Inhibitors of serine peptidases (ISPs) expressed byLeishmania majorenhance 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-expressingL. majorand 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 appliedL. majorpromastigotes (WT andΔisp2/3mutants) potently induced plasma leakage through the activation of bradykinin B₂receptors (B₂R). Next, using mAbs against kininogen domains, we showed that these BK-precursor proteins are sequestered byL. majorpromastigotes, being expressed at higher % in theΔisp2/3mutant population. Strikingly, analysis of the role of kinin pathway in the phagocytic uptake ofL. majorrevealed that antagonists of B₂R or B₁R reversed the upregulated uptake ofΔisp2/3mutants without inhibiting macrophage internalization of WTL. major. Collectively, our results suggest thatL. majorISP-2 fine-tunes macrophage phagocytosis by inhibiting the pericellular release of proinflammatory kinins from surface bound kininogens. Ongoing studies should clarify whetherL. majorISP-2 subverts TLR₄/PKR-dependent prooxidative responses of macrophages by preventing activation of G-protein coupled B₂R/B₁R.