Resolving Resident Colonic Muscularis Macrophage Diversity and Plasticity During Colitis

Kensuke Ohishi, David Dora, Christopher Y. Han, Richard A. Guyer, Takahiro Ohkura, Simon Kazimierczyk, Nicole Picard, Abigail R. Leavitt, Leah C. Ott, Ahmed A. Rahman, Jessica L. Mueller, Nahum Y. Shpigel, Nitya Jain, Nandor Nagy, Ryo Hotta, Allan M. Goldstein, Rhian Stavely

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Immune cell populations in the intestinal muscularis propria during colitis are poorly resolved. Maintaining homeostasis in this niche is critical, highlighted by the poorer prognosis of inflammatory bowel disease associated with muscularis propria inflammation. METHODS: This study utilizes single-cell RNA sequencing to survey the immune cell populations within the muscularis propria of normal colon and dextran sodium sulfate-induced colitis. Findings are validated by immunohistochemistry, flow cytometry and cell-lineage tracing in vivo, and in vitro assays with muscularis macrophages (MMφ). RESULTS: In naïve conditions, transcriptional duality is observed in MMφs with 2 major subpopulations: conventional resident Cx3cr1+ MMφs and Lyve1+ MMφs. The Lyve1+ population is phagocytic and expresses several known MMφ markers in mouse and human, confirming their identity as a bona fide MMφ subset. Single-cell transcriptomics indicate that resident MMφs are retained during colitis and exhibit plasticity toward an inflammatory profile. Lyve1+ MMφs, which express anti-inflammatory marker CD163, are absent during colitis, as confirmed by flow cytometry. In contrast, lineage tracing finds that resident Cx3cr1+ MMφs remain during colitis and are not completely replaced by the inflammatory infiltrating monocytes. In vitro studies provide biological evidence of the plasticity of resident Cx3cr1+ MMφs in response to lipopolysaccharide (LPS), mirroring transcriptional observations in vivo of their inflammatory plasticity. Potential markers for colitic MMφs, validated in animal models and in individuals with ulcerative colitis, are identified. CONCLUSIONS: Our findings contribute to the understanding of the immune system in the muscularis propria niche during colitis by resolving the heterogeneity and origins of colitic MMφs.

Original languageEnglish
Pages (from-to)151-168
Number of pages18
JournalInflammatory Bowel Diseases
Volume31
Issue number1
DOIs
StatePublished - 6 Jan 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journ

Keywords

  • colitis
  • immune
  • inflammation
  • muscularis macrophages
  • RNA-seq

Fingerprint

Dive into the research topics of 'Resolving Resident Colonic Muscularis Macrophage Diversity and Plasticity During Colitis'. Together they form a unique fingerprint.

Cite this