Human Intestinal Macrophages Are Involved in the Pathology of Both Ulcerative Colitis and Crohn Disease

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.

Interleukin-26 Expression in Inflammatory Bowel Disease and Its Immunoregulatory Effects on Macrophages

“…Different subgroups of macrophages perform different functions—host defense, wound healing, and immune regulation ( 19 ). Macrophage dysregulation is involved in the pathology of IBD ( 20 ). Macrophages can release multiple pro-inflammatory cytokines and chemokines, which are associated with tissue damage in IBD ( 21 ).…”

Intestinal strictures in Crohn’s disease: a 2021 update

“…Macrophages, especially tissue-resident macrophages, are actively involved in intestinal fibrosis. 16 Dharmasiri et al 17 analyzed the whole transcriptome of macrophages purified from the intestines of CD, ulcerative colitis (UC), and healthy individuals via RNA sequencing technology, and found that fibrotic-related genes were significantly upregulated in CD patients compared with UC patients and healthy controls. Interestingly, the expression of M2 signature genes, fibrotic genes, and TGF-β1 were enriched in macrophages from CD rather than from UC, which indicated that subsets of intestinal macrophages might be associated with CD fibrosis.…”

“…Interestingly, the expression of M2 signature genes, fibrotic genes, and TGF-β1 were enriched in macrophages from CD rather than from UC, which indicated that subsets of intestinal macrophages might be associated with CD fibrosis. 17 …”

The Role of the Immune System in IBD-Associated Colorectal Cancer: From Pro to Anti-Tumorigenic Mechanisms

“…Biopsies from IBD patients demonstrate a high abundance of monocyte-derived macrophages infiltrating the intestinal mucosa, predominantly of the M1 or pro-inflammatory phenotype [ 144 , 145 , 146 ]. More recently, it was shown that the non-dysplastic mucosa from IBD patients is populated by both M1 and M2 macrophages [ 147 ].…”