{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T16:15:01Z","timestamp":1792080901613,"version":"4.4.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2016,6,1]],"date-time":"2016-06-01T00:00:00Z","timestamp":1464739200000},"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":[[2016,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Leishmaniasis is an important parasitic disease found in the tropics and subtropics. Cutaneous and visceral leishmaniasis affect an estimated 1.5 million people worldwide. Despite its human health relevance, relatively little is known about the cell death pathways that control Leishmania replication in the host. Necroptosis is a recently identified form of cell death with potent antiviral effects. Receptor interacting protein kinase 1 (RIPK1) is a critical kinase that mediates necroptosis downstream of death receptors and TLRs. Heme, a product of hemoglobin catabolism during certain intracellular pathogen infections, is also a potent inducer of macrophage necroptosis. We found that human visceral leishmaniasis patients exhibit elevated serum levels of heme. Therefore, we examined the impact of heme and necroptosis on Leishmania replication. Indeed, heme potently inhibited Leishmania replication in bone marrow\u2013derived macrophages. Moreover, we found that inhibition of RIPK1 kinase activity also enhanced parasite replication in the absence of heme. We further found that the mitochondrial phosphatase phosphoglycerate mutase family member 5 (PGAM5), a putative downstream effector of RIPK1, was also required for inhibition of Leishmania replication. In mouse infection, both PGAM5 and RIPK1 kinase activity are required for IL-1\u03b2 expression in response to Leishmania. However, PGAM5, but not RIPK1 kinase activity, was directly responsible for Leishmania-induced IL-1\u03b2 secretion and NO production in bone marrow\u2013derived macrophages. Collectively, these results revealed that RIPK1 and PGAM5 function independently to exert optimal control of Leishmania replication in the host.<\/jats:p>","DOI":"10.4049\/jimmunol.1502492","type":"journal-article","created":{"date-parts":[[2016,5,17]],"date-time":"2016-05-17T01:55:14Z","timestamp":1463450114000},"page":"5056-5063","source":"Crossref","is-referenced-by-count":20,"title":["RIPK1 and PGAM5 Control <i>Leishmania<\/i> Replication through Distinct Mechanisms"],"prefix":"10.1093","volume":"196","author":[{"given":"Nivea","family":"Farias Luz","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Massachusetts Medical School , Worcester, MA 01605"},{"name":"Centro de Pesquisas Gon\u00e7alo Moniz, Funda\u00e7\u00e3o Oswaldo Cruz , Salvador-BA, 40110-060 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakthi","family":"Balaji","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Massachusetts Medical School , Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6471-9044","authenticated-orcid":false,"given":"Kendi","family":"Okuda","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Immunology, University of Massachusetts Medical School , Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline Silva","family":"Barreto","sequence":"additional","affiliation":[{"name":"Departamento de Medicina, Hospital Universit\u00e1rio, Universidade Federal de Sergipe , Aracaju 49010-390 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Bertin","sequence":"additional","affiliation":[{"name":"Laboratorio de Imunopatologia, Centro de Pesquisa, Rene Rachou, Funda\u00e7\u00e3o Oswaldo Cruz , 30190-002 Belo Horizonte ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5110-9300","authenticated-orcid":false,"given":"Peter J","family":"Gough","sequence":"additional","affiliation":[{"name":"Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline , Collegeville, PA 19422"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Gazzinelli","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Immunology, University of Massachusetts Medical School , Worcester, MA 01605"},{"name":"Laboratorio de Imunopatologia, Centro de Pesquisa, Rene Rachou, Funda\u00e7\u00e3o Oswaldo Cruz , 30190-002 Belo Horizonte ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roque P","family":"Almeida","sequence":"additional","affiliation":[{"name":"Departamento de Medicina, Hospital Universit\u00e1rio, Universidade Federal de Sergipe , Aracaju 49010-390 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3683-7550","authenticated-orcid":false,"given":"Marcelo