Aryl hydrocarbon receptor (AHR)-mediated inflammation and resolution: Non-genomic and genomic signaling

Abstract

Inflammation, an old medical problem, is being recognized as an active, well orchestrated biological process. When dysregulated, chronic inflammation may ensue, leading to tissue-dependent diseases. Depending upon the ligand and cellular context, aryl hydrocarbon receptor (AHR) may accelerate or attenuate inflammation and subsequent resolution. Three examples are discussed in which AHR modulates inflammation by a mixture of genomic and non-genomic signaling pathways: (i) AHR-agonistic bacterial virulence factors are leading to both microbial defense and resolution of inflammatory responses. (ii) TCDD-mediated persistent AHR activation initially leads to inflammation by non-genomic signaling, and may potentially lead to chronic inflammation. (iii) AHR may modulate anti-inflammatory actions in obesity-mediated non-alcoholic fatty liver disease (NAFLD): Hepatic lipotoxicity triggers generation of danger-associated molecular patterns (DAMPs) that facilitate the development of hepatitis. AHR is mainly involved in the resolution phase by induction of lipoxin A4 and Il-22. Moderate AHR activation by phytochemicals and microbial AHR ligands may facilitate resolution. In control of inflammation, AHR appears to integrate environmental conditions with coordinated cellular functions.

Keywords: 1-Hydroxyphenazine (PubChem CID: 135412648); 2,3,7,8-Tetrachlorodibenzo-p-dioxin = TCDD (PubChem CID: 15625); AHR ligands; Indole-3-acetate (PubChem: 801); Indole-3-carbinol (PubChem: 3712); Inflammation; Lipoxin A4 (LXA4) (PubChem CID: 5280914); Non-genomic AHR signaling; Pyocyanin (PubChem CID: 6817; Quercetin (PubChem CID: 5283343); Resolution; Resolvin D1 (PubChem CID: 44251266); TCDD.