{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T03:57:10Z","timestamp":1793937430516,"version":"4.8.0"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["KAKENHI 19H03716"],"award-info":[{"award-number":["KAKENHI 19H03716"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recruitment of bone marrow derived monocytes via bloodstream and their subsequent conversion to CX3CR1<jats:sup>+<\/jats:sup> macrophages in response to intestinal injury is dependent on CCR2, Nr4a1, and the microbiome. This process is critical for proper tissue repair; however, GATA6<jats:sup>+<\/jats:sup> peritoneal cavity macrophages might represent an alternative, more readily available source of mature and functional myeloid cells at the damaged intestinal locations. Here we show, using spinning-disk confocal microscopy, that large F4\/80<jats:sup>hi<\/jats:sup>GATA6<jats:sup>+<\/jats:sup> peritoneal cavity macrophages promptly accumulate at damaged intestinal sites upon intestinal thermal injury and upon dextran sodium sulfate induced colitis in mice via a direct route from the peritoneal cavity. In contrast to bloodstream derived monocytes\/macrophages, cavity macrophages do not depend on CCR2, Nr4a1 or the microbiome for recruitment, but rather on the ATP-release and exposed hyaluronan at the site of injury. They participate in the removal of necrotic cells, revascularization and collagen deposition and thus resolution of tissue damage. In summary, peritoneal cavity macrophages represent a rapid alternative route of intestinal tissue repair to traditional monocyte-derived macrophages.<\/jats:p>","DOI":"10.1038\/s41467-021-27614-9","type":"journal-article","created":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T11:05:44Z","timestamp":1639566344000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Directly recruited GATA6\u2009+\u2009peritoneal cavity macrophages contribute to the repair of intestinal serosal injury"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5526-2591","authenticated-orcid":false,"given":"Masaki","family":"Honda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Kadohisa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiki","family":"Yoshii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Komohara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taizo","family":"Hibi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,15]]},"reference":[{"key":"27614_CR1","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.1038\/nm.4430","volume":"23","author":"AM Mowat","year":"2017","unstructured":"Mowat, A. M., Scott, C. L. & Bain, C. C. Barrier-tissue macrophages: functional adaptation to environmental challenges. Nat. Med. 23, 1258\u20131270 (2017).","journal-title":"Nat. Med."},{"key":"27614_CR2","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.it.2014.04.003","volume":"35","author":"V Cerovic","year":"2014","unstructured":"Cerovic, V., Bain, C. C., Mowat, A. M. & Milling, S. W. Intestinal macrophages and dendritic cells: what\u2019s the difference? Trends Immunol. 35, 270\u2013277 (2014).","journal-title":"Trends Immunol."},{"key":"27614_CR3","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.it.2013.02.001","volume":"34","author":"E Zigmond","year":"2013","unstructured":"Zigmond, E. & Jung, S. Intestinal macrophages: well educated exceptions from the rule. Trends Immunol. 34, 162\u2013168 (2013).","journal-title":"Trends Immunol."},{"key":"27614_CR4","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1038\/ni.2967","volume":"15","author":"CC Bain","year":"2014","unstructured":"Bain, C. C. et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat. Immunol. 15, 929\u2013937 (2014).","journal-title":"Nat. Immunol."},{"key":"27614_CR5","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/mi.2012.89","volume":"6","author":"CC Bain","year":"2013","unstructured":"Bain, C. C. et al. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol. 6, 498\u2013510 (2013).","journal-title":"Mucosal Immunol."},{"key":"27614_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15068-4","volume":"11","author":"M Honda","year":"2020","unstructured":"Honda, M. et al. Perivascular localization of macrophages in the intestinal mucosa is regulated by Nr4a1 and the microbiome. Nat. Commun. 11, 1329 (2020).","journal-title":"Nat. Commun."