Lenore K Yalom, Caroline J Herrnreiter, Triet M Bui, Joey Lockhart, Enzo B Piccolo, Xingsheng Ren, Cenfu Wei, Anastasiia Serdiukova, Edward B Thorp, Parambir S Dulai, Ronen Sumagin
{"title":"空间分离的上皮相关中性粒细胞和固有层中性粒细胞在炎症的结肠粘膜中表现出不同的功能特征。","authors":"Lenore K Yalom, Caroline J Herrnreiter, Triet M Bui, Joey Lockhart, Enzo B Piccolo, Xingsheng Ren, Cenfu Wei, Anastasiia Serdiukova, Edward B Thorp, Parambir S Dulai, Ronen Sumagin","doi":"10.1016/j.mucimm.2025.02.008","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":" ","pages":""},"PeriodicalIF":7.9000,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Spatially separated epithelium-associated and lamina propria neutrophils present distinct functional identities in the inflamed colon mucosa.\",\"authors\":\"Lenore K Yalom, Caroline J Herrnreiter, Triet M Bui, Joey Lockhart, Enzo B Piccolo, Xingsheng Ren, Cenfu Wei, Anastasiia Serdiukova, Edward B Thorp, Parambir S Dulai, Ronen Sumagin\",\"doi\":\"10.1016/j.mucimm.2025.02.008\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":18877,\"journal\":{\"name\":\"Mucosal Immunology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":7.9000,\"publicationDate\":\"2025-03-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Mucosal Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.mucimm.2025.02.008\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Mucosal Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.mucimm.2025.02.008","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Spatially separated epithelium-associated and lamina propria neutrophils present distinct functional identities in the inflamed colon mucosa.
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.
期刊介绍:
Mucosal Immunology, the official publication of the Society of Mucosal Immunology (SMI), serves as a forum for both basic and clinical scientists to discuss immunity and inflammation involving mucosal tissues. It covers gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through original research articles, scholarly reviews, commentaries, editorials, and letters. The journal gives equal consideration to basic, translational, and clinical studies and also serves as a primary communication channel for the SMI governing board and its members, featuring society news, meeting announcements, policy discussions, and job/training opportunities advertisements.