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dc.contributor.authorLangan, D.
dc.contributor.authorPerkins, D.J.
dc.contributor.authorVogel, S.N.
dc.contributor.authorMoudgil, K.D.
dc.date.accessioned2021-04-12T16:48:47Z
dc.date.available2021-04-12T16:48:47Z
dc.date.issued2021-02-18
dc.identifier.urihttp://hdl.handle.net/10713/15231
dc.description.abstractRheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints. Inflammation, new blood vessel formation (angiogenesis) and bone resorption (osteoclastogenesis) are three key processes involved in the joint damage and deformities of arthritis. Various gut microbiota-derived metabolites are implicated in RA pathogenesis. However, there is barely any information about the impact of two such metabolites, indole-3-aldehyde (IAld) and indole-3-acetic acid (I3AA), on arthritis-related processes. We conducted a comparative analysis of IAld and I3AA using established cell-based models to understand how they might influence RA pathogenesis. Although structurally similar, the bioactivities of these two metabolites were profoundly different. IAld but not I3AA, inhibited the expression of pro-inflammatory cytokines (IL-1β and IL-6) in RAW 264.7 (RAW) cells stimulated with heat-killed M. tuberculosis sonicate (Mtb) and lipopolysaccharide (LPS). IAld also exhibited pro-angiogenic activity and pro-osteoclastogenic activity. In contrast, I3AA exhibited anti-angiogenic activity on endothelial cell tube formation but had no effect on osteoclastogenesis. Both IAld and I3AA have been proposed as aryl hydrocarbon receptor (AhR) agonists. Use of CH-223191, an inhibitor of the AhR, suppressed the anti-angiogenic activity of I3AA but failed to mitigate the effects of IAld. Further investigation of the anti-inflammatory activities of IAld and I3AA in LPS-treated RAW cells indicated that inhibition of MyD88-dependent activation of NF-κB and MAPK pathways was not likely involved. Our results suggest that the relative bioavailability of these indole derivatives may differentially impact RA progression and possibly other diseases that share similar cellular processes. Copyright 2021 by the authors. Licensee MDPI, Basel, Switzerland.en_US
dc.description.sponsorshipFunding: This research was funded by grants from the National Institutes of Health (R01 AT004321 (KDM) and T32 AI095190 (SNV)).en_US
dc.description.urihttps://doi.org/10.3390/ijms22042017en_US
dc.language.isoen_USen_US
dc.publisherMDPI AGen_US
dc.relation.ispartofInternational Journal of Molecular Sciences
dc.subjectAngiogenesisen_US
dc.subjectAryl hydrocarbon receptoren_US
dc.subjectIndole-3-acetic aciden_US
dc.subjectIndole-3-aldehydeen_US
dc.subjectInnate inflammation, cytokinesen_US
dc.subjectMAPKen_US
dc.subjectMicrobiotaen_US
dc.subjectNF-kBen_US
dc.subjectOsteoclastogenesisen_US
dc.subjectRheumatoid arthritisen_US
dc.titleMicrobiota-derived metabolites, indole-3-aldehyde and indole-3-acetic acid, differentially modulate innate cytokines and stromal remodeling processes associated with autoimmune arthritisen_US
dc.typeArticleen_US
dc.identifier.doi10.3390/ijms22042017
dc.identifier.pmid33670600


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