},{"key":"27614_CR7","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1016\/j.cell.2016.03.009","volume":"165","author":"J Wang","year":"2016","unstructured":"Wang, J. & Kubes, P. A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell 165, 668\u2013678 (2016).","journal-title":"Cell"},{"key":"27614_CR8","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1084\/jem.20140570","volume":"211","author":"EL Gautier","year":"2014","unstructured":"Gautier, E. L. et al. Gata6 regulates aspartoacylase expression in resident peritoneal macrophages and controls their survival. J. Exp. Med. 211, 1525\u20131531 (2014).","journal-title":"J. Exp. Med"},{"key":"27614_CR9","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1016\/j.cell.2014.04.016","volume":"157","author":"Y Okabe","year":"2014","unstructured":"Okabe, Y. & Medzhitov, R. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157, 832\u2013844 (2014).","journal-title":"Cell"},{"key":"27614_CR10","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1126\/science.1251414","volume":"344","author":"M Rosas","year":"2014","unstructured":"Rosas, M. et al. The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal. Science 344, 645\u2013648 (2014).","journal-title":"Science"},{"key":"27614_CR11","doi-asserted-by":"publisher","first-page":"3311","DOI":"10.1182\/blood-2010-02-271981","volume":"116","author":"S Huber","year":"2010","unstructured":"Huber, S., Hoffmann, R., Muskens, F. & Voehringer, D. Alternatively activated macrophages inhibit T-cell proliferation by Stat6-dependent expression of PD-L2. Blood 116, 3311\u20133320 (2010).","journal-title":"Blood"},{"key":"27614_CR12","doi-asserted-by":"publisher","first-page":"13","DOI":"10.12703\/P6-13","volume":"6","author":"FO Martinez","year":"2014","unstructured":"Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).","journal-title":"F1000Prime Rep."},{"key":"27614_CR13","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/nri2710","volume":"10","author":"LV Hooper","year":"2010","unstructured":"Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10, 159\u2013169 (2010).","journal-title":"Nat. Rev. Immunol."},{"key":"27614_CR14","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1038\/ni.2611","volume":"14","author":"EM Brown","year":"2013","unstructured":"Brown, E. M., Sadarangani, M. & Finlay, B. B. The role of the immune system in governing host-microbe interactions in the intestine. Nat. Immunol. 14, 660\u2013667 (2013).","journal-title":"Nat. Immunol."},{"key":"27614_CR15","doi-asserted-by":"publisher","first-page":"2026","DOI":"10.4049\/jimmunol.0901936","volume":"184","author":"JH Niess","year":"2010","unstructured":"Niess, J. H. & Adler, G. Enteric flora expands gut lamina propria CX3CR1+ dendritic cells supporting inflammatory immune responses under normal and inflammatory conditions. J. Immunol. 184, 2026\u20132037 (2010).","journal-title":"J. Immunol."},{"key":"27614_CR16","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.cellimm.2018.01.003","volume":"330","author":"CC Bain","year":"2018","unstructured":"Bain, C. C. & Jenkins, S. J. The biology of serous cavity macrophages. Cell Immunol. 330, 126\u2013135 (2018).","journal-title":"Cell Immunol."},{"key":"27614_CR17","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.immuni.2019.05.010","volume":"51","author":"MB Buechler","year":"2019","unstructured":"Buechler, M. B. et al. A stromal niche defined by expression of the transcription factor WT1 mediates programming and homeostasis of cavity-resident macrophages. Immunity 51, 119\u2013130 e115 (2019).","journal-title":"Immunity"},{"key":"27614_CR18","doi-asserted-by":"publisher","first-page":"2568","DOI":"10.1073\/pnas.0915000107","volume":"107","author":"EE Ghosn","year":"2010","unstructured":"Ghosn, E. E. et al. Two physically, functionally, and developmentally distinct peritoneal macrophage subsets. Proc. Natl Acad. Sci. USA 107, 2568\u20132573 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"27614_CR19","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1038\/ni.2419","volume":"13","author":"EL Gautier","year":"2012","unstructured":"Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118\u20131128 (2012).","journal-title":"Nat. Immunol."