Control of immune-mediated pathology via the aryl hydrocarbon receptor

Abstract

Edited by George M. Carman Genetic and environmental factors contribute to the development of immune-mediated diseases. Although numerous genetic factors contributing to autoimmunity have been identified in recent years, our knowledge on environmental factors contributing to the pathogenesis of autoimmune diseases and the mechanisms involved is still limited. In this context, the diet, microbiome, geographical location, as well as environmental pollutants have been shown to modulate autoimmune disease development. These environmental factors interact with cellular components of the immune system in distinct and defined ways and can influence immune responses at the transcriptional and protein level. Moreover, endogenous metabolites generated from basic cellular processes such as glycolysis and oxidative phosphorylation also contribute to the shaping of the immune response. In this minireview, we highlight recent progress in our understanding of the modulation of the immune response by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor whose activity is regulated by small molecules provided by diet, commensal flora, environmental pollutants, and metabolism. We focus on the role of AhR in integrating signals from the diet and the intestinal flora to modulate ongoing inflammation in the central nervous system, and we also discuss the potential therapeutic value of AhR agonists for multiple sclerosis and other autoimmune diseases. Multiple sclerosis (MS)4 is an autoimmune disease of the central nervous system (CNS). In 85% of the affected individuals, MS initially presents with a relapsing-remitting course characterized by temporally defined relapses, which are followed by a varying degree of remission. Most patients eventually enter the secondary progressive phase of MS, which is characterized by the progressive and irreversible accumulation of neurological deficits (1). Several biological pathways are involved in the regulation of the immune response in MS both in the peripheral and central immune compartment and are thought to play dominant roles in the different stages of the disease. Although the role of several molecules such as cytokines and toll-like receptor agonists in MS pathology has been studied at length, particularly in relation to the relapsing-remitting phase of the disease, only recently has the role of metabolites generated in basic biological processes such as glycolysis and oxidative phosphorylation become appreciated with regard to their relevance for the development, propagation, and resolution of autoimmune inflammation. Prominent examples of endogenous metabolites with central roles in MS pathology include bioactive lipids, reactive oxygen species, and adenosine triphosphate (ATP) (2-13). The effects of these endogenous metabolites are modulated by a multitude of exogenous factors such as pollutants, dietary factors, and products from the commensal flora to trigger transcriptional programs that control the immune response during MS. Ultimately, the understanding of ...

Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation

“…In this sense, Sigmar1 resembles the AHR, a ligand-activated transcription factor activated by diverse ligands ranging from pollutants to microbial metabolites. AHR has been shown to control astrocytes in CNS inflammation and is considered a candidate therapeutic target for inflammation and cancer (Gutié rrez-Vá zquez and Quintana, 2018; Wheeler et al, 2017). Similarly, Sigmar1 may provide a target for the therapeutic modulation of astrocyte responses in MS and other neurologic disorders.…”

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies novel methylation loci

“…Over the last decade, there have been a wealth of studies describing the role of the aryl hydrocarbon receptor in the immune system, with specific roles in T cells, B cells, monocytes and dendritic cells (DC) 32,[51][52][53] . The aryl hydrocarbon receptor (AhR) pathway works in a regulatory capacity.…”

“…We next evaluated other biological factors that could contribute to aryl-hydrocarbon receptor (AHR) expression. AHR is activated in many immune cell types, including T cells, B cells, and NK cells, by indolamine-mediated tryptophan catabolism 32 . Inflammation can shift tryptophan metabolism away from serotonin synthesis towards kynurenine synthesis 33 .…”

Lack of the aryl hydrocarbon receptor accelerates aging in mice

“…Inflammaging is likely to be spurred by different sources, which include exogenous molecules and pathogens, endogenous waste substances and metabolites, different nutrients, and products from gut microbiota (41). Interestingly, AhR, the activity of which is modulated by molecules derived from diet, commensal flora, environmental pollutants, and metabolism (45), is at the crossroads of several of these pathways. An accumulation of causes together with an attrition of AhR along time could be responsible, at least in part, of aging-associated CNS dysfunction.…”