{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T14:54:07Z","timestamp":1777992847569,"version":"3.51.4"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2015,10,1]],"date-time":"2015-10-01T00:00:00Z","timestamp":1443657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Microbicidal NO production is reliant on inducible NO synthase\u2013mediated l-arginine metabolism in macrophages (M\u03a6s). However, l-arginine supply can be restricted by arginase activity, resulting in inefficient NO output and inhibition of antimicrobial M\u03a6 function. M\u03a6s circumvent this by converting l-citrulline to l-arginine, thereby resupplying substrate for NO production. In this article, we define the metabolic signature of mycobacteria-infected murine M\u03a6s supplied l-arginine, l-citrulline, or both amino acids. Using liquid chromatography\u2013tandem mass spectrometry, we determined that l-arginine synthesized from l-citrulline was less effective as a substrate for arginase-mediated l-ornithine production compared with l-arginine directly imported from the extracellular milieu. Following Mycobacterium bovis bacillus Calmette\u2013Gu\u00e9rin infection and costimulation with IFN-\u03b3, we observed that M\u03a6 arginase activity did not inhibit production of NO derived from l-citrulline, contrary to NO inhibition witnessed when M\u03a6s were cultured in l-arginine. Furthermore, we found that arginase-expressing M\u03a6s preferred l-citrulline over l-arginine for the promotion of antimycobacterial activity. We expect that defining the consequences of l-citrulline metabolism in M\u03a6s will provide novel approaches for enhancing immunity, especially in the context of mycobacterial disease.<\/jats:p>","DOI":"10.4049\/jimmunol.1500800","type":"journal-article","created":{"date-parts":[[2015,8,27]],"date-time":"2015-08-27T01:59:27Z","timestamp":1440640767000},"page":"3293-3300","source":"Crossref","is-referenced-by-count":43,"title":["Differential Requirements for <scp>l<\/scp>-Citrulline and <scp>l<\/scp>-Arginine during Antimycobacterial Macrophage Activity"],"prefix":"10.1093","volume":"195","author":[{"given":"Shannon M","family":"Rapovy","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junfang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Division of Pathology and Laboratory Medicine, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca L","family":"Bricker","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie M","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth D R","family":"Setchell","sequence":"additional","affiliation":[{"name":"Division of Pathology and Laboratory Medicine, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph E","family":"Qualls","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH 45229"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,10,1]]},"reference":[{"key":"2025030704164233900_r1","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1038\/labinvest.3780146","article-title":"Lethal Mycobacterium bovis Bacillus Calmette Gu\u00e9rin infection in nitric oxide synthase 2-deficient mice: cell-mediated immunity requires nitric oxide synthase 2","volume":"80","author":"Garcia","year":"2000","journal-title":"Lab. Invest."},{"key":"2025030704164233900_r2","doi-asserted-by":"crossref","first-page":"5243","DOI":"10.1073\/pnas.94.10.5243","article-title":"Identification of nitric oxide synthase as a protective locus against tuberculosis","volume":"94","author":"MacMicking","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030704164233900_r3","doi-asserted-by":"crossref","first-page":"479","DOI":"10.3389\/fimmu.2014.00479","article-title":"\u201cOf mice and men\u201d: arginine metabolism in macrophages","volume":"5","author":"Thomas","year":"2014","journal-title":"Front. Immunol."},{"key":"2025030704164233900_r4","doi-asserted-by":"crossref","first-page":"3343","DOI":"10.1128\/IAI.00443-12","article-title":"Innate immune gene polymorphisms in tuberculosis","volume":"80","author":"Azad","year":"2012","journal-title":"Infect. Immun."},{"key":"2025030704164233900_r5","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.tube.2007.03.002","article-title":"A polymorphism in the inducible nitric oxide synthase gene is associated with tuberculosis","volume":"87","author":"G\u00f3mez","year":"2007","journal-title":"Tuberculosis (Edinb.)"},{"key":"2025030704164233900_r6","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/sj.gene.6364029","article-title":"Evidence for a cluster of genes on chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians","volume":"5","author":"Jamieson","year":"2004","journal-title":"Genes Immun."},{"key":"2025030704164233900_r7","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.tube.2008.10.001","article-title":"Investigation of chromosome 17 candidate genes in susceptibility to TB in a South African population","volume":"89","author":"M\u00f6ller","year":"2009","journal-title":"Tuberculosis (Edinb.)"},{"key":"2025030704164233900_r8","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s00439-009-0713-y","article-title":"NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans","volume":"126","author":"Velez","year":"2009","journal-title":"Hum. Genet."},{"key":"2025030704164233900_r9","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1093\/infdis\/jit248","article-title":"Impaired pulmonary nitric oxide bioavailability in pulmonary tuberculosis: association with disease severity and delayed mycobacterial clearance with treatment","volume":"208","author":"Ralph","year":"2013","journal-title":"J. Infect. Dis."