Epigenetic Modulation by Panobinostat primes Immune Readiness in Alveolar Macrophages

ABSTRACT: Epigenetic regulation through histone post-translational modifications (PTMs) enables macrophages to fine-tune gene expression and adapt to environmental cues. Alveolar macrophages (AMs), which reside in the lipid-rich lung microenvironment, must maintain lung homeostasis while preserving antimicrobial readiness, a balance often exploited by intracellular pathogens to ensure their survival. Here, we identify histone H3 lysine 14 acetylation (H3K14ac) as a central epigenetic switch coupling chromatin accessibility, lipid metabolism, and immune activation in murine AMs (mAMs) infected by Mycobacterium abscessus (Mab). Single-cell imaging revealed that unchallenged mAMs segregate into two spatially organized subpopulations, H3K14acHigh and H3K14acLow, which differ in proliferative capacity and MHC-II expression. Upon infection, this bimodal acetylation landscape converged toward a globally hypoacetylated state, particularly within bacilli-containing cells, indicating that Mab exerts HDAC-dependent epigenetic suppression to attenuate antigen presentation. Pharmacological inhibition of HDACs with Panobinostat (a pan-HDAC inhibitor) transiently restored H3K14ac, expanded the MHC-IIBright subset, and reduced intracellular lipid accumulation. Multi-omics revealed that Panobinostat induces coordinated chromatin, inflammatory, and metabolic reprogramming, enhancing oxidative and biosynthetic capacity while repressing to sustain energy-demanding immune activation while repressinglipid storage and scavenger programs that favor pathogen tolerance. Strikingly, this acetylation-driven remodeling correlated with a measurable restriction of intracellular Mab burden, linking histone acetylation to antimicrobial efficacy. Collectively, our data delineate a tunable epigenetic–metabolic circuit in mAMs where HDAC activity integrates chromatin state, lipid handling, and antigen-presentation capacity. The hereby presented results outline an epigenetic-metabolic framework for how transient acetylation gains can reconfigure mAMs state during early Mab infection, paving the way for future studies of host-directed modulation in mycobacterial disease.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Alessandra Altomare  

LAB HEAD: Alessandra Altomare

PROVIDER: PXD071228 | Pride | 2026-10-15

REPOSITORIES: Pride