Monocytes Mobilized by Gut Neurons Remodel the Enteric Nervous System
Monocytes Mobilized by Gut Neurons Remodel the Enteric Nervous System
ABSTRACT The proper organization of the enteric nervous system (ENS) is critical for normal gastrointestinal (GI) physiology. Inflammatory bowel disease (IBD) dysregulates GI physiology, including bowel movements (motility), but in many IBD patients, GI motility disorders persist in remission through a poorly understood pathological process. Here we uncover that post-inflammatory GI dysmotility (PI-GID) stems from structural ENS remodeling driven by a combination of neuronal loss and neurogenesis. Enteric neurons respond to mucosal inflammation by upregulating CCL2 expression and facilitating the recruitment of CCR2+ monocytes into the neural myenteric plexus within the intestinal muscle. This is followed by the expansion of monocyte-derived macrophages and their migration into the myenteric ganglia and phagocytosis of neurons. However, excessive recruitment of monocytes results in disproportionate ENS remodeling and PI-GID. The expansion of inflammatory cells is known to promote tissue hypoxia. We find that enteric neurons become hypoxic upon colitis, but hypoxia-induced signaling via HIF1α initiates an adaptation program in enteric neurons to attenuate CCL2 expression and limit monocyte recruitment. We demonstrate that reinforcing HIF1α signaling in enteric neurons prevents PI-GID by reducing colitis-associated monocyte recruitment in the myenteric plexus and protecting against ENS remodeling. In summary, our findings unveil PI-GID pathogenesis and identify a regulatory axis for its prevention. One Sentence SummaryIntestinal mucosal inflammation engages enteric neurons in the inflammatory response leading to neurogenic recruitment of monocytes into the extra-mucosal myenteric plexus followed by pathological structural remodeling of the enteric nervous system by monocyte-derived macrophages.
Szabo Krisztina、Kulkarni Subhash、Liu Yu、Koscso Balazs、Navarro Leonardo、Wang Wenhui、Peters Lauren A.、Zhu Jun、Saha Monalee、Srinivasan Shanthi、Kurapati Sravya、Baer Christina E.、Pasricha Pankaj Jay、Nagaraj Sushma、Ashraf Azree Zaffran、Dash Chinmayee、Shulzhenko Natalya、Bogunovic Milena、Shin Changsik
Department of Pathology, University of Massachusetts Chan Medical SchoolCenter for Neurogastroenterology, The Johns Hopkins University School of Medicine||Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Genetics & Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Pathology, University of Massachusetts Chan Medical SchoolDepartment of Pathology, University of Massachusetts Chan Medical SchoolDepartment of Genetics & Genomic Sciences, Icahn School of Medicine at Mount SinaiDepartment of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai||Windreich Department of AI & Human Health, Icahn School of Medicine at Mount SinaiDepartment of Genetics & Genomic Sciences, Icahn School of Medicine at Mount SinaiCenter for Neurogastroenterology, The Johns Hopkins University School of MedicineDivision of Digestive Diseases, Department of Medicine, Emory University School of MedicineDepartment of Pathology, University of Massachusetts Chan Medical School||The Biomedical Sciences PhD Program, Penn State University College of MedicineSanderson Center for Optical Experimentation (SCOPE), Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical SchoolCenter for Neurogastroenterology, The Johns Hopkins University School of Medicine||Department of Medicine, Mayo ClinicCenter for Neurogastroenterology, The Johns Hopkins University School of MedicineDepartment of Pathology, University of Massachusetts Chan Medical SchoolThe Morningside Graduate School of Biomedical Sciences at UMass Chan Medical SchoolCollege of Veterinary Medicine, Oregon State UniversityDepartment of Pathology, University of Massachusetts Chan Medical School||Department of Microbiology and Immunology, Penn State University College of MedicineDepartment of Microbiology and Immunology, Penn State University College of Medicine
基础医学神经病学、精神病学生理学
Szabo Krisztina,Kulkarni Subhash,Liu Yu,Koscso Balazs,Navarro Leonardo,Wang Wenhui,Peters Lauren A.,Zhu Jun,Saha Monalee,Srinivasan Shanthi,Kurapati Sravya,Baer Christina E.,Pasricha Pankaj Jay,Nagaraj Sushma,Ashraf Azree Zaffran,Dash Chinmayee,Shulzhenko Natalya,Bogunovic Milena,Shin Changsik.Monocytes Mobilized by Gut Neurons Remodel the Enteric Nervous System[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2024.06.09.598124.点此复制
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