Macrophage and neutrophil heterogeneity at single-cell spatial resolution in inflammatory bowel disease

Abstract

Ulcerative colitis (UC) and Crohns disease (CD) are chronic inflammatory intestinal diseases that show a perplexing heterogeneity in manifestations and response to treatment. The molecular basis for this heterogeneity remains uncharacterized. We applied single-cell RNA sequencing and CosMxTM Spatial Molecular Imaging to human colon and found the highest diversity in cellular composition in the myeloid compartment of UC and CD patients. Besides resident macrophage subsets (M0 and M2), patients showed a variety of activated macrophages including classical (M1 CXCL5 and M1 ACOD1) and new inflammation-dependent alternative (IDA) macrophages. In addition, we captured intestinal neutrophils in three transcriptional states. Subepithelial IDA macrophages expressed NRG1, which promotes epithelial differentiation. In contrast, NRG1low IDA macrophages were expanded within the submucosa and in granulomas, in proximity to abundant inflammatory fibroblasts, which we suggest may promote macrophage activation. We conclude that macrophages sense and respond to unique tissue microenvironments, potentially contributing to patient-to-patient heterogeneity.

Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis

“…6a,b) . To further evaluate the colonic tissue microenvironment in this setting, we then performed 960- plex RNA-ISH (CosMx from Nanostring) on our FFPE TMA at subcellular resolution, as recently described 39,40 ( Fig. 6c ).…”

Serotonin attenuates tumor-necrosis-factor-alpha-induced intestinal inflammation by interacting with human mucosal tissue

“…Monocytes, in particular, are pluripotent plastic cells that can differentiate and perform various effector functions after migration to target tissues (12), thus influencing the course and resolution of inflammation in various human pathologies. Recent study using single-cell spatial transcriptomic showed presence of inflammation-dependent alternative (IDA) MΦ specifically in colon of IBD patients (51). IDA MΦ expressed neuregulin 1, molecule involved in epithelial cell expansion and differentiation, suggesting their role in epithelium regeneration during inflammation.…”

Neutrophil-fibroblast crosstalk drives immunofibrosis in Crohn’s disease through IFNα pathway

“…At the time of this writing, emerging single-cell transcriptome data in mucosal samples reveal the heterogeneity of tissue neutrophils in IBD patients. Noteworthy, A. Garrido-Trigo et al report that, in contrast to UC, the majority of intestinal neutrophils in CD display a marked IFN-response signature (26) . This is in agreement with, and further supports, our transcriptome findings in peripheral neutrophils of CD.…”