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.

Keywords: aryl hydrocarbon receptor; immunomodulation; immunosuppression; inflammation; macrophages.

Figure 1.

Diverse outcomes of AHR signaling in macrophages. a, Upon ligand binding, activated AHR translocates to nucleus, dimerizes with ARNT, and binds XREs leading to transcription of target genes. b, AHR promotes a proinflammatory response by modulating genes through genomic and nongenomic mechanisms. c, Activation of AHR in monocytes decreases macrophage differentiation through BLIMP1 and MAFB. d, AHR regulates macrophage immune responses through regulation of Il10, Ido1, and Ido2. AHR, aryl hydrocarbon receptor; p23, co-chaperone protein p23; Hsp90, Heat Shock Protein 90; XAP2, X-associated protein 2; Src, proto-oncogene tyrosine-protein kinase Src; ARNT, aryl hydrocarbon receptor nuclear translocator; AHRR, aryl hydrocarbon receptor repressor; AHRE, AHR response element; BLIMP1, B lymphocyte-induced maturation protein 1; IRF4, interferon regulatory factor 4; MAFB, V-maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog B; DC, dendritic cell; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; PAMP, pathogen-associated molecular pattern; TLR, Toll-like receptor; ssRNA, single-stranded RNA; ssDNA, single-stranded DNA; dsDNA, double-stranded DNA; MyD88, myeloid differentiation primary response 88; LPS, lipopolysaccharide; TRIF, TIR-domain-containing adapter-inducing interferon-β; p65; nuclear factor NF-kappa-β p65 subunit; p50, nuclear factor NF-kappa-Beta p50 subunit; TF, transcription factor; RelB, RelB transcription factor; C/EBPβ, CCAAT/enhancer binding protein beta; IKB, inhibitor of Kappa B; STAT3, signal transducer and activator of transcription 3; Cyp1a1, cytochrome P450 1A1; Cyp1b1: cytochrome P450 1B1; Tnf: tumor necrosis factor; Il8: interleukin 8; Il22: interleukin 22; Il1b: interleukin 1-beta; Il10: interleukin 10; Ido1: indoleamine 2,3-dioxygenase 1; Ido2: indoleamine 2,3-dioxygenase 2. Key references for figure: (b) proinflammatory modulation (Cheon et al. 2007; Ishihara et al. 2022; Vogel et al. 2007), (c) differentiation in vitro (Goudot et al. 2017), and (d) immunoregulatory function (Vogel et al. 2008; Zhu et al. 2018). Figure was generated with Biorender.