Macrophage and neutrophil heterogeneity in human inflammatory bowel disease

Garrido-Trigo A, Corraliza A, Veny M, et al. Macrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease. Nat Commun 2023: 14(1):4506. doi: 10.1038/s41467-023-40156-6.

Patients with underlying ulcerative colitis (UC) and Crohn’s disease (CD) have heterogeneous differences in clinical manifestations and response to treatments. The molecular basis for this heterogeneity remains uncharacterised. Garrido-Trigo et al applied single-cell RNA sequencing and CosMx Spatial Molecular Imaging to human inflamed tissue to try and unravel the underlying mechanisms behind this heterogeneity. Using colonic samples from six healthy controls, six patients with UC and six patients with CD, Garrido-Trigo et al, found the highest diversity in cellular composition was in the myeloid compartment of patients with UC and CD. Resident macrophages were closest to mucosal surface in healthy controls whereas remodelling of myeloid compartment was evident with M1 macrophages and neutrophils closest to the ulcerated areas of the mucosal surface. M0 and M2 were the main resident macrophage subsets and represented two independent states. Compared with healthy controls, patients with inflammatory bowel disease (IBD) showed a marked increase in total number and transcriptional heterogeneity of macrophages including the resident macrophage subsets (M0 and M2) and a variety of activated macrophages including classical (M1 CXCL5 (C-X-C motif chemokine 5) and M1 aconitate decarboxylase 1) and new inflammation-dependent alternative (IDA) macrophages. In addition, Garrido-Trigo et al also captured intestinal neutrophils in three transcriptional states. Subepithelial IDA macrophages overexpressed neuregulin 1 (NRG1) in IBD, which promoted the expansion of transit-amplifying epithelial compartment, playing a role in epithelial regeneration. In contrast, NRG1^low macrophages accumulated within granulomas in CD and submucosa of patients with both UC and CD, in proximity to abundant inflammatory fibroblasts, suggesting it may promote macrophage activation.

The authors concluded that macrophages sense and respond to unique tissue microenvironments, potentially …