Abstract
Mast cells (MC) are innate immune cells present in virtually all body tissues with key roles in allergic disease and host defense. MCs recognize damage-associated molecular patterns (DAMPs) through expression of multiple receptors including Toll-like receptors and the IL-33 receptor ST2. MCs can be activated to degranulate and release pre-formed mediators, to synthesize and secrete cytokines and chemokines without degranulation, and/or to produce lipid mediators. MC numbers are generally increased at sites of fibrosis. They are potent, resident, effector cells producing mediators that regulate the fibrotic process. The nature of the secretory products produced by MCs depend on micro-environmental signals and can be both pro- and anti-fibrotic. MCs have been repeatedly implicated in the pathogenesis of cardiac fibrosis and in angiogenic responses in hypoxic tissues, but these findings are controversial. Several rodent studies have indicated a protective role for MCs. MC-deficient mice have been reported to have poorer outcomes after coronary artery ligation and increased cardiac function upon MC reconstitution. In contrast, MCs have also been implicated as key drivers of fibrosis. MC stabilization during a hypertensive rat model and an atrial fibrillation mouse model rescued associated fibrosis. Discrepancies in the literature could be related to problems with mouse models of MC deficiency. To further complicate the issue, mice generally have a much lower density of MCs in their cardiac tissue than humans, and as such comparing MC deficient and MC containing mouse models is not necessarily reflective of the role of MCs in human disease. In this review, we will evaluate the literature regarding the role of MCs in cardiac fibrosis with an emphasis on what is known about MC biology, in this context. MCs have been well-studied in allergic disease and multiple pharmacological tools are available to regulate their function. We will identify potential opportunities to manipulate human MC function and the impact of their mediators with a view to preventing or reducing harmful fibrosis. Important therapeutic opportunities could arise from increased understanding of the impact of such potent, resident immune cells, with the ability to profoundly alter long term fibrotic processes.
Highlights
Mast cells (MCs) are tissue-specific innate immune cells located in sites throughout the body, including the heart [1]
After differentiation from hematopoietic stem cells along the myeloid pathway, committed MC precursors which can be identified by flow cytometry transiently travel through the blood and enter into tissues to differentiate into a terminal tissue-specific MC phenotype [2]
MCs are known as sentinel cells, surveying the microenvironment and responding to stimuli via expression of Pattern Recognition Receptors (PRRs) that detect Pathogen and Damage-Associated Molecular Patterns (PAMPs and damage-associated molecular patterns (DAMPs)) [3, 4]
Summary
Mast cells (MCs) are tissue-specific innate immune cells located in sites throughout the body, including the heart [1]. Dogs and mice have shown that inhibition of MC degranulation or chymase activity reduces expression of fibrosis-associated genes and collagen deposition in models of dilated cardiomyopathy (DCM), ovariectomy-induced left ventricular diastolic dysfunction and MI [22,23,24, 26, 29]. Studies assessing MCs in cardiac fibrosis often analyze MC density changes that occur during remodeling, concluding a pro-fibrotic role.
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