PRELP negatively regulates IL-17A-mediated proliferation and the inflammatory response in psoriasis.

Psoriasis is a common immune-mediated skin disease driven largely by interleukin-17A (IL-17A). Although IL-17A plays a key role in disease pathogenesis, the underlying mechanisms remain incompletely understood. Through bioinformatic analysis, we discovered that proline/arginine-rich end leucine-rich repeat protein (PRELP) expression is upregulated in skin lesions from psoriasis patients following treatment with IL-17A inhibitors (secukinumab, ixekizumab, and brodalumab), despite being significantly downregulated in lesional compared to nonlesional skin at baseline. Experimental assays confirmed that IL-17A suppressed PRELP expression in keratinocytes, consistent with its reduced expression in lesional tissues from both murine models and human patients. Functionally, PRELP suppressed keratinocyte proliferation, promoted apoptosis, and attenuated activation of the NF-κB and MAPK pathways, along with downstream proinflammatory cytokine and chemokine production. By downregulating IL6 in keratinocytes, PRELP further attenuated local IL-17A production via IL6 modulation, suggesting a break in the feed-forward loop of psoriatic inflammation. Intradermal administration of AAV-K14-PRELP ameliorated psoriasis-like findings in mice, including erythema, scaling, epidermal hyperplasia, and Th17 cell infiltration. Mechanistically, IL-17A suppressed PRELP transcription by activating STAT3, which directly binds to the PRELP promoter as a transcriptional repressor. Collectively, our findings identify PRELP as a negative regulator of IL-17A signaling in psoriasis, acting through keratinocyte dysregulation and modulation of Th17 cells. Therapeutic strategies aimed at enhancing PRELP expression may represent a novel approach for treating psoriasis and other Th17-driven inflammatory diseases.