Modulation of Inflammation and Stromal Remodeling Processes in Autoimmune Arthritis by Microbial Indole Derivatives

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial tissue that can lead to joint damage and deformities. Inflammation, new blood vessel formation (angiogenesis), and bone resorption (osteoclastogenesis) are three key processes of the pathophysiology of RA. ‘Dysbiosis’ of the gut microbiota is implicated in RA pathogenesis because it can cause an imbalance in the microbial metabolites that regulate host health and disease. However, there is little information about the impact of two such indole derivatives, indole-3-aldehyde (IAld) and indole-3-acetic acid (I3AA), on arthritis-related processes. Using established cell-based models and the adjuvant-induced arthritis animal model, we conducted a comparative analysis of IAld and I3AA to understand how these metabolites might impact RA pathogenesis. To our surprise, despite their structural similarities, the bioactivities of these two metabolites were profoundly different. IAld, but not I3AA, altered the expression of genes encoding arthritis-associated cytokines (IL-1β, IL-6, VEGF) in RAW 264.7 (murine macrophage) cells stimulated with heat-killed M. tuberculosis. Further investigation of this anti-inflammatory activity of IAld suggested that inhibition of the MyD88-dependent activation of NF-κB and MAPK pathways was unlikely to be involved. IAld also exhibited pro-osteoclastogenic and pro-angiogenic activity. In contrast, I3AA exhibited only anti-angiogenic activity. Both IAld and I3AA are proposed agonists of the aryl hydrocarbon receptor (AhR). However, AhR inhibitor CH-223191 suppressed the anti-angiogenic activity of I3AA, but failed to mitigate any of the effects of IAld. There is a cross-talk between the AhR and Nrf2 pathways, and some plant-derived phytochemicals are multifunctional ligands of both pathways. Our findings show that IAld, unlike I3AA, can suppress the Nrf2-dependent antioxidant response of macrophages to an Nrf2 agonist, but that IAld also potentially reduces intracellular ROS levels during osteoclast differentiation. Furthermore, oral administration of IAld to rats resulted in the reduction of arthritis severity compared to the arthritic control group. Taken together, our findings suggest that the relative bioavailability of these microbial indole derivatives has the potential to influence their immunomodulatory effects in healthy individuals as well as patients with RA.