A22-19 Alveolar Macrophage Histone Deacetylase 6 Promotes Silica-Induced Lung Inflammation and Fibrosis by Deacetylating and Phosphorylating Tank-Binding Kinase 1

Rationale Silicosis is a progressive fibrotic lung disease characterized by persistent alveolar macrophage (AM)-mediated inflammation after crystalline silica (CS) exposure. The cytoplasmic mechanisms sustaining this inflammation are not fully defined. We investigated the role of histone deacetylase 6 (HDAC6) in regulating inflammatory and fibrotic signaling in silicosis. Methods HDAC6 expression and activity were assessed in lung tissues from patients and mice with silicosis. Myeloid-specific HDAC6 knockout mice were used to determine its functional contribution to CS-induced injury. Mechanistic studies, including immunoprecipitation and site-directed mutagenesis, examined the interaction between HDAC6 and TANK-binding kinase 1 (TBK1). Pharmacological inhibition was tested using the selective HDAC6 inhibitor CAY10603. Results HDAC6 expression and activity were increased in both human and experimental silicosis and correlated with disease severity. Myeloid-specific HDAC6 deficiency reduced CS-induced AM activation, cytokine production, collagen deposition, and loss of lung function. Mechanistically, HDAC6 bound TBK1 and deacetylated Lys60, facilitating TBK1 phosphorylation at Ser172 and downstream activation of interferon regulatory factor 3 (IRF3). This HDAC6–TBK1–IRF3 pathway promoted transcription of proinflammatory and profibrotic genes. CAY10603 treatment suppressed TBK1 activation, mitigated fibrosis, and preserved pulmonary function. Conclusions Our results identify HDAC6 as a critical cytoplasmic regulator of TBK1–IRF3 signaling through deacetylation-dependent TBK1 activation. These findings reveal a novel posttranslational pathway underlying silica-induced lung injury and support the therapeutic targeting of HDAC6 for the treatment of silicosis and potentially other macrophage-mediated fibrotic diseases.