},{"key":"2025030704164233900_r10","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1084\/jem.183.5.2293","article-title":"Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis","volume":"183","author":"Nicholson","year":"1996","journal-title":"J. Exp. Med."},{"key":"2025030704164233900_r11","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S0962-8479(97)90005-8","article-title":"Mycobacterium tuberculosis (MTB)-stimulated production of nitric oxide by human alveolar macrophages and relationship of nitric oxide production to growth inhibition of MTB","volume":"78","author":"Rich","year":"1997","journal-title":"Tuber. Lung Dis."},{"key":"2025030704164233900_r12","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1183\/09031936.98.11040809","article-title":"Increased exhaled nitric oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in alveolar macrophages","volume":"11","author":"Wang","year":"1998","journal-title":"Eur. Respir. J."},{"key":"2025030704164233900_r13","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1006\/niox.1998.9999","article-title":"Induction of nitric oxide in human monocytes and monocyte cell lines by Mycobacterium tuberculosis","volume":"2","author":"Jagannath","year":"1998","journal-title":"Nitric Oxide"},{"key":"2025030704164233900_r14","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1164\/rccm.2201023","article-title":"Analysis of nitric oxide synthase and nitrotyrosine expression in human pulmonary tuberculosis","volume":"166","author":"Choi","year":"2002","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030704164233900_r15","doi-asserted-by":"crossref","first-page":"3644","DOI":"10.1128\/iai.65.9.3644-3647.1997","article-title":"Mechanism of nitric oxide-dependent killing of Mycobacterium bovis BCG in human alveolar macrophages","volume":"65","author":"Nozaki","year":"1997","journal-title":"Infect. Immun."},{"key":"2025030704164233900_r16","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.1574-695X.2012.01012.x","article-title":"Arginase-1 expression in granulomas of tuberculosis patients","volume":"66","author":"Pessanha","year":"2012","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"2025030704164233900_r17","doi-asserted-by":"crossref","first-page":"773","DOI":"10.4049\/jimmunol.1300113","article-title":"Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms","volume":"191","author":"Mattila","year":"2013","journal-title":"J. Immunol."},{"key":"2025030704164233900_r18","doi-asserted-by":"crossref","first-page":"E4024","DOI":"10.1073\/pnas.1408839111","article-title":"Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas","volume":"111","author":"Duque-Correa","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030704164233900_r19","doi-asserted-by":"crossref","first-page":"ra62","DOI":"10.1126\/scisignal.2000955","article-title":"Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling","volume":"3","author":"Qualls","year":"2010","journal-title":"Sci. Signal."},{"key":"2025030704164233900_r20","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1038\/ni.1671","article-title":"Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens","volume":"9","author":"El Kasmi","year":"2008","journal-title":"Nat. Immunol."},{"key":"2025030704164233900_r21","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1042\/bj2810045","article-title":"Macrophages can convert citrulline into arginine","volume":"281","author":"Wu","year":"1992","journal-title":"Biochem. J."},{"key":"2025030704164233900_r22","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.chom.2012.07.012","article-title":"Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1","volume":"12","author":"Qualls","year":"2012","journal-title":"Cell Host Microbe"},{"key":"2025030704164233900_r23","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1111\/bph.12144","article-title":"Arginase inhibition alleviates hypertension in the metabolic syndrome","volume":"169","author":"El-Bassossy","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"2025030704164233900_r24","first-page":"E181","article-title":"Differential regulation of macrophage arginine metabolism: a proposed role in wound healing","volume":"272","author":"Shearer","year":"1997","journal-title":"Am. J. Physiol."},{"key":"2025030704164233900_r25","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1111\/j.1527-3466.2006.00275.x","article-title":"Therapeutic use of citrulline in cardiovascular disease","volume":"24","author":"Romero","year":"2006","journal-title":"Cardiovasc. Drug Rev."},{"key":"2025030704164233900_r26","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1038\/nm.2544","article-title":"Requirement of argininosuccinate lyase for systemic nitric oxide production","volume":"17","author":"Erez","year":"2011","journal-title":"Nat. Med."},{"key":"2025030704164233900_r27","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.clim.2014.01.010","article-title":"Progression of clinical tuberculosis is associated with a Th2 immune response signature in combination with elevated levels of SOCS3","volume":"151","author":"Ashenafi","year":"2014","journal-title":"Clin. Immunol."},{"key":"2025030704164233900_r28","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1002\/path.4399","article-title":"The IL-13\/IL-4R\u03b1 axis is involved in tuberculosis-associated pathology","volume":"234","author":"Heitmann","year":"2014","journal-title":"J. Pathol."},{"key":"2025030704164233900_r29","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.it.2004.06.005","article-title":"IL-4 in tuberculosis: implications for vaccine design","volume":"25","author":"Rook","year":"2004","journal-title":"Trends Immunol."