Abstract: The FASEB JournalVolume 35, Issue 5 e21552 RESEARCH ARTICLE Microbial-derived indoles inhibit neutrophil myeloperoxidase to diminish bystander tissue damage Erica E. Alexeev, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USASearch for more papers by this authorAlexander S. Dowdell, orcid.org/0000-0002-0513-6623 Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorMorkos A. Henen, Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA Department of Pharmaceutical Organic Chemistry, Mansoura University, Mansoura, EgyptSearch for more papers by this authorJordi M. Lanis, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorJ. Scott Lee, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorIan M. Cartwright, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorRachel E. M. Schaefer, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorAlfredo Ornelas, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorJoseph C. Onyiah, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorBeat Vögeli, Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorSean P. Colgan, Corresponding Author [email protected] Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA Correspondence Sean P. Colgan, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue MS B-146, Aurora, CO 80045, USA. Email: [email protected] for more papers by this author Erica E. Alexeev, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USASearch for more papers by this authorAlexander S. Dowdell, orcid.org/0000-0002-0513-6623 Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorMorkos A. Henen, Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA Department of Pharmaceutical Organic Chemistry, Mansoura University, Mansoura, EgyptSearch for more papers by this authorJordi M. Lanis, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorJ. Scott Lee, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorIan M. Cartwright, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorRachel E. M. Schaefer, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorAlfredo Ornelas, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorJoseph C. Onyiah, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorBeat Vögeli, Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USASearch for more papers by this authorSean P. Colgan, Corresponding Author [email protected] Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA Correspondence Sean P. Colgan, Mucosal Inflammation Program, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue MS B-146, Aurora, CO 80045, USA. Email: [email protected] for more papers by this author First published: 07 April 2021 https://doi.org/10.1096/fj.202100027RCitations: 2 Erica E. Alexeev, Alexander S. Dowdell, Morkos A. Henen contributed equally to this work. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract During episodes of acute inflammation, polymorphonuclear leukocytes (PMNs) are actively recruited to sites of inflammation or injury where they provide anti-microbial and wound-healing functions. One enzyme crucial for fulfilling these functions is myeloperoxidase (MPO), which generates hypochlorous acid from Cl− and hydrogen peroxide. The potential exists, however, that uncontrolled the extracellular generation of hypochlorous acid by MPO can cause bystander tissue damage and inhibit the healing response. Previous work suggests that the microbiota-derived tryptophan metabolites 1H-indole and related molecules (“indoles”) are protective during intestinal inflammation, although their precise mechanism of action is unclear. In the present work, we serendipitously discovered that indoles are potent and selective inhibitors of MPO. Using both primary human PMNs and recombinant human MPO in a cell-free system, we revealed that indoles inhibit MPO at physiologic concentrations. Particularly, indoles block the chlorinating activity of MPO, a reliable marker for MPO-associated tissue damage, as measured by coulometric-coupled HPLC. Further, we observed direct interaction between indoles and MPO using the established biochemical techniques microscale thermophoresis and STD-NMR. Utilizing a murine colitis model, we demonstrate that indoles inhibit bystander tissue damage, reflected in decreased colon 3-chlorotyrosine and pro-inflammatory chemokine expression in vivo. Taken together, these results identify microbiota-derived indoles that acts as endogenous immunomodulatory compounds through their actions on MPO, suggesting a symbiotic association between the gut microbiota and host innate immune system. Such findings offer exciting new targets for future pharmacological intervention. Citing Literature Supporting Information Filename Description fsb221552-sup-0001-FigS1.pdfPDF document, 117.9 KB Fig S1 fsb221552-sup-0002-FigS2.pdfPDF document, 171.3 KB Fig S2 fsb221552-sup-0003-Supinfo.docxWord document, 12.7 KB Supplementary Material Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume35, Issue5May 2021e21552 RelatedInformation