK/STAT pathway is a central driver of both microglial function and AU progression. While our lab has shown that peptides mimicking the suppressor of cytokine signaling 1-kinase inhibitory region (SOCS1-KIR) can mitigate JAK/STAT-associated AU in induced rodent disease models and equine recurrent uveitis patients, the ability of the peptide to modulate microglial function is unknown. The goal of this study was to assess the tolerability and efficacy of SOCS1-KIR mimetics on microglia through immune regulation and Jak2 inhibition. Methods Human microglial (HMC3) cells were stimulated with TNFα in the presence or absence of SOCS1-KIR mimetics to evaluate the effects on viability (MTT assay) and inflammatory gene expression (qPCR). In vitro Jak2 kinase assays were conducted to assess SOCS1-KIR mediated modulation of kinase activity. Results SOCS1-KIR mimetics showed IC50 values of 11.5µM and 3.2µM for inhibiting Jak2 kinase activity. SOCS1-KIR mimetics were well tolerated by HMC3 cells, with the monomer showing no toxicity from 0-33µM and the dimer from 0-11µM. TNF-α induced a robust pro-inflammatory response, with IL-1β, IL-6, and MCP-1 transcripts increasing 10- to 50-fold. Preliminary data suggest that the peptides reduce TNFα-induced IL-6 mRNA expression, indicating potential attenuation of microglial activation at the transcriptional level. Conclusion SOCS1-KIR mimetics are non-toxic and exert immunomodulatory effects in TNFα-stimulated microglia. Jak2 inhibition supports the mechanism of JAK/STAT pathway suppression. Future studies will examine IFNγ-driven activation to further define the role of SOCS1-KIR in modulating JAK/STAT-associated inflammation. These findings will not only clarify the immunomodulatory mechanism of SOCS1-KIR but also advance development of targeted therapies to restore immune homeostasis in sight-threatening ocular diseases. Funding Source The University of Florida Topic Categories Therapeutic Approaches to Autoimmunity (THER)