Spatial Profiling of the Mouse Colonic Immune Landscape Associated with Colitis and Sex

Overview

Journal Commun Biol

Specialty Biology

Date 2024 Nov 29

PMID 39613949

Authors

Matilda Holm

Lina Stepanauskaite

Anna Backstrom

Madeleine Birgersson

Fabio Socciarelli

Amena Archer

Charlotte Stadler

Cecilia Williams

Affiliations

Soon will be listed here.

Abstract

Inflammatory intestinal conditions are a major disease burden. Numerous factors shape the distribution of immune cells in the colon, but a spatial characterization of the homeostatic and inflamed colonic immune microenvironment is lacking. Here, we use the COMET platform for multiplex immunofluorescence to profile the infiltration of nine immune cell populations in mice of both sexes (N = 16) with full spatial context, including in regions of squamous metaplasia. Unsupervised clustering, neighborhood analysis, and manual quantification along the proximal-distal axis characterized the colonic immune landscape, quantified cell-cell interactions, and revealed sex differences. The distal colon was the most affected region during colitis, which was pronounced in males, who exhibited a sex-dependent increase of B cells and reduction of M2-like macrophages. Regions of squamous metaplasia exhibited strong infiltration of numerous immune cell populations, especially in males. Females exhibited more helper T cells and neutrophils at homeostasis and increased M2-like macrophage infiltration in the mid-colon upon colitis. Sex differences were corroborated by plasma cytokine profiles. Our results provide a foundation for future studies of inflammatory intestinal conditions.

References

Garrido-Trigo A, Corraliza A, Veny M, Dotti I, Melon-Ardanaz E, Rill A . Macrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease. Nat Commun. 2023; 14(1):4506. PMC: 10372067. DOI: 10.1038/s41467-023-40156-6. View

Tyler C, Guzman M, Lundborg L, Yeasmin S, Perez-Jeldres T, Yarur A . Inherent Immune Cell Variation Within Colonic Segments Presents Challenges for Clinical Trial Design. J Crohns Colitis. 2020; 14(10):1364-1377. PMC: 7533898. DOI: 10.1093/ecco-jcc/jjaa067. View

Veglia F, Sanseviero E, Gabrilovich D . Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021; 21(8):485-498. PMC: 7849958. DOI: 10.1038/s41577-020-00490-y. View

Jayasingam S, Citartan M, Thang T, Mat Zin A, Ang K, Chng E . Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice. Front Oncol. 2020; 9:1512. PMC: 6992653. DOI: 10.3389/fonc.2019.01512. View

Zhang Y, Pu W, Bousquenaud M, Cattin S, Zaric J, Sun L . Emodin Inhibits Inflammation, Carcinogenesis, and Cancer Progression in the AOM/DSS Model of Colitis-Associated Intestinal Tumorigenesis. Front Oncol. 2021; 10:564674. PMC: 7821392. DOI: 10.3389/fonc.2020.564674. View

Ito R, Shin-Ya M, Kishida T, Urano A, Takada R, Sakagami J . Interferon-gamma is causatively involved in experimental inflammatory bowel disease in mice. Clin Exp Immunol. 2006; 146(2):330-8. PMC: 1942055. DOI: 10.1111/j.1365-2249.2006.03214.x. View

Fleming A, Castro-Dopico T, Clatworthy M . B cell class switching in intestinal immunity in health and disease. Scand J Immunol. 2022; 95(2):e13139. PMC: 9285483. DOI: 10.1111/sji.13139. View

van Wijk F, Cheroutre H . Mucosal T cells in gut homeostasis and inflammation. Expert Rev Clin Immunol. 2010; 6(4):559-66. PMC: 2976609. DOI: 10.1586/eci.10.34. View

Moreno P, Fexova S, George N, Manning J, Miao Z, Mohammed S . Expression Atlas update: gene and protein expression in multiple species. Nucleic Acids Res. 2021; 50(D1):D129-D140. PMC: 8728300. DOI: 10.1093/nar/gkab1030. View

10.

Frigerio S, Lartey D, DHaens G, Grootjans J . The Role of the Immune System in IBD-Associated Colorectal Cancer: From Pro to Anti-Tumorigenic Mechanisms. Int J Mol Sci. 2021; 22(23). PMC: 8657929. DOI: 10.3390/ijms222312739. View

11.

James K, Gomes T, Elmentaite R, Kumar N, Gulliver E, King H . Distinct microbial and immune niches of the human colon. Nat Immunol. 2020; 21(3):343-353. PMC: 7212050. DOI: 10.1038/s41590-020-0602-z. View

12.

Ho Y, Shimbo T, Wijaya E, Kitayama T, Takaki S, Ikegami K . Longitudinal Single-Cell Transcriptomics Reveals a Role for Serpina3n-Mediated Resolution of Inflammation in a Mouse Colitis Model. Cell Mol Gastroenterol Hepatol. 2021; 12(2):547-566. PMC: 8258998. DOI: 10.1016/j.jcmgh.2021.04.004. View

13.

Agrawal M, Petralia F, Tepler A, Durbin L, Reinisch W, Colombel J . Gender-Based Differences in Response to Tumor Necrosis Factor Inhibitor Therapies for Ulcerative Colitis: Individual Participant Data Meta-Analyses of Clinical Trials. Inflamm Bowel Dis. 2022; 29(1):1-8. PMC: 10091488. DOI: 10.1093/ibd/izac067. View

14.

Hahne F, LeMeur N, Brinkman R, Ellis B, Haaland P, Sarkar D . flowCore: a Bioconductor package for high throughput flow cytometry. BMC Bioinformatics. 2009; 10:106. PMC: 2684747. DOI: 10.1186/1471-2105-10-106. View

15.

Davies L, Rosas M, Jenkins S, Liao C, Scurr M, Brombacher F . Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation. Nat Commun. 2013; 4:1886. PMC: 3842019. DOI: 10.1038/ncomms2877. View

16.

Kim S, Paik H, Yoon H, Lee J, Kim N, Sung M . Sex- and gender-specific disparities in colorectal cancer risk. World J Gastroenterol. 2015; 21(17):5167-75. PMC: 4419057. DOI: 10.3748/wjg.v21.i17.5167. View

17.

Isidro R, Appleyard C . Colonic macrophage polarization in homeostasis, inflammation, and cancer. Am J Physiol Gastrointest Liver Physiol. 2016; 311(1):G59-73. PMC: 4967174. DOI: 10.1152/ajpgi.00123.2016. View

18.

Gomez-Bris R, Saez A, Herrero-Fernandez B, Rius C, Sanchez-Martinez H, Gonzalez-Granado J . CD4 T-Cell Subsets and the Pathophysiology of Inflammatory Bowel Disease. Int J Mol Sci. 2023; 24(3). PMC: 9916759. DOI: 10.3390/ijms24032696. View

19.

Sugimoto S, Iwao Y, Shimoda M, Takabayashi K, Sato T, Kanai T . Epithelium Replacement Contributes to Field Expansion of Squamous Epithelium and Ulcerative Colitis-Associated Neoplasia. Gastroenterology. 2021; 162(1):334-337.e5. DOI: 10.1053/j.gastro.2021.09.051. View

20.

Elderman M, van Beek A, Brandsma E, De Haan B, Savelkoul H, de Vos P . Sex impacts Th1 cells, Tregs, and DCs in both intestinal and systemic immunity in a mouse strain and location-dependent manner. Biol Sex Differ. 2016; 7:21. PMC: 4820953. DOI: 10.1186/s13293-016-0075-9. View