IL-1β–induced STAT3 activation drives IL-17–producing CD8⁺ tissue-resident memory T cells and exacerbates chronic psoriasis

Background The accumulation of IL-17–producing CD8 ⁺ tissue-resident memory T (TRM) cells contributes to chronic and recurrent psoriasis. Suppressor of cytokine signaling 3 (SOCS3) plays a critical role in limiting pSTAT3 and pNF-κB activity to restrain excessive IL-17–mediated inflammation. This study investigated how IL-1–induced activation of pSTAT3 and pNF-κB leads to SOCS3 downregulation in CD8 ⁺ TRM cells, facilitating the expansion of IL-17 ⁺ subsets in psoriasis. It also evaluated the therapeutic potential of restoring SOCS3 through targeted STAT3 inhibition and STAT5 activation. Methods Using both in vitro assays and an IL-1 receptor antagonist knockout mouse model of imiquimod-induced psoriasis, we examined hyperactive IL-1 signaling in CD8 ⁺ TRM cells isolated from ex vivo psoriatic samples. The STAT3 inhibitor STA-21 was used to assess its effect on SOCS3 expression and IL-17–producing TRM cell frequency. Results Hyperactivation of IL-1 signaling in chronic psoriasis established a pathogenic feedback loop in CD8⁺ TRM cells, where elevated pSTAT3 and pNF-κB activity suppressed SOCS3 expression, promoting the expansion of IL-17–producing CD8⁺ TRM cells and exacerbating disease severity. Therapeutic modulation via STA-21 restored SOCS3 levels, reduced IL-17⁺ TRM cell numbers, and disrupted this inflammatory cycle. Dual regulation of STAT3 inhibition and STAT5 activation emerged as a promising approach to attenuate psoriatic inflammation. Conclusion Our findings highlight the IL-1/pNF-κB/pSTAT3 axis in CD8⁺ TRM cells as a central driver of psoriasis pathogenesis. Restoring SOCS3 expression through combined STAT3 inhibition and STAT5 activation offers a novel immunomodulatory strategy for treating severe or recurrent psoriasis.