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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 TLR 4 /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 Δ isp 2/3 mutants) potently induced plasma leakage through the activation of bradykinin B 2  receptors (B 2 R). 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 Δ isp 2/3 mutant population. Strikingly, analysis of the role of kinin pathway in the phagocytic uptake of  L. major  revealed that antagonists of B 2 R or B 1 R reversed the upregulated uptake of Δ isp 2/3 mutants 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 TLR 4 /PKR-dependent prooxidative responses of macrophages by preventing activation of G-protein coupled B 2 R/B 1 R.

mediators of inflammation

Ecotin-Like ISP ofL. majorPromastigotes 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 B2and B1Receptors