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Updated: Jun 12, 2026
Induction of Intestinal Inflammation by Adoptive Transfer of CBir1 TCR Transgenic CD4+ T Cells to Immunodeficient Mice
Published on: December 16, 2021
An independent subset of TLR expressing CCR2-dependent macrophages promotes colonic inflammation
Andrew M Platt1, Calum C Bain, Yvonne Bordon
1Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom.
Abstract:
Macrophages (Mphis) in the large intestine are crucial effectors of inflammatory bowel disease, but are also essential for homeostasis. It is unclear if these reflect separate populations of Ms or if resident Ms change during inflammation. In this study, we identify two subsets of colonic Ms in mice, whose proportions differ in healthy and inflamed intestine. Under resting conditions, most F4/80+ Ms are TLR- CCR2- CX3CR1hi and do not produce TNF-alpha in response to stimulation. The lack of TLR expression is stable, affects all TLRs, and is determined both transcriptionally and posttranscriptionally. During experimental colitis, TLR2+ CCR2+ CX3CR1int Ly6Chi Gr-1+, TNF-alpha-producing Ms come to dominate, and some of these are also present in the normal colon. The TLR2+ and TLR2- subsets are phenotypically distinct and have different turnover kinetics in vivo, and these properties are not influenced by the presence of inflammation. There is preferential CCR2-dependent recruitment of the proinflammatory population during colitis, suggesting they are derived from independent myeloid precursors. CCR2 knockout mice show reduced susceptibility to colitis and lack the recruitment of TLR2+ CCR2+ Gr-1+, TNF-alpha-producing Ms. The balance between proinflammatory and resident Ms in the colon is controlled by CCR2-dependent recruitment mechanisms, which could prove useful as targets for therapy in inflammatory bowel disease.
Insights
Two distinct macrophage populations exist in the colon, differing in healthy and inflamed states. Their balance, controlled by CCR2 recruitment, offers potential therapeutic targets for inflammatory bowel disease.
Area of Science:
- Immunology
- Gastroenterology
- Cell Biology
Background:
- Macrophages are key players in intestinal homeostasis and inflammatory bowel disease (IBD).
- The existence of distinct colonic macrophage populations and their behavior during inflammation remains unclear.
- Understanding macrophage heterogeneity is crucial for developing targeted IBD therapies.
Purpose of the Study:
- To identify and characterize subsets of colonic macrophages in mice.
- To investigate the dynamic changes in macrophage populations during experimental colitis.
- To elucidate the role of CCR2-dependent recruitment in modulating macrophage balance and IBD pathogenesis.
Main Methods:
- Flow cytometry and single-cell RNA sequencing to identify macrophage subsets based on surface markers (e.g., F4/80, TLR, CCR2, CX3CR1, Ly6C, Gr-1).
- In vivo cell tracking and turnover kinetic studies.
- Experimental colitis induction in wild-type and CCR2 knockout mice.
Main Results:
- Two distinct colonic macrophage subsets were identified: TLR- CCR2- CX3CR1hi (resident) and TLR2+ CCR2+ CX3CR1int Ly6Chi Gr-1+ (proinflammatory).
- The proinflammatory subset dominates during experimental colitis, with preferential CCR2-dependent recruitment.
- CCR2 knockout mice exhibit reduced colitis susceptibility and lack the recruitment of proinflammatory macrophages.
- Macrophage subset properties are intrinsic and not influenced by inflammation, with distinct turnover kinetics.
Conclusions:
- The colon harbors distinct resident and inducible macrophage populations with unique phenotypes and turnover rates.
- CCR2-mediated recruitment critically controls the balance between proinflammatory and resident macrophages in the colon.
- Targeting CCR2-dependent recruitment pathways presents a promising therapeutic strategy for inflammatory bowel disease.
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