Mechanisms underlying aryl hydrocarbon receptor-driven divergent macrophage function

Abstract

Macrophages play an essential role in the innate immune system by differentiating into functionally diverse subsets in order to fight infection, repair damaged tissues, and regulate inappropriate immune responses. This functional diversity stems from their ability to adapt and respond to signals in the environment, which is in part mediated through aryl hydrocarbon receptor (AHR)-signaling. AHR, an environmental sensor, can be activated by various ligands, ranging from environmental contaminants to microbially derived tryptophan metabolites. This review discusses what is currently known about how AHR-signaling influences macrophage differentiation, polarization, and function. By discussing studies that are both consistent and divergent, our goal is to highlight the need for future research on the mechanisms by which AHR acts as an immunological switch in macrophages. Ultimately, understanding the contexts in which AHR-signaling promotes and/or inhibits differentiation, proinflammatory functions, and immunoregulatory functions, will help uncover functional predictions of immunotoxicity following exposure to environmental chemicals as well as better design AHR-targeted immunotherapies.

Vertical Transfer of Maternal Gut Microbes to Offspring of Western Diet-Fed Dams Drives Reduced Levels of Tryptophan Metabolites and Postnatal Innate Immune Response

“…Indole and I3A are endogenous ligands of AHR and we found that decreased circulating abundance of these ligands in offspring of WD-fed dams (and offspring of GF recipients of maternal WD-exposed microbes) was associated with decreased AHR signaling at PND21. AHR has been shown to exert pleiotropic effects in macrophages that are highly dependent on the microenvironment in vivo [83]. In our model, we found that the combination of exposure to maternal and post-weaning WD suppresses AHR signaling and dampens the immune response of BMDMs to LPS.…”

“…AHR is expressed in many cell types, including macrophages, and mediates cellular responses to environmental toxins and dietary metabolites [83]. Acting through STAT3, AHR activation upregulates expression of IL-10 to reduce inflammatory injury [83], suggesting that AHR has immunoregulatory functions that contribute to resolving inflammation and promoting tissue repair.…”

“…AHR is expressed in many cell types, including macrophages, and mediates cellular responses to environmental toxins and dietary metabolites [83]. Acting through STAT3, AHR activation upregulates expression of IL-10 to reduce inflammatory injury [83], suggesting that AHR has immunoregulatory functions that contribute to resolving inflammation and promoting tissue repair. Indole and I3A are endogenous ligands of AHR and we found that decreased circulating abundance of these ligands in offspring of WD-fed dams (and offspring of GF recipients of maternal WD-exposed microbes) was associated with decreased AHR signaling at PND21.…”

Vertical Transfer of Maternal Gut Microbes to Offspring of Western Diet-Fed Dams Drives Reduced Levels of Tryptophan Metabolites and Postnatal Innate Immune Response

“…AHR is expressed in many cell types, including macrophages, and mediates cellular responses to environmental toxins and dietary metabolites [ 78 ]. Acting through STAT3, AHR activation upregulates expression of IL-10 to reduce inflammatory injury [ 78 ], suggesting that AHR has immunoregulatory functions that contribute to resolving inflammation and promoting tissue repair.…”

“…AHR is expressed in many cell types, including macrophages, and mediates cellular responses to environmental toxins and dietary metabolites [ 78 ]. Acting through STAT3, AHR activation upregulates expression of IL-10 to reduce inflammatory injury [ 78 ], suggesting that AHR has immunoregulatory functions that contribute to resolving inflammation and promoting tissue repair. Indole and I3A are endogenous ligands of AHR, and we found that decreased circulating abundance of these ligands in offspring of WD-fed dams (and offspring of GF recipients of maternal WD-exposed microbes) was associated with decreased AHR signaling at PND21.…”