Abstract
BackgroundIntestinal 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.MethodsWe 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.ResultsCompared 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).ConclusionsOur 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.
Highlights
Inflammatory bowel disease (IBD) comprises 2 chronic relapsing and remitting inflammatory disorders: Crohn disease (CD) and ulcerative colitis (UC)
We identified a total of 1287 dysregulated genes in intestinal macrophages from patients with UC and 840 dysregulated genes in intestinal macrophages from patients with CD, compared with those from healthy donors
We explored the immune role of intestinal macrophages in CD and UC using gene set expression analysis (GSEA) to identify genes known to be associated with M1 and M2 macrophage phenotypes
Summary
Inflammatory bowel disease (IBD) comprises 2 chronic relapsing and remitting inflammatory disorders: Crohn disease (CD) and ulcerative colitis (UC). The etiology of IBD is complex and not fully understood, it is believed to result from a complex interplay between the host genetics, the microbiome, and an aberrant mucosal immune response.[1] The interaction of the innate immune system and the gut microbiota in the pathogenesis of IBD seems to be of key importance This hypothesis is supported by studies that have identified characteristic changes in the gut microbiota of patients with IBD.[2] Genome-wide association studies and, more recently, exome sequencing have highlighted susceptible loci related to the innate immune system, in particular those involved with microbial recognition and processing such as NOD2, IRGM, and ATG16L1.3. The mechanisms by which macrophages exert a pathological influence in both ulcerative colitis (UC) and Crohn disease (CD) are not yet well understood
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