title: Degranulating Neutrophils Promote Leukotriene B4 Production by Infected Macrophages To Kill Leishmania amazonensis Parasites.
abstract: Neutrophils mediate early responses against pathogens, and they become activated during endothelial transmigration toward the inflammatory site. In the current study, human neutrophils were activated in vitro with immobilized extracellular matrix proteins, such as fibronectin (FN), collagen, and laminin. Neutrophil activation by FN, but not other extracellular matrix proteins, induces the release of the granules' contents, measured as matrix metalloproteinase 9 and neutrophil elastase activity in culture supernatant, as well as reactive oxygen species production. Upon contact with Leishmania amazonensis-infected macrophages, these FN-activated neutrophils reduce the parasite burden through a mechanism independent of cell contact. The release of granule proteases, such as myeloperoxidase, neutrophil elastase, and matrix metalloproteinase 9, activates macrophages through TLRs, leading to the production of inflammatory mediators, TNF-α and leukotriene B4 (LTB4), which are involved in parasite killing by infected macrophages. The pharmacological inhibition of degranulation reverted this effect, abolishing LTB4 and TNF production. Together, these results suggest that FN-driven degranulation of neutrophils induces the production of LTB4 and TNF by infected macrophages, leading to the control of Leishmania infection.
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil;
authors.forename: Natália
authors.initials: N
authors.lastname: Tavares
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil;
authors.forename: Lilian
authors.initials: L
authors.lastname: Afonso
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil; Universidade Federal da Bahia, Salvador, Bahia, Brazil;
authors.forename: Martha
authors.initials: M
authors.lastname: Suarez
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil; Universidade Federal da Bahia, Salvador, Bahia, Brazil;
authors.forename: Mariana
authors.initials: M
authors.lastname: Ampuero
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil; Universidade Federal da Bahia, Salvador, Bahia, Brazil;
authors.forename: Deboraci Brito
authors.initials: DB
authors.lastname: Prates
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil;
authors.forename: Théo
authors.identifier: http://orcid.org/0000-0001-9861-6660
authors.initials: T
authors.lastname: Araújo-Santos
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil; Universidade Federal da Bahia, Salvador, Bahia, Brazil; Instituto de Investigação em Imunologia, São Paulo, Brazil;
authors.forename: Manoel
authors.identifier: http://orcid.org/0000-0002-5823-7903
authors.initials: M
authors.lastname: Barral-Netto
authors.affiliation: Instituto de Biofísica Carlos Chagas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; and Instituto Nacional de Saúde e Ambiente na Região Amazônica, Rio de Janeiro, Brazil.
authors.forename: George A
authors.identifier: http://orcid.org/0000-0002-8924-4727
authors.initials: GA
authors.lastname: DosReis
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil; Universidade Federal da Bahia, Salvador, Bahia, Brazil; brodskyn@bahia.fiocruz.br vborges@bahia.fiocruz.br.
authors.forename: Valéria Matos
authors.initials: VM
authors.lastname: Borges
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Bahia, Brazil; Universidade Federal da Bahia, Salvador, Bahia, Brazil; Instituto de Investigação em Imunologia, São Paulo, Brazil; brodskyn@bahia.fiocruz.br vborges@bahia.fiocruz.br.
authors.forename: Cláudia
authors.initials: C
authors.lastname: Brodskyn
mesh_terms: D015550:Cell Degranulation / Q000276:immunology; D002460:Cell Line; D018920:Coculture Techniques; D005353:Fibronectins / Q000276:immunology; D006801:Humans; D007891:Leishmania; D007894:Leishmania mexicana; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D007975:Leukotriene B4 / Q000096:biosynthesis* / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000469:parasitology*; D046529:Microscopy, Electron, Transmission; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*
chemical_list: D005353:Fibronectins; D007975:Leukotriene B4