The role of the aryl hydrocarbon receptor (AhR) in modulating intestinal ILC3s to optimise gut pathogen resistance in lupus and benefits of nutritional AhR ligands

Abstract

Background and aims: Dysbiosis is emerging as a potential trigger of systemic lupus erythematosus (SLE). Group 3 innate lymphoid cells (ILC3s) are recognised as key regulators of intestinal homeostasis. The aryl hydrocarbon receptor (AhR) is critical to intestinal ILC3 development and function. This mechanistic review aimed to investigate whether AhR activation of gut ILC3s facilitates IL-22-mediated antimicrobial peptide (AMP) production to enhance colonisation resistance and ameliorate SLE pathology associated with intestinal dysbiosis. Furthermore, nutritional AhR ligand potential to enhance pathogen resistance was explored.

Methodology: This mechanistic review involved a three-tranche systematic literature search (review, mechanism, intervention) using PubMed with critical appraisal. Data was synthesised into themes and summarised in a narrative analysis.

Results: Preclinical mechanistic data indicate that AhR modulation of intestinal ILC3s optimises pathogen resistance via IL-22-derived AMPs. Pre-clinical research is required to validate this mechanism in SLE. Data on systemic immune consequences of AhR modulation in lupus suggest UVB-activated ligands induce aberrant AhR signalling while many dietary ligands exert beneficial effects. Data on xenobiotic-origin ligands is varied, although considerable evidence has demonstrated negative effects on Th17 to Treg balance. Limited human evidence supports the role of nutritional AhR ligands in modulating SLE pathology. Preclinical and clinical data support anti-inflammatory effects of dietary AhR ligands.

Conclusion: Current evidence is insufficient to fully validate the hypothesis that AhR modulation of intestinal ILC3s can enhance pathogen resistance to ameliorate lupus pathology driven by dysbiosis. However, anti-inflammatory effects of dietary AhR ligands suggest a promising role as a therapeutic intervention for SLE.

Keywords: Aryl hydrocarbon-receptor; Dysbiosis; IL-22 derived antimicrobial peptides; ILC3s; Nutritional aryl hydrocarbon receptor ligands; Systemic lupus erythematosus.