Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses

Abstract

Toll-like receptor (TLR) signals perform a crucial role in innate immune responses to pathogens. In this study, we found that the aryl hydrocarbon receptor (Ahr) negatively regulates inflammatory responses mediated by lipopolysaccharide (LPS) in macrophages. Ahr was induced in macrophages stimulated by LPS, but not by transforming growth factor (TGF)-β plus interleukin (IL)-6, which can induce Ahr in naive T cells. The production of IL-6 and tumor necrosis factor (TNF)-α by LPS was significantly elevated in Ahr-deficient macrophages compared with that in wild-type (WT) cells. Ahr-deficient mice were more highly sensitive to LPS-induced lethal shock than WT mice. Signal transducer and activator of transcription 1 (Stat1) deficiency, as well as Ahr deficiency, augmented LPS-induced IL-6 production. We found that Ahr forms a complex with Stat1 and nuclear factor-kappa B (NF-κB) in macrophages stimulated by LPS, which leads to inhibition of the promoter activity of IL-6. Ahr thus plays an essential role in the negative regulation of the LPS signaling pathway through interaction with Stat1.

Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription

“…AhR inhibited LPS-induced expression of proinflammatory cytokines (for example, IL-6, TNF-a) through suppressing NF-kB transcriptional activity together with STAT1 (ref. 25). Consistently, we found that AhR activation inhibited LPS-mediated pro-IL-1b expression at both the protein and mRNA levels (Fig.…”

“…For example, various AhR ligands such as TCDD regulate the differentiation of Treg cells and Th17 cells 26,[32][33][34] , and modulate Th1/Th2 balance 35 . AhR in combination with STAT1 negatively regulates proinflammatory cytokine production by inhibiting NF-kB activation in macrophages after LPS stimulation 25 . AhR knockout mice are hypersensitive to LPS-induced septic shock, mainly due to macrophage dysfunction 36 .…”

“…Following engagement by its cognate ligands, AhR undergoes conformation changes, translocates to the nucleus, forms a heterodimer with ARNT (AhR nuclear translocator) and binds to the xenobiotic response element (XRE) in the promoter of target genes, which causes a variety of regulatory effects 22,23 . Recent results highlight major roles of AhR in both adaptive and innate immune system [22][23][24][25] . However, the functional role of AhR in inflammasome activation has never been described.…”

Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17–producing T-helper cell differentiation

“…Given that IL-6 is produced by several types of cells, including antigen-presenting cells such as macrophages and dendritic cells, we cannot exclude the possibility that expression of the miR-132/212 cluster in these cells is important for EAE development. Therefore, it is also necessary to gain an understanding of how the miR-132/212 cluster regulates the immune system in various types of immune cells, such as T cells, macrophages, and dendritic cells, by conducting research similar to our study of AHR in these immune cells (7,39,40). For instance, we recently found that AHR deficiency in peritoneal macrophages results in failure to induce the miR-132/212 cluster in response to LPS.…”

LeA(H)Rning self-control

“…AhR participates in the differentiation of effector and regulatory T cells as a result of AhR activation in T cells and dendritic cells (DCs) [1]. In addition, AhR in macrophages modulates their activation by lipopolysaccharide (LPS) [5,6] but the molecular mechanisms involved are not clearly understood. A study by Puccetti and colleagues describes a pathway by which AhR limits the inflammatory response to LPS [7].…”