Ecotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B-2 and B-1 Receptors

Ecotin-Like ISP of L. major Promastigotes Fine-Tunes Macrophage Phagocytosis by Limiting the Pericellular Release of Bradykinin from Surface-Bound Kininogens: A Survival Strategy Based on the Silencing of Proinflammatory G-Protein Coupled Kinin B-2 and B-1 Receptors

Author Svensjo, Erik Google Scholar
Almeida, Larissa Nogueira de Google Scholar
Vellasco, Lucas Google Scholar
Juliano, Luiz Autor UNIFESP Google Scholar
Scharfstein, Julio Google Scholar
Institution Universidade Federal do Rio de Janeiro (UFRJ)
Universidade Federal de São Paulo (UNIFESP)
Abstract Inhibitors of serine peptidases (ISPs) expressed by Leishmania major enhance intracellular parasitism in macrophages by targeting neutrophil elastase (NE), a serine protease that couples phagocytosis to the prooxidative TLR4/PKR pathway. Here we investigated the functional interplay between ISP-expressing L. major and the kallikrein-kinin system (KKS). Enzymatic assays showed that NE inhibitor or recombinant ISP-2 inhibited KKS activation in human plasma activated by dextran sulfate. Intravital microscopy in the hamster cheek pouch showed that topically applied L. major promastigotes (WT and Delta isp2/3 mutants) potently induced plasma leakage through the activation of bradykinin B-2 receptors (B2R). Next, using mAbs against kininogen domains, we showed that these BK-precursor proteins are sequestered by L. major promastigotes, being expressed at higher % in the Delta isp2/3 mutant population. Strikingly, analysis of the role of kinin pathway in the phagocytic uptake of L. major revealed that antagonists of B2R or B1R reversed the upregulated uptake of Delta isp2/3mutants without inhibiting macrophage internalization of WT L. major. Collectively, our results suggest that L. major ISP-2 fine-tunes macrophage phagocytosis by inhibiting the pericellular release of proinflammatory kinins from surface bound kininogens. Ongoing studies should clarify whether L. major ISP-2 subverts TLR4/PKR-dependent prooxidative responses of macrophages by preventing activation of G-protein coupled B2R/B1R.
Language English
Sponsor Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)
PRONEX
Date 2014-01-01
Published in Mediators of Inflammation. New York: Hindawi Publishing Corporation, 12 p., 2014.
ISSN 0962-9351 (Sherpa/Romeo, impact factor)
Publisher Hindawi Publishing Corporation
Extent 12
Origin http://dx.doi.org/10.1155/2014/143450
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000344254200001
URI http://repositorio.unifesp.br/handle/11600/37126

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