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Human intestinal macrophages are involved in the pathology of both ulcerative colitis and Crohn disease

Human intestinal macrophages are involved in the pathology of both ulcerative colitis and Crohn disease
Human intestinal macrophages are involved in the pathology of both ulcerative colitis and Crohn disease
Background: Intestinal macrophages are key immune cells in the maintenance of intestinal immune homeostasis and have a role in the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms by which macrophages exert a pathological influence in both ulcerative colitis (UC) and Crohn disease (CD) are not yet well understood.

Methods: We purified intestinal macrophages from gastrointestinal mucosal biopsies (patients with UC, patients with CD, and healthy donors) and analyzed their transcriptome by RNA sequencing and bioinformatics, confirming results with quantitative polymerase chain reaction and immunohistochemistry.

Results: Compared with those of healthy donors, intestinal macrophages in patients with UC and with CD showed cellular reprograming of 1287 and 840 dysregulated genes, respectively (false discovery rate ≤ 0.1). The UC and CD intestinal macrophages showed an activated M1 inflammatory phenotype and the downregulation of genes engaged in drug/xenobiotic metabolism. Only macrophages from CD showed, concomitant to an M1 phenotype, a significant enrichment in the expression of M2 and fibrotic and granuloma-related genes. For the first time, we showed (and validated by quantitative polymerase chain reaction and immunohistochemistry) that intestinal macrophages in patients with IBD present both M1 and M2 features, as recently described for tumor-associated macrophages, that affect key pathways for IBD pathology, represented by key markers such as MMP12 (fibrosis), CXCL9 (T-cell attraction), and CD40 (T-cell activation).

Conclusions: Our data support the therapeutic targeting of macrophages to maintain remission in IBD but also indicate that a shift toward an M2 program-as proposed by some reports-may not limit the recruitment and activation of T cells because M2 features do not preclude M1 activation in patients with UC or CD and could exacerbate M2-related CD-specific features such as fibrosis and the formation of granulomas.

Keywords: Crohn disease; inflammation; inflammatory bowel disease; intestinal macrophages; ulcerative colitis.
Crohn disease, inflammation, inflammatory bowel disease, intestinal macrophages, ulcerative colitis
1536-4844
1641-1652
Dharmasiri, Suranga
5c391f42-3441-48ab-a231-1e50bf769b80
Garrido-Martin, Eva M.
bba99077-0684-4516-8a15-e80409c12734
Harris, Richard, James
2ad9d9db-d1e6-46cc-9c37-b012ea561f93
Bateman, Adrian C.
28ae82e3-b93a-429a-81f5-04e8f1ff4cc7
Collins, Jane E.
be0e66f1-3036-47fa-9d7e-914c48710ba4
Cummings, J.R. Fraser
89e8e80c-b6e8-4387-a63c-3796b5ad7e14
Sanchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d
Dharmasiri, Suranga
5c391f42-3441-48ab-a231-1e50bf769b80
Garrido-Martin, Eva M.
bba99077-0684-4516-8a15-e80409c12734
Harris, Richard, James
2ad9d9db-d1e6-46cc-9c37-b012ea561f93
Bateman, Adrian C.
28ae82e3-b93a-429a-81f5-04e8f1ff4cc7
Collins, Jane E.
be0e66f1-3036-47fa-9d7e-914c48710ba4
Cummings, J.R. Fraser
89e8e80c-b6e8-4387-a63c-3796b5ad7e14
Sanchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d

Dharmasiri, Suranga, Garrido-Martin, Eva M., Harris, Richard, James, Bateman, Adrian C., Collins, Jane E., Cummings, J.R. Fraser and Sanchez-Elsner, Tilman (2021) Human intestinal macrophages are involved in the pathology of both ulcerative colitis and Crohn disease. Inflammatory Bowel Diseases, 27 (10), 1641-1652. (doi:10.1093/ibd/izab029).

Record type: Article

Abstract

Background: Intestinal macrophages are key immune cells in the maintenance of intestinal immune homeostasis and have a role in the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms by which macrophages exert a pathological influence in both ulcerative colitis (UC) and Crohn disease (CD) are not yet well understood.

Methods: We purified intestinal macrophages from gastrointestinal mucosal biopsies (patients with UC, patients with CD, and healthy donors) and analyzed their transcriptome by RNA sequencing and bioinformatics, confirming results with quantitative polymerase chain reaction and immunohistochemistry.

Results: Compared with those of healthy donors, intestinal macrophages in patients with UC and with CD showed cellular reprograming of 1287 and 840 dysregulated genes, respectively (false discovery rate ≤ 0.1). The UC and CD intestinal macrophages showed an activated M1 inflammatory phenotype and the downregulation of genes engaged in drug/xenobiotic metabolism. Only macrophages from CD showed, concomitant to an M1 phenotype, a significant enrichment in the expression of M2 and fibrotic and granuloma-related genes. For the first time, we showed (and validated by quantitative polymerase chain reaction and immunohistochemistry) that intestinal macrophages in patients with IBD present both M1 and M2 features, as recently described for tumor-associated macrophages, that affect key pathways for IBD pathology, represented by key markers such as MMP12 (fibrosis), CXCL9 (T-cell attraction), and CD40 (T-cell activation).

Conclusions: Our data support the therapeutic targeting of macrophages to maintain remission in IBD but also indicate that a shift toward an M2 program-as proposed by some reports-may not limit the recruitment and activation of T cells because M2 features do not preclude M1 activation in patients with UC or CD and could exacerbate M2-related CD-specific features such as fibrosis and the formation of granulomas.

Keywords: Crohn disease; inflammation; inflammatory bowel disease; intestinal macrophages; ulcerative colitis.

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Accepted/In Press date: 13 January 2021
e-pub ahead of print date: 11 February 2021
Published date: 1 October 2021
Keywords: Crohn disease, inflammation, inflammatory bowel disease, intestinal macrophages, ulcerative colitis

Identifiers

Local EPrints ID: 452707
URI: http://eprints.soton.ac.uk/id/eprint/452707
ISSN: 1536-4844
PURE UUID: 42b994dc-e3e7-4e45-9974-22052cab4130
ORCID for Tilman Sanchez-Elsner: ORCID iD orcid.org/0000-0003-1915-2410

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Date deposited: 15 Dec 2021 17:31
Last modified: 17 Mar 2024 03:11

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Contributors

Author: Suranga Dharmasiri
Author: Eva M. Garrido-Martin
Author: Richard, James Harris
Author: Adrian C. Bateman
Author: Jane E. Collins
Author: J.R. Fraser Cummings

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