Proteolytic generation of kinins in tissues infected by Trypanosoma cruzi depends on CXC chemokine secretion by macrophages activated via Toll‐like 2 receptors
2009
Previous analysis of the endogenous in- nate signals that steer T cell-dependent immunity in mice acutely infected by the protozoan Trypanosoma cruzi revealed that bradykinin (BK) or lysyl-BK, i.e., the short-lived peptides excised from plasma-borne kininogens through the activity of cruzipain, induces dendritic cell maturation via BK B2 receptors (B2R). Here, we used the s.c. model of T. cruzi infection to study the functional interplay of TLR2, CXCR2, and B2R in edema development. Using intravital micros- copy, we found that repertaxin (CXCR2 antago- nist) blocked tissue-culture trypomastigotes (TCT)- induced plasma leakage and leukocyte accumulation in the hamster cheek pouch topically exposed to TCT. Furthermore, we found that TCT-evoked paw edema in BALB/c mice was blocked by repertaxin or HOE-140 (B2R antagonist), suggesting that CXCR2 propels the extravascular activation of the kinin/B2R pathway. We then asked if TLR2-mediated sensing of TCT by innate sentinel cells could induce secretion of CXC chemokines, which would then evoke neutro- phil-dependent plasma leakage via the CXCR2/B2R pathway. Consistent with this notion, in vitro studies revealed that TCT induce robust secretion of CXC chemokines by resident macrophages in a TLR2- dependent manner. In contrast, TLR2 / macro- phages stimulated with insect-derived metacyclic try- pomastigotes or epimastigotes, which lack the devel- opmentally regulated TLR2 agonist displayed by TCT, failed to secrete keratinocyte-derived chemo- kine/MIP-2. Collectively, these results suggest that secretion of CXC chemokines by innate sentinel cells links TLR2-dependent recognition of TCT to the ki- nin system, a proteolytic web that potently amplifies vascular inflammation and innate immunity through the extravascular release of BK. J. Leukoc. Biol. 85: 1005-1014; 2009.
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