Mucosal Immunol. 2025 Mar 6:S1933-0219(25)00026-1. doi: 10.1016/j.mucimm.2025.02.008. Online ahead of print.
ABSTRACT
Inflammatory Bowel Disease (IBD) features en masse neutrophil (PMN) infiltration of the colon tissue, where PMNs occupy spatially distinct niches, including the lamina propria mucosa (LPNs) and the crypt epithelium (epithelium-associated neutrophils or EANs). Spatial PMN localization is currently used as a clinical disease scoring parameter, and EAN presence has been correlated with disease severity prognosis and reduced response to therapy. Surprisingly, although PMN heterogeneity and their clinical relevance in IBD is now well-recognized, localization-driven PMN specialization has not been investigated. We found that following initial PMN influx during the active disease phase, EANs were near-completely resolved in both UC remission patients and in murine colitis, whereas LPNs persisted throughout the resolution phase, implicating EANs as likely drivers of disease. Local profiling of transcriptional programs (by murine and human single-cell RNA sequencing, coupled with human spatial RNA transcriptomics) and functional phenotypes, including real-time intravital imaging of murine LPNs versus EANs in inflamed colon revealed LPNs and EANs to have distinct functional identities. LPN programs allowed for heightened motility and pathogen uptake, whereas EANs were overrepresented by hyperactivated/pro-apoptotic states with elevated ROS and inflammatory TNFα production. Thus, we demonstrate that colon LPNs and EANs have distinct functional identities, with EANs exhibiting activated states and apparent cytotoxicity, which may actively contribute to tissue damage. Our findings further identify EANs as potential therapeutic targets for improving mucosal healing and sustaining clinical remission in UC.
PMID:40057307 | DOI:10.1016/j.mucimm.2025.02.008