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 (IL-17+ CD8+ 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+ CD8+ TRM cells frequency.

RESULTS

Hyperactivation of IL-1 signaling in chronic psoriasis established a pathogenic NF-κB-STAT3 feedback loop in CD8+ TRM cells, where elevated pSTAT3 and pNF-κB activity suppressed SOCS3 expression, promoting the expansion of IL-17+ CD8+ TRM cells and exacerbating disease severity. Therapeutic modulation via STA-21 restored SOCS3 levels, reduced IL-17+ CD8+ TRM numbers, and attenuated the pathogenic feedback loop. Dual regulation of STAT3 inhibition and STAT5 activation emerged as a promising approach to attenuate psoriatic inflammation.

CONCLUSION

Our findings demonstrate that the IL-1/pNF-κB/pSTAT3 axis in CD8+ TRM cells as a major contributor of psoriasis pathogenesis. Restoring SOCS3 expression through combined STAT3 inhibition and STAT5 activation represents a potential immunomodulatory approach that may contribute to treatment strategies for severe or recurrent psoriasis. However, further studies, including direct comparisons with current biological combination therapies, are needed to fully evaluate its efficacy and safety.