PRELP negatively regulates IL-17A-mediated proliferation and the inflammatory response in psoriasis
Summary
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 sign
Content
# PRELP negatively regulates IL-17A-mediated proliferation and the inflammatory response in psoriasis
*Published: 2026 May 27*
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.
DOI: 10.1038/s41392-026-02693-6