title: Arginase I, polyamine, and prostaglandin E2 pathways suppress the inflammatory response and contribute to diffuse cutaneous leishmaniasis.
abstract: Diffuse cutaneous leishmaniasis (DCL) is a rare clinical manifestation of tegumentary leishmaniasis. The molecular mechanisms underlying DCL pathogenesis remain unclear, and there is no efficient treatment available. This study investigated the systemic and in situ expression of the inflammatory response that might contribute to suppression in DCL. The plasma levels of arginase I, ornithine decarboxylase (ODC), transforming growth factor β (TGF-β), and prostaglandin E2 (PGE2) were higher in patients with DCL, compared with patients with localized cutaneous leishmaniasis (LCL) or with controls from an area of endemicity. In situ transcriptomic analyses reinforced the association between arginase I expression and enzymes involved in prostaglandin and polyamine synthesis. Immunohistochemistry confirmed that arginase I, ODC, and cyclooxygenase2 expression was higher in lesion biopsy specimens from patients with DCL than in those from patients with LCL. Inhibition of arginase I or ODC abrogates L. amazonensis replication in infected human macrophages. Our data implicate arginase I, ODC, PGE2, and TGF-β in the failure to mount an efficient immune response and suggest perspectives in the development of new strategies for therapeutic intervention for patients with DCL.
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/FIOCRUZ-BA.
authors.forename: Jaqueline
authors.initials: J
authors.lastname: França-Costa
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/FIOCRUZ-BA.
authors.forename: Johan
authors.initials: J
authors.lastname: Van Weyenbergh
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/FIOCRUZ-BA Faculdade de Medicina, Universidade Federal da Bahia, Salvador.
authors.forename: Viviane S
authors.initials: VS
authors.lastname: Boaventura
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/FIOCRUZ-BA Faculdade de Medicina, Universidade Federal da Bahia, Salvador.
authors.forename: Nívea F
authors.initials: NF
authors.lastname: Luz
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/FIOCRUZ-BA Faculdade de Medicina, Universidade Federal da Bahia, Salvador.
authors.forename: Hayna
authors.initials: H
authors.lastname: Malta-Santos
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/FIOCRUZ-BA Faculdade de Medicina, Universidade Federal da Bahia, Salvador.
authors.forename: Murilo Cezar Souza
authors.initials: MC
authors.lastname: Oliveira
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/FIOCRUZ-BA Faculdade de Medicina, Universidade Federal da Bahia, Salvador.
authors.forename: Daniela Conceição
authors.initials: DC
authors.lastname: Santos de Campos
authors.affiliation: Universidade Federal do Maranhão, UFMA.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Saldanha
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/FIOCRUZ-BA.
authors.forename: Washington L C
authors.initials: WL
authors.lastname: dos-Santos
authors.affiliation: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro.
authors.forename: Patrícia T
authors.initials: PT
authors.lastname: Bozza
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/FIOCRUZ-BA Faculdade de Medicina, Universidade Federal da Bahia, Salvador Instituto Nacional de Ciência e Tecnologia de Investigação em Imunologia, São Paulo, Brazil.
authors.forename: Manoel
authors.initials: M
authors.lastname: Barral-Netto
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/FIOCRUZ-BA Faculdade de Medicina, Universidade Federal da Bahia, Salvador Instituto Nacional de Ciência e Tecnologia de Investigação em Imunologia, São Paulo, Brazil.
authors.forename: Aldina
authors.initials: A
authors.lastname: Barral
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/FIOCRUZ-BA.
authors.forename: Jackson M
authors.initials: JM
authors.lastname: Costa
authors.affiliation: Centro de Pesquisas Gonçalo Moniz/FIOCRUZ-BA Faculdade de Medicina, Universidade Federal da Bahia, Salvador Instituto Nacional de Ciência e Tecnologia de Investigação em Imunologia, São Paulo, Brazil.
authors.forename: Valeria M
authors.initials: VM
authors.lastname: Borges
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001119:Arginase / Q000097:blood / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015232:Dinoprostone / Q000097:blood / Q000235:genetics*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics*; D016774:Leishmaniasis, Diffuse Cutaneous / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009955:Ornithine Decarboxylase / Q000097:blood / Q000235:genetics; D011073:Polyamines / Q000097:blood / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000097:blood / Q000235:genetics; D055815:Young Adult
chemical_list: D011073:Polyamines; D016212:Transforming Growth Factor beta; C574619:ARG1 protein, human; D001119:Arginase; D009955:Ornithine Decarboxylase; D015232:Dinoprostone
keywords: Leishmania amazonensis; TGF-β; arginase I; diffuse cutaneous leishmaniasis; ornithine decarboxylase; prostaglandin E2