Spatially separated epithelium-associated and lamina propria neutrophils present distinct functional identities in the inflamed colon mucosa

• DOI: 10.1016/j.mucimm.2025.02.008
• Publication Date: 2025-03-06T17:44:45Z
• Authors: Lenore K. Yalom; Caroline J. Herrn...; Triet M. Bui; Joey Lockhart; Enzo B. Piccolo; Xingsheng Ren; Cenfu Wei; Anastasiia Serdiu...; Edward B. Thorp; Parambir S. Dulai; Ronen Sumagin
• Keywords: Lamina propria; Intestinal mucosa; Mucous membrane

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