T","family":"Bozza","sequence":"additional","affiliation":[{"name":"Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro , Rio de Janeiro-RJ, 21941-902 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2775-5409","authenticated-orcid":false,"given":"Valeria M","family":"Borges","sequence":"additional","affiliation":[{"name":"Centro de Pesquisas Gon\u00e7alo Moniz, Funda\u00e7\u00e3o Oswaldo Cruz , Salvador-BA, 40110-060 ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4803-8353","authenticated-orcid":false,"given":"Francis Ka-Ming","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Massachusetts Medical School , Worcester, MA 01605"},{"name":"Immunology and Microbiology Program, University of Massachusetts Medical School , Worcester, MA 01605"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,6,15]]},"reference":[{"key":"2025030702182780700_r1","doi-asserted-by":"crossref","first-page":"e35671","DOI":"10.1371\/journal.pone.0035671","article-title":"Leishmaniasis worldwide and global estimates of its incidence","volume":"7","author":"Alvar","year":"2012","journal-title":"PLoS One"},{"key":"2025030702182780700_r2","doi-asserted-by":"crossref","first-page":"e877","DOI":"10.1371\/journal.pntd.0000877","article-title":"Risk factors for death in children with visceral leishmaniasis","volume":"4","author":"Sampaio","year":"2010","journal-title":"PLoS Negl. Trop. Dis."},{"key":"2025030702182780700_r3","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/nrmicro1748","article-title":"Visceral leishmaniasis: what are the needs for diagnosis, treatment and control?","volume":"5","author":"Chappuis","year":"2007","journal-title":"Nat. Rev. Microbiol."},{"key":"2025030702182780700_r4","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1111\/imr.12291","article-title":"Inflammasomes in host response to protozoan parasites","volume":"265","author":"Zamboni","year":"2015","journal-title":"Immunol. Rev."},{"key":"2025030702182780700_r5","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/nm.3221","article-title":"Inflammasome-derived IL-1\u03b2 production induces nitric oxide-mediated resistance to Leishmania","volume":"19","author":"Lima-Junior","year":"2013","journal-title":"Nat. Med."},{"key":"2025030702182780700_r6","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1172\/JCI79526","article-title":"An NLRP3 inflammasome-triggered Th2-biased adaptive immune response promotes leishmaniasis","volume":"125","author":"Gurung","year":"2015","journal-title":"J. Clin. Invest."},{"key":"2025030702182780700_r7","doi-asserted-by":"crossref","first-page":"4460","DOI":"10.4049\/jimmunol.1103072","article-title":"Heme oxygenase-1 promotes the persistence of Leishmania chagasi infection","volume":"188","author":"Luz","year":"2012","journal-title":"J. Immunol."},{"key":"2025030702182780700_r8","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1146\/annurev-micro-091313-103537","article-title":"The peculiarities and paradoxes of Plasmodium heme metabolism","volume":"68","author":"Sigala","year":"2014","journal-title":"Annu. Rev. Microbiol."},{"key":"2025030702182780700_r9","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.4049\/jimmunol.0904179","article-title":"Heme impairs prostaglandin E2 and TGF-beta production by human mononuclear cells via Cu\/Zn superoxide dismutase: insight into the pathogenesis of severe malaria","volume":"185","author":"Andrade","year":"2010","journal-title":"J. Immunol."},{"key":"2025030702182780700_r10","first-page":"245","article-title":"Immune responses in kala-azar","volume":"123","author":"Saha","year":"2006","journal-title":"Indian J. Med. 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Biol."},{"key":"2025030702182780700_r27","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.cell.2011.11.031","article-title":"Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase","volume":"148","author":"Sun","year":"2012","journal-title":"Cell"},{"key":"2025030702182780700_r28","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.immuni.2013.06.018","article-title":"The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism","volume":"39","author":"Murphy","year":"2013","journal-title":"Immunity"},{"key":"2025030702182780700_r29","doi-asserted-by":"crossref","first-page":"407","DOI":"10.4049\/jimmunol.1501662","article-title":"The mitochondrial phosphatase PGAM5 is dispensable for necroptosis but promotes inflammasome activation in macrophages","volume":"196","author":"Moriwaki","year":"2016","journal-title":"J. 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