Abstract
Activated macrophages play an important role in both innate and adaptive immune responses, and aberrant activation of macrophages often leads to inflammatory and immune disorders. However, the molecular mechanisms of how macrophages are activated are not fully understood. In this study, we identify a novel role for histone deacetylse 6 (HDAC6) in lipopolysaccharide (LPS)-induced macrophage activation. Our data show that suppression of HDAC6 activity significantly restrains LPS-induced activation of macrophages and production of pro-inflammatory cytokines. Further study reveals that the regulation of macrophage activation by HDAC6 is independent of F-actin polymerization and filopodium formation; instead, it is mediated by the effects of HDAC6 on cell adhesion and microtubule acetylation. These data thus suggest that HDAC6 is an important regulator of LPS-induced macrophage activation and might be a potential target for the management of inflammatory disorders.
Highlights
Macrophages with great diversity and plasticity are present in all tissues, where they are engaged in a range of activities including development, homeostasis, tissue remodeling, and immunity [1]
We found that the pan-HDAC inhibitor trichostatin A (TSA) increased the acetylation of both atubulin and histone H4, and the histone deacetylse 6 (HDAC6)-resistant HDAC inhibitor NaB increased histone H4 acetylation with minimal elevation of a-tubulin acetylation; by contrast, tubacin significantly increased a-tubulin acetylation without affecting histone H4 acetylation (Fig. 1A)
To further investigate the role of HDAC6 in macrophage activation, we analyzed primary bone marrow-derived macrophages (BMMs) isolated from 8- to 12-week-old mice
Summary
Macrophages with great diversity and plasticity are present in all tissues, where they are engaged in a range of activities including development, homeostasis, tissue remodeling, and immunity [1]. Primary macrophages are developed from monocytes which circulate in the blood and are recruited to the injured or infected tissues, where they undergo a series of alterations to become tissue resident macrophages [2]. In response to infection or injury, tissue macrophages are primed to the affected sites where they are activated to fulfill their role in innate and adaptive immune response [3,4]. Activated macrophages produce proinflammatory cytokines/chemokines, which recruit other cells to the sites to eliminate the pathogens [5]. Deregulated activation of macrophages may result in inflammatory diseases, such as sepsis, atherosclerosis, rheumatoid arthritis, and fibrosis [8,9], suggesting that targeting macrophage activation would be an effective approach for the management of inflammatory disorders [10]
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