title: CCR2 signaling contributes to the differentiation of protective inflammatory dendritic cells in Leishmania braziliensis infection.
abstract: In vertebrate hosts, Leishmania braziliensis parasites infect mainly mononuclear phagocytic system cells, which when activated by T helper cell type 1 cytokines produce nitric oxide and kill the pathogens. Chemokine (C-C motif) receptor 2 is a chemokine receptor that binds primarily chemokine (C-C motif) ligand 2 and has an important role in the recruitment of monocytic phagocytes. Although it has been reported that Leishmania braziliensis infection induces CCR2 expression in the lesions, the role of CCR2 during Leishmania braziliensis infection remains unknown. Here, we showed that CCR2 has a role in mediating protection against Leishmania braziliensis infection in mice. The absence of CCR2 resulted in increased susceptibility to infection and was associated with low amounts of Ly6C(+) inflammatory dendritic cells in the lesions, which we found to be the major sources of tumor necrosis factor production and induced nitric oxide synthase expression in C57BL/6 mice lesions. Consequently, CCR2(-/-) mice showed decreased tumor necrosis factor production and induced nitric oxide synthase expression, resulting in impaired parasite elimination. We also demonstrated that CCR2 has a role in directly mediating the differentiation of monocytes into inflammatory dendritic cells at the infection sites, contributing to the accumulation of inflammatory dendritic cells in Leishmania braziliensis lesions and subsequent control of parasite replication. Therefore, these data provide new information on the role of chemokines during the immune response to infections and identify a potential target for therapeutic interventions in cutaneous leishmaniasis.
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; and.
authors.forename: Diego L
authors.initials: DL
authors.lastname: Costa
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; and.
authors.forename: Djalma S
authors.initials: DS
authors.lastname: Lima-Júnior
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; and.
authors.forename: Manuela S
authors.initials: MS
authors.lastname: Nascimento
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; and.
authors.forename: Laís A
authors.initials: LA
authors.lastname: Sacramento
authors.affiliation: Department of Internal Medicine and Pathology, Center for Biological and Health Sciences, Federal University of Sergipe, Aracajú, SE, Brazil.
authors.forename: Roque P
authors.initials: RP
authors.lastname: Almeida
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; and.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Carregaro
authors.affiliation: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; and jsdsilva@fmrp.usp.br.
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000469:parasitology; D005260:Female; D007249:Inflammation / Q000276:immunology* / Q000469:parasitology; D007892:Leishmania braziliensis / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000469:parasitology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D054390:Receptors, CCR2 / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D054390:Receptors, CCR2; D052247:Nitric Oxide Synthase Type II
keywords: TNF; cutaneous leishmaniasis; iNOS; monocytes