Mast cell coupling to the Kallikrein-Kinin system Fuels intracardiac Parasitism and Worsens heart Pathology in experimental chagas Disease

• Autor(a) principal: Nascimento, Clarissa R.
• Data de Publicação: 2017
• Outros Autores: Andrade, Daniele, Carvalho-Pinto, Carla Eponina, Serra, Rafaela Rangel, Vellasco, Lucas, Brasil, Guilherme, Ramos-Junior, Erivan Schnaider, da Mota, Julia Barbalho, Almeida, Larissa Nogueira, Andrade, Marcus V., Correia Soeiro, Maria de Nazare, Juliano, Luiz [UNIFESP], Alvarenga, Patricia Hessab, Oliveira, Ana Carolina, Sicuro, Fernando Lencastre, de Carvalho, Antonio C. Campos, Svensjo, Erik, Scharfstein, Julio
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Institucional da UNIFESP
• Texto Completo: http://dx.doi.org/10.3389/fimmu.2017.00840; http://repositorio.unifesp.br/handle/11600/51404
• topic: bradykinin; Chagas disease; endothelin; G protein-coupled receptors; kallikrein; mast cells; Trypanosoma cruzi

During the course of Chagas disease, infectious forms of Trypanosoma cruzi are occasionally liberated from parasitized heart cells. Studies performed with tissue culture trypomastigotes (TCTs, Dm28c strain) demonstrated that these parasites evoke neutrophil/CXCR2-dependent microvascular leakage by activating innate sentinel cells via toll-like receptor 2 (TLR2). Upon plasma extravasation, proteolytically derived kinins and C5a stimulate immunoprotective Th1 responses via cross-talk between bradykinin B2 receptors (B2Rs) and C5aR. Awareness that TCTs invade cardiovascular cells in vitro via interdependent activation of B2R and endothelin receptors [endothelin A receptor (ETAR)/endothelin B receptor (ETBR)] led us to hypothesize that T. cruzi might reciprocally benefit from the formation of infection-associated edema via activation of kallikrein-kinin system (KKS). Using intravital microscopy, here we first examined the functional interplay between mast cells (MCs) and the KKS by topically exposing the hamster cheek pouch (HCP) tissues to dextran sulfate (DXS), a potent "contact" activator of the KKS. Surprisingly, although DXS was inert for at least 30 min, a subtle MC-driven leakage resulted in factor XII (FXII)-dependent activation of the KKS, which then amplified inflammation via generation of bradykinin (BK). Guided by this mechanistic insight, we next exposed TCTs to "leaky" HCP-forged by low dose histamine application-and found that the proinflammatory phenotype of TCTs was boosted by BK generated via the MC/KKS pathway. Measurements of footpad edema in MC-deficient mice linked TCT-evoked inflammation to MC degranulation (upstream) and FXII-mediated generation of BK (downstream). We then inoculated TCTs intracardiacally in mice and found a striking decrease of parasite DNA (quantitative polymerase chain reaction