The SWI/SNF chromatin-remodeling subunit DPF2 regulates macrophage inflammation in intestinal injury via the CACNA1D-mediated MAPK pathway

The immune system plays a pivotal role in pathogenesis of intestinal injury and subsequent regenerative processes, particularly macrophages, orchestrate the inflammatory response and tissue repair. Here, we identified that loss of double PHD fingers 2 (DPF2) enhances intestinal regeneration and reduces inflammation. Using a combination of mouse genetics, single cell RNA sequencing, and spatial transcriptomics, we found that <i>Dpf2</i> loss in macrophage modulates inflammatory polarization, thus protecting against intestinal injury. Mechanistically, <i>Dpf2</i> deficiency leads to loss of H3K27ac and H3K4me1 marks at <i>Cacna1d</i> enhancer, impairing <i>Cacna1d</i> messenger RNA (mRNA) expression and reducing intracellular calcium. Consequently, loss of <i>Dpf2</i> attenuates mitogen-activated protein kinases signaling activity, promoting an anti-inflammatory macrophage polarization. Finally, through analysis of clinical inflammatory bowel disease (IBD) single cell RNA and spatial transcriptome data, patient-derived organoids and clinical samples, we validated a positive correlation between DPF2, CACNA1D, and intestinal inflammation. Our findings establish an essential role for DPF2 in facilitating CACNA1D expression in macrophages to regulate intestinal inflammation and regeneration.