},{"key":"27614_CR20","doi-asserted-by":"publisher","first-page":"134","DOI":"10.4049\/jimmunol.1500369","volume":"195","author":"C Louis","year":"2015","unstructured":"Louis, C. et al. Specific contributions of CSF-1 and GM-CSF to the dynamics of the mononuclear phagocyte system. J. Immunol. 195, 134\u2013144 (2015).","journal-title":"J. Immunol."},{"key":"27614_CR21","first-page":"225","volume":"6","author":"A Cassado Ados","year":"2015","unstructured":"Cassado Ados, A., D\u2019Imperio Lima, M. R. & Bortoluci, K. R. Revisiting mouse peritoneal macrophages: heterogeneity, development, and function. Front. Immunol. 6, 225 (2015).","journal-title":"Front. Immunol."},{"key":"27614_CR22","doi-asserted-by":"publisher","first-page":"1951","DOI":"10.1084\/jem.20160486","volume":"213","author":"KW Kim","year":"2016","unstructured":"Kim, K. W. et al. MHC II+ resident peritoneal and pleural macrophages rely on IRF4 for development from circulating monocytes. J. Exp. Med. 213, 1951\u20131959 (2016).","journal-title":"J. Exp. Med."},{"key":"27614_CR23","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1002\/jlb.57.3.361","volume":"57","author":"MW Barth","year":"1995","unstructured":"Barth, M. W., Hendrzak, J. A., Melnicoff, M. J. & Morahan, P. S. Review of the macrophage disappearance reaction. J. Leukoc. Biol. 57, 361\u2013367 (1995).","journal-title":"J. Leukoc. Biol."},{"key":"27614_CR24","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1053\/j.gastro.2020.01.029","volume":"158","author":"S Stengel","year":"2020","unstructured":"Stengel, S. et al. Peritoneal level of CD206 associates with mortality and an inflammatory macrophage phenotype in patients with decompensated cirrhosis and spontaneous bacterial peritonitis. Gastroenterology 158, 1745\u20131761 (2020).","journal-title":"Gastroenterology"},{"key":"27614_CR25","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1084\/jem.20182024","volume":"216","author":"N Zhang","year":"2019","unstructured":"Zhang, N. et al. Expression of factor V by resident macrophages boosts host defense in the peritoneal cavity. J. Exp. Med. 216, 1291\u20131300 (2019).","journal-title":"J. Exp. Med."},{"key":"27614_CR26","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.immuni.2019.06.010","volume":"51","author":"JF Deniset","year":"2019","unstructured":"Deniset, J. F. et al. Gata6(+) pericardial cavity macrophages relocate to the injured heart and prevent cardiac fibrosis. Immunity 51, 131\u2013140 e135 (2019).","journal-title":"Immunity"},{"key":"27614_CR27","doi-asserted-by":"publisher","first-page":"2714","DOI":"10.1182\/blood-2013-01-478206","volume":"122","author":"EL Gautier","year":"2013","unstructured":"Gautier, E. L., Ivanov, S., Lesnik, P. & Randolph, G. J. Local apoptosis mediates clearance of macrophages from resolving inflammation in mice. Blood 122, 2714\u20132722 (2013).","journal-title":"Blood"},{"key":"27614_CR28","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/nature12331","volume":"500","author":"K Atarashi","year":"2013","unstructured":"Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232\u2013236 (2013).","journal-title":"Nature"},{"key":"27614_CR29","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1126\/science.1198469","volume":"331","author":"K Atarashi","year":"2011","unstructured":"Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337\u2013341 (2011).","journal-title":"Science"},{"key":"27614_CR30","unstructured":"Constantinides, M. G. et al. MAIT cells are imprinted by the microbiota in early life and promote tissue repair. Science 366, eaax6624 (2019)."},{"key":"27614_CR31","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1038\/nature12721","volume":"504","author":"Y Furusawa","year":"2013","unstructured":"Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446\u2013450 (2013).","journal-title":"Nature"},{"key":"27614_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-30787-x","volume":"8","author":"AJ Ruiz-Alcaraz","year":"2018","unstructured":"Ruiz-Alcaraz, A. J. et al. Characterization of human peritoneal monocyte\/macrophage subsets in homeostasis: phenotype, GATA6, phagocytic\/oxidative activities and cytokines expression. Sci. Rep. 8, 12794 (2018).","journal-title":"Sci. Rep."