Mast Cells in Cardiac Fibrosis: New Insights Suggest Opportunities for Intervention

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.

Leukocyte-Dependent Regulation of Cardiac Fibrosis

“…To date, a plethora of compelling results suggest roles for MCs in cardiac fibrosis (Legere et al, 2019). For one, in injury, the presence of DAMPs can trigger MC degranulation, which results in the release of inflammatory mediators like tryptase, chymase, IL-1β, and TNFα (Legere et al, 2019).…”

“…To date, a plethora of compelling results suggest roles for MCs in cardiac fibrosis (Legere et al, 2019). For one, in injury, the presence of DAMPs can trigger MC degranulation, which results in the release of inflammatory mediators like tryptase, chymase, IL-1β, and TNFα (Legere et al, 2019). Studies have shown that both tryptase and chymase activate TGFβ, a potent fibrogenic mediator known to promote myofibroblast differentiation and collagen production (Lindstedt et al, 2001;Tatler et al, 2008;Legere et al, 2019).…”

“…For one, in injury, the presence of DAMPs can trigger MC degranulation, which results in the release of inflammatory mediators like tryptase, chymase, IL-1β, and TNFα (Legere et al, 2019). Studies have shown that both tryptase and chymase activate TGFβ, a potent fibrogenic mediator known to promote myofibroblast differentiation and collagen production (Lindstedt et al, 2001;Tatler et al, 2008;Legere et al, 2019). Similarly, inflammatory cytokines including TNFα have been implicated in the development of cardiac fibrosis during hypertension (Mayr et al, 2016).…”

Elevated Serum Tryptase in Non-Anaphylaxis Cases: A Concise Review

“…The observation that baseline tryptase is positively correlated with the degree of coronary artery disease suggests either a role for MCs in the pathogenesis of coronary artery disease or activation as a bystander process [57]. MCs found in cardiac tissue are increasingly being recognized in the pathophysiology of various cardiac disorders [58].…”

Immunomodulatory Contribution of Mast Cells to the Regenerative Biomaterial Microenvironment

“…From a general tissue disease perspective, several studies have similarly emphasized their detrimental role to tissue remodeling outcomes [12][13][14] . However, research has also produced confounding results [15][16][17][18] or evidence of their beneficial contributions to select cases of native tissue repair or inflammatory resolution 16,19,20 , suggesting a greater functional complexity and potential to be utilized in therapeutic design. Based on recent evidence suggesting that mast cells can have beneficially influences on native tissue remodeling outcomes, we explored the role mast cells play in regulation of biomaterial scaffold-induced immunomodulatory responses, demonstrating its critical regulatory contribution to the pro-inflammatory to anti-inflammatory/pro-remodeling transition that deviates in a gender specific manner.…”