title: Proteolytic generation of kinins in tissues infected by Trypanosoma cruzi depends on CXC chemokine secretion by macrophages activated via Toll-like 2 receptors.
abstract: Previous analysis of the endogenous innate 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 B(2) receptors (B(2)R). Here, we used the s.c. model of T. cruzi infection to study the functional interplay of TLR2, CXCR2, and B(2)R in edema development. Using intravital microscopy, we found that repertaxin (CXCR2 antagonist) 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 (B(2)R antagonist), suggesting that CXCR2 propels the extravascular activation of the kinin/B(2)R pathway. We then asked if TLR2-mediated sensing of TCT by innate sentinel cells could induce secretion of CXC chemokines, which would then evoke neutrophil-dependent plasma leakage via the CXCR2/B(2)R 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(+/+) macrophages stimulated with insect-derived metacyclic trypomastigotes or epimastigotes, which lack the developmentally regulated TLR2 agonist displayed by TCT, failed to secrete keratinocyte-derived chemokine/MIP-2. Collectively, these results suggest that secretion of CXC chemokines by innate sentinel cells links TLR2-dependent recognition of TCT to the kinin system, a proteolytic web that potently amplifies vascular inflammation and innate immunity through the extravascular release of BK.
authors.affiliation: 373 Cidade Universitária, Edifício do Centro de Ciências da Saúde (CCS)-Bloco D-sala 7, Rio de Janeiro, RJ, Brazil, CEP 21941-902.
authors.forename: Veronica
authors.initials: V
authors.lastname: Schmitz
authors.forename: Erik
authors.initials: E
authors.lastname: Svensjö
authors.forename: Rafaela Rangel
authors.initials: RR
authors.lastname: Serra
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Julio
authors.initials: J
authors.lastname: Scharfstein
mesh_terms: D000818:Animals; D019743:Chemokines, CXC / Q000378:metabolism*; D006224:Cricetinae; D004487:Edema / Q000150:complications / Q000276:immunology / Q000469:parasitology; D005838:Genotype; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000469:parasitology; D007705:Kinins / Q000378:metabolism*; D008018:Life Cycle Stages; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology; D051379:Mice; D018448:Models, Immunological; D009928:Organ Specificity; D010271:Parasites / Q000254:growth & development; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000254:growth & development / Q000502:physiology*
chemical_list: D019743:Chemokines, CXC; D007705:Kinins; D043782:Receptor, Bradykinin B2; D023063:Receptors, Interleukin-8B; D051195:Toll-Like Receptor 2