Targeting KAT8 alleviates self-RNA-driven skin inflammation by modulating histone H4 lysine 16 acetylation in psoriasis

Abstract

Psoriasis is a persistent inflammatory skin disease characterized by the adverse infiltration of inflammatory cells and epidermal hyperplasia. Self-RNA is the most abundant damage-associated molecular pattern (DAMP) in psoriasis tissues, which triggers and amplifies inflammatory responses through TLR7 pathway. However, the pathogenic effects of self-RNA on immune cell activation and chemotaxis during psoriasis and the underlying mechanisms remain largely unknown. Epigenetic modifications are widely acknowledged to link the environmental signals to gene expression in various immune cells, whose dysfunction tends to cause or worsen various inflammatory diseases. Through a comprehensive analysis of histone modifications in lesional skin from both psoriasis patients and mice, the significantly increased level of histone acetylation at H4 lysine 16 (H4K16ac) in macrophages was found, which was positively correlated with the accumulation of self-RNA in the dermis and psoriasis pathology. Further studies showed that lysine acetyltransferase 8 (KAT8) was responsible for self-RNA-driven H4K16ac modification and psoriasis-associated pathogenic chemokine expression in macrophages of lesional skin. Mechanistically, KAT8 was selectively recruited to the gene promoters of pathogenic chemokines including Cxcl2 and Ccl3 through interaction with AP-1 transcription complex. The auto-acetylation of KAT8 enhanced its acetyltransferase activity. KAT8-mediated H4K16ac modification at these chemokine promoters, coupling with increased chromatin accessibility, facilitated the production and secretion of pro-inflammatory chemokines CXCL2 and CCL3 for neutrophil chemotaxis, neutrophil extracellular traps (NETs) formation and aggravated inflammatory damage in psoriasis. KAT8 deficiency in macrophages or pharmacological inhibition restricted the secretion of macrophage-derived pro-inflammatory chemokines and ameliorated TLR7-dependent tissue inflammatory injury in experimental psoriasis and arthritis model. Taken together, our finding provides new insight into the role of epigenetic modification in self-RNA/TLR7 pathway-dependent immune cell activation and chemotaxis during psoriasis, which proposes the promising therapeutic strategy to control the inflammatory damage and psoriatic skin dysfunction by targeting KAT8 and KAT8-mediated H4K16ac modification in dermis macrophages.