For decades, activation of Aryl Hydrocarbon Receptor (AhR) was excluded from consideration as a therapeutic approach due to the potential toxic effects of AhR ligands and the induction of the cytochrome P450 enzyme, Cyp1a1, following AhR activation. However, it is now understood that AhR activation not only serves as an environmental sensor that regulates the effects of environmental toxins, but also as a key immunomodulator where ligands induce a variety of cellular and epigenetic mechanisms to attenuate inflammation. Thus, the emergence of further in-depth research into diverse groups of compounds capable of activating this receptor has prompted reconsideration of its use therapeutically. The aim of this review is to summarize the body of research surrounding AhR and its role in regulating inflammation. Specifically, evidence supporting the potential of targeting this receptor to modulate the immune response in inflammatory and autoimmune diseases will be highlighted. Additionally, the opportunities and challenges of developing AhR-based therapies to suppress inflammation will be discussed.

During endotoxin-induced acute lung injury (ALI), immune cell recruitment resulting from chemotaxis is mediated by CXC and CC chemokines and their receptors. In this study, we investigated the role of chemokines and their receptors in the regulation of myeloid cell populations in the circulation and the lungs of C57BL/6J mice exhibiting LPS-mediated ALI using single-cell RNA sequencing. During ALI, there was an increase in the myeloid cells, M1 macrophages, monocytes, neutrophils, and other granulocytes, whereas there was a decrease in the residential alveolar macrophages and M2 macrophages. Interestingly, LPS triggered the upregulation of CCL3, CCL4, CXCL2/3, and CXCL10 genes associated with cellular migration of various subsets of macrophages, neutrophils, and granulocytes. Furthermore, there was an increase in the frequency of myeloid cells expressing CCR1, CCR3, CCR5, and CXCR2 receptors during ALI. MicroRNA sequencing studies of vehicle versus LPS groups identified several dysregulated microRNAs targeting the upregulated chemokine genes. This study suggests that chemokine ligand–receptors interactions are responsible for myeloid cell heterogenicity and cellular recruitment to the lungs during ALI. The single-cell transcriptomics allowed for an in-depth assessment and characterization of myeloid cells involved in immune cell trafficking during ALI.

IFN-β, a type I interferon, has been used as a first-line therapy for patients with multiple sclerosis (MS) for more than 30 years; however, the cellular and molecular basis of its therapeutic efficacy remains unclear. Here, we first used experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, to show that the therapeutic effects of IFN-β were associated with a down-regulation of microRNA-21 (miR-21) and pathogenic T _H 17 (pT _H 17) cells. In vitro experiments demonstrated that genetic knockout of miR-21 directly inhibited pathogenic T _H 17 cell differentiation. Further mechanistic investigations revealed that miR-21 promoted pathogenic T _H 17 differentiation by inhibiting the transcription factor Forkhead box protein O1 ( Foxo1 ). Accordingly, miR-21 loss abrogated pathogenic T _H 17 differentiation and conferred resistance to EAE. Treatment of T cell monocultures with IFN-β showed that IFN-β did not directly limit miR-21 expression. Instead, IFN-β treatment inhibited the secretion of miR-21–inducing cytokines from myeloid cells, reduced miR-21 induction within cocultured T cells, and inhibited pathogenic T _H 17 development. In patient samples, immunophenotypic and targeted transcriptomic analyses revealed that compared with IFN-β treatment responders, nonresponders expressed elevated miR-21–inducing cytokines within myeloid cells, alongside increased miR-21 and pathogenic T _H 17 cytokines within CD4 ⁺ T cells. Direct miR-21 inhibition reduced pathogenic T _H 17 differentiation in nonresponder CD4 ⁺ T cells. These results suggest that type I IFN signaling limits central nervous system autoimmunity by inhibiting miR-21–mediated pathogenic T _H 17 development. miR-21 inhibition may be of potential therapeutic value specifically for the IFN-β nonresponder cohort.

FICZ (6-formylindolo[3,2-b]carbazole) is a potent aryl hydrocarbon receptor agonist that has a poorly understood function in the regulation of inflammation. In this study, we investigated the effect of aryl hydrocarbon receptor activation by FICZ in a murine model of autoimmune hepatitis induced by concanavalin A. High-throughput sequencing techniques such as single-cell RNA sequencing and assay for transposase accessible chromatin sequencing were used to explore the mechanisms through which FICZ induces its effects. FICZ treatment attenuated concanavalin A–induced hepatitis, evidenced by decreased T-cell infiltration, decreased circulating alanine transaminase levels, and suppression of proinflammatory cytokines. Concanavalin A revealed an increase in natural killer T cells, T cells, and mature B cells upon concanavalin A injection while FICZ treatment reversed the presence of these subsets. Surprisingly, concanavalin A depleted a subset of CD55⁺ B cells, while FICZ partially protected this subset. The immune cells showed significant dysregulation in the gene expression profiles, including diverse expression of migratory markers such as CCL4, CCL5, and CXCL2 and critical regulatory markers such as Junb. Assay for transposase accessible chromatin sequencing showed more accessible chromatin in the CD3e promoter in the concanavalin A–only group as compared to the naive and concanavalin A–exposed, FICZ-treated group. While there was overall more accessible chromatin of the Adgre1 (F4/80) promoter in the FICZ-treated group, we observed less open chromatin in the Itgam (CD11b) promoter in Kupffer cells, supporting the ability of FICZ to reduce the infiltration of proinflammatory cytokine producing CD11b⁺ Kupffer cells. Taken together, these data demonstrate that aryl hydrocarbon receptor activation by FICZ suppresses liver injury through the limitation of CD3⁺ T-cell activation and CD11b⁺ Kupffer cell infiltration.