Reprogramming of the LXRα Transcriptome Sustains Macrophage Secondary Inflammatory Responses

Macrophages regulate essential aspects of innate immunity against pathogens. In response to microbial components, macrophages activate primary and secondary inflammatory gene programs crucial for host defense. The liver X receptors (LXRα, LXRβ) are ligand‐dependent nuclear receptors that direct gene expression important for cholesterol metabolism and inflammation, but little is known about the individual roles of LXRα and LXRβ in antimicrobial responses. Here, the results demonstrate that induction of LXRα transcription by prolonged exposure to lipopolysaccharide (LPS) supports inflammatory gene expression in macrophages. LXRα transcription is induced by NF‐κB and type‐I interferon downstream of TLR4 activation. Moreover, LPS triggers a reprogramming of the LXRα cistrome that promotes cytokine and chemokine gene expression through direct LXRα binding to DNA consensus sequences within cis‐regulatory regions including enhancers. LXRα‐deficient macrophages present fewer binding of p65 NF‐κB and reduced histone H3K27 acetylation at enhancers of secondary inflammatory response genes. Mice lacking LXRα in the hematopoietic compartment show impaired responses to bacterial endotoxin in peritonitis models, exhibiting reduced neutrophil infiltration and decreased expansion and inflammatory activation of recruited F4/80lo‐MHC‐IIhi peritoneal macrophages. Together, these results uncover a previously unrecognized function for LXRα‐dependent transcriptional cis‐activation of secondary inflammatory gene expression in macrophages and the host response to microbial ligands. The inflammatory response is a defense mechanism of the innate immune system against infections and other injuries. In response to microbial components, macrophages activate primary and secondary inflammatory gene programs crucial for host defense. De la Rosa et al. provide evidence that inflammation triggers a reprogramming of the transcription factor liver X receptor α (LXRα), that sustains cytokine and chemokine gene expression through direct binding to DNA consensus sequences and collaboration with NF‐κB at enhancers of secondary inflammatory response genes. This novel TLR4‐LXRα‐NF‐κB axis supports macrophage inflammatory gene expression and in vivo immune‐cell recruitment during inflammatory responses to microbial ligands, positioning LXRα as a key factor in the transcriptional regulation in the late stages of inflammation.