biostudies-literatureStettner NMinervaEuropean Research ProgramNICHD NIH HHSDukler Fund for Cancer ResearchPaul Sparr FoundationBaylor College of Medicine Intellectual and Developmental Disabilities Research CenterJoseph Piko BaruchWeizmann InstituteHenry S. and Anne S. Reich Research FundEuropean Research CouncilTelethonDoris Duke Charitable FoundationAdelis FoundationIsrael Science FoundationFannie SherrSaul and Theresa Esman FoundationIsrael Cancer Research Fund1962-1976https://www.ebi.ac.uk/biostudies/studies/S-EPMC5976577biostudies-literatureUnknown23(7)Nitric oxide (NO) plays an established role in numerous physiological and pathological processes, but the specific cellular sources of NO in disease pathogenesis remain unclear, preventing the implementation of NO-related therapy. Argininosuccinate lyase (ASL) is the only enzyme able to produce arginine, the substrate for NO generation by nitric oxide synthase (NOS) isoforms. Here, we generated cell-specific conditional ASL knockout mice in combination with genetic and chemical colitis models. We demonstrate that NO derived from enterocytes alleviates colitis by decreasing macrophage infiltration and tissue damage, whereas immune cell-derived NO is associated with macrophage activation, resulting in increased severity of inflammation. We find that induction of endogenous NO production by enterocytes with supplements that upregulate ASL expression and complement its substrates results in improved epithelial integrity and alleviation of colitis and of inflammation-associated colon cancer.Cell reportsInduction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer.PMC5976577IEMTxDDCF 20130951 U54 HD083092ICRF 711982ERC614204711730U54 HD0830921952/13TGM16S01CIG6181131343/13Silberman AMazkereth Rdi Bernardo DBrunetti-Pierri NBernshtein BBahar Halpern KPevsner-Fischer MBiton IPremkumar MHStettner NGur-Cohen SRosen CSarver ANagamani SCSDank GCarmel-Neiderman NNErez AFrug JZmora NEilam RBrandis AJung SHarmelin AfalseInduction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer.Nitric oxide (NO) plays an established role in numerous physiological and pathological processes, but the specific cellular sources of NO in disease pathogenesis remain unclear, preventing the implementation of NO-related therapy. Argininosuccinate lyase (ASL) is the only enzyme able to produce arginine, the substrate for NO generation by nitric oxide synthase (NOS) isoforms. Here, we generated cell-specific conditional ASL knockout mice in combination with genetic and chemical colitis models. We demonstrate that NO derived from enterocytes alleviates colitis by decreasing macrophage infiltration and tissue damage, whereas immune cell-derived NO is associated with macrophage activation, resulting in increased severity of inflammation. We find that induction of endogenous NO production by enterocytes with supplements that upregulate ASL expression and complement its substrates results in improved epithelial integrity and alleviation of colitis and of inflammation-associated colon cancer.2018-01-01T00:00:00Z2018 May2026-04-29T17:00:59.65Z2019-03-26T23:39:42ZS-EPMC59765772976819710.1016/j.celrep.2018.04.053