Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic inflammatory intestinal diseases that show a perplexing heterogeneity in manifestations and response to treatment. The molecular basis for this heterogeneity has remained unclear, until now.
A new collaborative study led by Dr. Azucena Salas at IDIBAPS and our lab used single-cell RNA sequencing and CosMx™ Spatial Molecular Imaging to investigate the cellular composition of the colon in patients with UC and CD. We found the highest diversity in cellular composition in the myeloid compartment of UC and CD patients, including a variety of activated macrophages, such as classical (M1 CXCL5 and M1 ACOD1) and new inflammation-dependent alternative (IDA) macrophages.
Interestingly, subepithelial IDA macrophages expressed NRG1, a protein that promotes epithelial differentiation. Conversely, NRG1low IDA macrophages were expanded within the submucosa and in granulomas, in proximity to abundant inflammatory fibroblasts. These fibroblasts may promote macrophage activation and contribute to the patient-to-patient heterogeneity seen in UC and CD.
Our findings suggest that macrophages sense and respond to unique tissue microenvironments, which can contribute to the heterogeneity seen in patients with UC and CD. These findings offer novel insights into the molecular mechanisms underlying chronic inflammatory intestinal diseases and open up possibilities for the development of innovative approaches to diagnose and treat UC and CD.