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- Title
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<sub>2</sub> and B<sub>1</sub> Receptors
- Authors
Svensjö, Erik; De Almeida, Larissa Nogueira; Vellasco, Lucas; Juliano, Luiz; Scharfstein, Julio
- 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 Δis2/3 mutants) potently induced plasma leakage through the activation of bradykinin B2 receptors (B2R).Next, usingmAbs against kininogen domains, we showed that these BK-precursor proteins are sequestered by L. major promastigotes, being expressed at higher % in the Δis2/3 mutant population. Strikingly, analysis of the role of kinin pathway in the phagocytic uptake of L. major revealed that antagonists of B2Ror B1R reversed the upregulated uptake of Δis2/3mutants without inhibiting macrophage internalization ofWT 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 subvertsTLR4/PKR-dependent prooxidative responses of macrophages by preventing activation of G-protein coupled B2R/B1R.
- Subjects
SERINE proteinases; PROMASTIGOTE; MACROPHAGES; PHAGOCYTOSIS; BRADYKININ; G protein coupled receptors; KININOGENS
- Publication
Mediators of Inflammation, 2014, Vol 2014, p1
- ISSN
0962-9351
- Publication type
Article
- DOI
10.1155/2014/143450