},{"key":"27614_CR33","doi-asserted-by":"publisher","first-page":"2769","DOI":"10.1016\/S0140-6736(17)32448-0","volume":"390","author":"SC Ng","year":"2018","unstructured":"Ng, S. C. et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 390, 2769\u20132778 (2018).","journal-title":"Lancet"},{"key":"27614_CR34","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1038\/nrgastro.2017.183","volume":"15","author":"M Honda","year":"2018","unstructured":"Honda, M. & Kubes, P. Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system. Nat. Rev. Gastroenterol. Hepatol. 15, 206\u2013221 (2018).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"27614_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-00840-2","volume":"7","author":"DH Seo","year":"2017","unstructured":"Seo, D. H. et al. Interleukin-33 regulates intestinal inflammation by modulating macrophages in inflammatory bowel disease. Sci. Rep. 7, 851 (2017).","journal-title":"Sci. Rep."},{"key":"27614_CR36","doi-asserted-by":"publisher","DOI":"10.1038\/srep16760","volume":"5","author":"T Liu","year":"2015","unstructured":"Liu, T. et al. Treatment of dextran sodium sulfate-induced experimental colitis by adoptive transfer of peritoneal cells. Sci. Rep. 5, 16760 (2015).","journal-title":"Sci. Rep."},{"key":"27614_CR37","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1084\/jem.20141539","volume":"212","author":"D Dal-Secco","year":"2015","unstructured":"Dal-Secco, D. et al. A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury. J. Exp. Med. 212, 447\u2013456 (2015).","journal-title":"J. Exp. Med."},{"key":"27614_CR38","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","volume":"9","author":"CA Schneider","year":"2012","unstructured":"Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH image to imageJ: 25 years of image analysis. Nat. Methods 9, 671\u2013675 (2012).","journal-title":"Nat. Methods"},{"key":"27614_CR39","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1126\/science.1195491","volume":"330","author":"B McDonald","year":"2010","unstructured":"McDonald, B. et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330, 362\u2013366 (2010).","journal-title":"Science"},{"key":"27614_CR40","doi-asserted-by":"crossref","unstructured":"Macpherson, A. J., Geuking, M. B., Kirundi, J., Collins, S. & McCoy, K. D. Gnotiobiotic and Axenic Animals. In Encyclopedia of Microbiology (ed. Moselio, S.) 237\u2013246 (Elsevier, 2009).","DOI":"10.1016\/B978-012373944-5.00215-7"},{"key":"27614_CR41","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.jhep.2009.12.009","volume":"52","author":"L Gailhouste","year":"2010","unstructured":"Gailhouste, L. et al. Fibrillar collagen scoring by second harmonic microscopy: a new tool in the assessment of liver fibrosis. J. Hepatol. 52, 398\u2013406 (2010).","journal-title":"J. Hepatol."},{"key":"27614_CR42","doi-asserted-by":"publisher","first-page":"1840","DOI":"10.1292\/jvms.17-0045","volume":"79","author":"M Omori","year":"2017","unstructured":"Omori, M. et al. Fecal microbiome in dogs with inflammatory bowel disease and intestinal lymphoma. J. Vet. Med. Sci. 79, 1840\u20131847 (2017).","journal-title":"J. Vet. Med. Sci."},{"key":"27614_CR43","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1084\/jem.20081499","volume":"206","author":"BC Taylor","year":"2009","unstructured":"Taylor, B. C. et al. TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J. Exp. Med. 206, 655\u2013667 (2009).","journal-title":"J. Exp. Med."},{"key":"27614_CR44","first-page":"4557","volume":"7","author":"U Erben","year":"2014","unstructured":"Erben, U. et al. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J. Clin. Exp. Pathol. 7, 4557\u20134576 (2014).","journal-title":"Int J. Clin. Exp. Pathol."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-27614-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-27614-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-27614-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T19:46:31Z","timestamp":1670010391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-27614-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,15]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["27614"],"URL":"https:\/\/doi.org\/10.1038\/s41467-021-27614-9","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,15]]},"assertion":[{"value":"28 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 December 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7294"}}