Mast Cell Coupling to the Kallikrein–Kinin System Fuels Intracardiac Parasitism and Worsens Heart Pathology in Experimental Chagas Disease

Abstract

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; 3 d.p.i.) in the heart of MC-deficient mutant mice. Moreover, the intracardiac parasite load was significantly reduced in WT mice pretreated with (i) cromoglycate (MC stabilizer) (ii) infestin-4, a specific inhibitor of FXIIa (iii) HOE-140 (specific antagonist of B2R), and (iv) bosentan, a non-selective antagonist of ETAR/ETBR. Notably, histopathology of heart tissues from mice pretreated with these G protein-coupled receptors blockers revealed that myocarditis and heart fibrosis (30 d.p.i.) was markedly and redundantly attenuated. Collectively, our study suggests that inflammatory edema propagated via activation of the MC/KKS pathway fuels intracardiac parasitism by generating infection-stimulatory peptides (BK and endothelins) in the edematous heart tissues.

Pathology and Pathogenesis of Chagas Heart Disease

“…Due to the prominent role of adipose tissue in energy metabolism, insulin sensitivity, and inflammation, it has been suggested that T. cruzi infection may be linked to other adipocyte-associated diseases, such as diabetes and obesity (98). Chagas cardiomyopathy may be further affected by the activation of the kallikrein-kinin system, leading to a proinflammatory response that is characterized by mast cell expansion, vasodilation, increased vascular permeability, and cardiac edema and is accompanied by increased myocardial parasitism (99). Evidence that cardiac dysautonomia is a significant component of Chagas cardiomyopathy includes reports of impaired parasympathetic heart rate regulation, tachycardia, and other functional abnormalities linked to cardiac neuropathy, as well as a notable reduction of parasympathetic innervation in the myocardium observed upon autopsy of individuals who had chronic Chagas disease (35,36).…”

Mast Cells in Alveolar Septa of COVID-19 Patients: A Pathogenic Pathway That May Link Interstitial Edema to Immunothrombosis

“…Strategically localized in the subendothelial region, mast cells (MCs) are specialized innate sentinel cells that, upon activation, induce microvascular leakage, thereby linking immunity to pro-inflammatory and procoagulative networks as complement and the contact/kallikrein-kinin system ( 4 – 6 ). Despite evidence that MCs sense RNA viruses via TLR7 ( 7 ), MC-dependent increases in microvascular permeability might be potentiated by a myriad of soluble inflammatory mediators, including complement anaphylatoxins and tissue-derived alarmins ( 7 , 8 ).…”

Calming Down Mast Cells with Ketotifen: A Potential Strategy for Multiple Sclerosis Therapy?

“…Besides being associated with parasitic and allergic pathologies, these cells have also been linked to a plethora of other conditions, such as metabolic disorders [24], pathological fibrosis [25], infectious [26] and autoimmune [27,28] pathologies. Strong evidence supports the contribution of mast cells to MS immunopathogenesis, as for example, their accumulation in patient's demyelinating plaques [29], increased mast cell transcripts within and outside patient's lesions [30] and the presence of tryptase, which is a mast cell typical enzyme, in the patient's cerebrospinal fluid [31].…”