Histone deacetylase 2 is essential for LPS‐induced inflammatory responses in macrophages

Abstract

The role of specific histone deacetylase (HDAC) proteins in regulating the lipopolysaccharide (LPS)‐induced inflammatory response and its underlying mechanisms are unclear. Here, HDAC2, a class I HDAC family protein, is essential for the LPS‐triggered inflammatory response in macrophages. LPS stimulation increases HDAC2 expression in macrophages. Knockdown of HDAC2 decreases the expression of proinflammatory genes, such as IL‐12, TNF‐α and iNOS following stimulation with LPS. The adoptive transfer of HDAC2 knockdown macrophages attenuates the LPS‐triggered innate inflammatory response in vivo, and these mice are less sensitive to endotoxin shock and Escherichia coli‐induced sepsis. Mechanistically, the c‐Jun protein is the main target of HDAC2‐mediated LPS‐induced production of proinflammatory cytokines. Moreover, HDAC2 knockdown increases the expression of c‐Jun, which directly binds the promoters of proinflammatory genes and forms nuclear receptor corepressor complexes to inhibit the transcription of proinflammatory genes in macrophages. These effects are rescued by c‐Jun expression. According to the chromatin immunoprecipitation analysis, HDAC2 also selectively suppresses c‐Jun expression by directly binding to its promoter and modifying histone acetylation after LPS stimulation. Our findings define a new function and mechanism of the HDAC2/c‐Jun signaling network that regulates the LPS‐induced immune response in macrophages.