HDAC6 Promotes Host Defense Against Chlamydial Lung Infections by Regulating M2-Th2 Responses

Histone deacetylase 6 (HDAC6), a member of the class IIb HDAC family, plays a crucial role in epigenetic regulation and cytoskeletal dynamics, while participating in host anti-infective immune responses. However, its precise functions and mechanisms during Chlamydia muridarum (C. muridarum) infection remain incompletely defined. Our study demonstrated that C. muridarum respiratory infection upregulates HDAC6 expression at the infection site and in immune organs. Comparative analysis of wild-type (WT) and HDAC6-deficient (HDAC6^-/-) mice in this infection model revealed that HDAC6 deficiency exacerbates disease progression, including significant weight loss, severe pulmonary inflammation, and impaired C. muridarum clearance. Relative to WT mice, HDAC6^-/- mice exhibited elevated Signal Transducer and Activator of Transcription 6 (Stat6) and GATA Binding Protein 3 (Gata3) mRNA expression, enhanced pathological Th2 responses with increased IL-4 secretion, and no significant differences in protective Th1 or Th17 responses following C. muridarum infection. Concurrently, these mice displayed enhanced M2 macrophage polarization, as evidenced by upregulated CD206 and Arg-1 expression, whereas M1 marker expression remained unchanged. The vitro studies confirmed that HDAC6^-/- bone marrow-derived macrophages (BMDMs) promote M2 polarization, characterized by increased Arg-1, IL-10, and TGF-β production, and further co-culture experiments showed that C. muridarum -stimulated HDAC6^-/- BMDMs drive Th2 differentiation. These findings elucidate the critical role of HDAC6 in regulating Th2-M2 immune responses during C. muridarum respiratory infection and suggest targeted modulation of HDAC6 as a novel therapeutic strategy for chlamydial respiratory infection.