},{"key":"2025030704164233900_r30","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1006\/niox.2001.0340","article-title":"Caveolar localization of arginine regeneration enzymes, argininosuccinate synthase, and lyase, with endothelial nitric oxide synthase","volume":"5","author":"Flam","year":"2001","journal-title":"Nitric Oxide"},{"key":"2025030704164233900_r31","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1096\/fj.04-2317fje","article-title":"Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension","volume":"18","author":"Xu","year":"2004","journal-title":"FASEB J."},{"key":"2025030704164233900_r32","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1161\/01.HYP.0000146907.82869.f2","article-title":"Upregulation of vascular arginase in hypertension decreases nitric oxide-mediated dilation of coronary arterioles","volume":"44","author":"Zhang","year":"2004","journal-title":"Hypertension"},{"key":"2025030704164233900_r33","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1161\/01.HYP.0000198543.34502.d7","article-title":"Knockdown of arginase I restores NO signaling in the vasculature of old rats","volume":"47","author":"White","year":"2006","journal-title":"Hypertension"},{"key":"2025030704164233900_r34","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.niox.2007.07.001","article-title":"Endothelial nitric oxide production is tightly coupled to the citrulline-NO cycle","volume":"17","author":"Flam","year":"2007","journal-title":"Nitric Oxide"},{"key":"2025030704164233900_r35","doi-asserted-by":"crossref","first-page":"2536","DOI":"10.1074\/jbc.M110.180489","article-title":"Endothelial argininosuccinate synthetase 1 regulates nitric oxide production and monocyte adhesion under static and laminar shear stress conditions","volume":"286","author":"Mun","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2025030704164233900_r36","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1002\/jnr.1233","article-title":"Expression of arginase isozymes in mouse brain","volume":"66","author":"Yu","year":"2001","journal-title":"J. Neurosci. Res."},{"key":"2025030704164233900_r37","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1046\/j.1365-2567.2003.01713.x","article-title":"Arginase and autoimmune inflammation in the central nervous system","volume":"110","author":"Xu","year":"2003","journal-title":"Immunology"},{"key":"2025030704164233900_r38","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1089\/ars.2008.2234","article-title":"Nitric oxide in health and disease of the nervous system","volume":"11","author":"Knott","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"2025030704164233900_r39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/niox.2001.0355","article-title":"Effects of arginase isoforms on NO production by nNOS","volume":"6","author":"Que","year":"2002","journal-title":"Nitric Oxide"},{"key":"2025030704164233900_r40","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1006\/exnr.2000.7448","article-title":"nNOS expression in reactive astrocytes correlates with increased cell death related DNA damage in the hippocampus and entorhinal cortex in Alzheimer\u2019s disease","volume":"165","author":"Simic","year":"2000","journal-title":"Exp. Neurol."},{"key":"2025030704164233900_r41","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1097\/00004647-199801000-00008","article-title":"Neuronal nitric oxide synthase expression is induced in neocortical astrocytes after spreading depression","volume":"18","author":"Caggiano","year":"1998","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"2025030704164233900_r42","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1002\/(SICI)1098-1136(199812)24:4<428::AID-GLIA8>3.0.CO;2-1","article-title":"Argininosuccinate synthetase: localization in astrocytes and role in the production of glial nitric oxide","volume":"24","author":"Schmidlin","year":"1998","journal-title":"Glia"},{"key":"2025030704164233900_r43","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/S0301-0082(00)00056-3","article-title":"Arginine metabolism and the synthesis of nitric oxide in the nervous system","volume":"64","author":"Wiesinger","year":"2001","journal-title":"Prog. Neurobiol."},{"key":"2025030704164233900_r44","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1183\/09031936.03.00090702","article-title":"Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis","volume":"21","author":"Sch\u00f6n","year":"2003","journal-title":"Eur. Respir. J."},{"key":"2025030704164233900_r45","doi-asserted-by":"crossref","first-page":"e70032","DOI":"10.1371\/journal.pone.0070032","article-title":"L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial","volume":"8","author":"Ralph","year":"2013","journal-title":"PLoS One"},{"key":"2025030704164233900_r46","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s00726-005-0235-4","article-title":"Almost all about citrulline in mammals","volume":"29","author":"Curis","year":"2005","journal-title":"Amino Acids"},{"key":"2025030704164233900_r47","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.nut.2012.07.002","article-title":"Citrulline: from metabolism to therapeutic use","volume":"29","author":"Bahri","year":"2013","journal-title":"Nutrition"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/7\/3293\/62249336\/1500800.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/7\/3293\/62249336\/1500800.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T04:34:24Z","timestamp":1741322064000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/195\/7\/3293\/7973468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,1]]},"references-count":47,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2015,10,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1500800","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,10]]},"published":{"date-parts":[[2015,10,1]]}}}