HDAC10 promotes Th17 differentiation and IL-17A-driven neutrophilic airway inflammation in severe asthma.

Severe asthma frequently manifests as a neutrophilic phenotype associated with dysregulated Th17 cell response, yet the molecular mechanism regulating Th17 cell-driven pathology remain poorly defined. Here, we identified histone deacetylase (HDAC) 10 as a critical regulator of Th17 cell differentiation in severe asthma. HDAC10 expression in CD4+ T cells was upregulated in asthmatic mice and patients with asthma. CD4+ T cell-specific deletion of Hdac10 attenuated neutrophilic airway inflammation by dampening Th17 cell differentiation and subsequent IL-17A secretion. Mechanistically, HDAC10 directly bound to signal transducer and activator of transcription 3 (STAT3) and deacetylated it at lysine 631 (K631) in Th17 cells, a post-translational modification essential for Il-17a transcription and subsequent neutrophilic airway inflammation. Importantly, pharmacological inhibition of HDAC10 abrogated Th17 cell response and neutrophilic airway inflammation. Together, our findings reveal an unrecognized role for HDAC10 in governing Th17 cell pathogenicity, highlighting HDAC10 as a promising therapeutic target for severe asthma.