Keratinocyte-specific H4K12 lactylation drives a non-canonical IL-17-dependent signaling in psoriasis progression in mice
Xuecheng Shen, Wenxuan Qiao, Wei Yan, Hao Xie, Chenyang Zhang, Yang Sun, Qiong Luo, Qiang Xu
Abstract
IL-17 signaling contributes to the pathogenesis of psoriasis; however, IL-17 involvement in keratinocyte hyperactivation of epidermis remains unclear. Here, we describe an IL-17A-induced, skin-specific, positive feedback loop, which operates independently of canonical chemokine production, thus untangling skin inflammation and epithelial hyperproliferation in psoriasis. We show that IL-17A-induced, keratinocyte-specific KLK8 interacts with IL-17R to promote histone H4 lysine lactylation (H4K12la) catalyzed by the acetyltransferase HAT1. H4K12la further promotes IL-17A-mediated keratinocyte proliferation and the expression of KLK8 and IL-17R, creating a feedback loop that drives psoriasis progression. Importantly, excessive lactate in the microenvironment exacerbates H4K12la and psoriasis severity, thereby impairing the efficacy of anti-IL-17A antibody. Silencing KLK8, HAT1, or inhibiting lactate accumulation attenuates psoriasis in mice. Moreover, combining lactylation inhibition with anti-IL-17A therapy exhibits synergistic effects against antibody-resistant psoriasis. Thus, our findings unveil a lactylation-driven, keratinocyte-specific IL-17A signaling and offer a promising approach for psoriasis treatment, particularly in patients with comorbid metabolic syndrome. IL-17A signaling contributes to the pathogenesis of psoriasis via the production of inflammatory mediators. Here, by integrating in vitro experiments and in vivo analysis, the authors report a non-canonical IL-17-KLK8 axis that induces lactate accumulation and histone lactylation, ultimately driving keratinocyte hyperactivation, and highlight the therapeutic value of targeting this lactylation-driven pathway for psoriasis treatment.