title: Inflammasome-derived IL-1β production induces nitric oxide-mediated resistance to Leishmania.
abstract: Parasites of the Leishmania genus are the causative agents of leishmaniasis in humans, a disease that affects more than 12 million people worldwide. These parasites replicate intracellularly in macrophages, and the primary mechanisms underlying host resistance involve the production of nitric oxide (NO). In this study we show that the Nlrp3 inflammasome is activated in response to Leishmania infection and is important for the restriction of parasite replication both in macrophages and in vivo as demonstrated through the infection of inflammasome-deficient mice with Leishmania amazonensis, Leishmania braziliensis and Leishmania infantum chagasi. Inflammasome-driven interleukin-1β (IL-1β) production facilitated host resistance to infection, as signaling through IL-1 receptor (IL-1R) and MyD88 was necessary and sufficient to trigger inducible nitric oxide synthase (NOS2)-mediated production of NO. In this manuscript we identify a major signaling platform for host resistance to Leishmania spp. infection and describe the molecular mechanisms underlying Leishmania-induced NO production.
authors.affiliation: Departmento de Biologia Celular, Molecular e Bioagentes Patogêncios, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Djalma S
authors.initials: DS
authors.lastname: Lima-Junior
authors.forename: Diego L
authors.initials: DL
authors.lastname: Costa
authors.forename: Vanessa
authors.initials: V
authors.lastname: Carregaro
authors.forename: Larissa D
authors.initials: LD
authors.lastname: Cunha
authors.forename: Alexandre L N
authors.initials: AL
authors.lastname: Silva
authors.forename: Tiago W P
authors.initials: TW
authors.lastname: Mineo
authors.forename: Fredy R S
authors.initials: FR
authors.lastname: Gutierrez
authors.forename: Maria
authors.initials: M
authors.lastname: Bellio
authors.forename: Karina R
authors.initials: KR
authors.lastname: Bortoluci
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Marcelo T
authors.initials: MT
authors.lastname: Bozza
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
authors.forename: Dario S
authors.identifier: 0000000278567512
authors.initials: DS
authors.lastname: Zamboni
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics; D020170:Caspase 1 / Q000235:genetics; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics; D060467:Disease Resistance / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D005260:Female; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism*; D007891:Leishmania; D007896:Leishmaniasis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009569:Nitric Oxide / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020170:Caspase 1