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.

Keywords: cardiac fibrosis; immunology; inflammation; mast cell; tissue remodeling.

Figure 1

(A) Mast cell granule products are typically associated with fibrosis. Mast cell chymase converts Angiotensin I (AngI) to AngII independently of ACE. AngII generation directly contributes to fibrosis by inducing differentiation of fibroblasts to myofibroblasts. Mast cell degranulation-derived TNF and IL-1β induce cardiomyocyte apoptosis, MMP-9 production and inflammatory cell recruitment that enhances tissue remodeling. Mast cell tryptase can act directly on fibroblasts to induce proliferation and differentiation to the myofibroblast phenotype. Tryptase and chymase both act on latent TGF-β to convert it to the active form, which also induces fibroblast differentiation to the myofibroblast phenotype and collagen deposition. Additionally, mast cells release TGF-β upon degranulation, further contributing to the activation and differentiation of fibroblasts. (B) Mast cell secretion products can protect against fibrosis. Mast cells can produce IL-13, which in the presence of apoptotic neutrophils can induce M2c phenotype macrophages. M2c macrophages are associated with decreased fibrosis. IL-13 can also induce proliferation of local cTRM via IL-4Rα signaling, which are known to be anti-fibrotic. Mast cells can also produce IL-10, which acts in the heart to decrease IL-1β and TNF levels, reduce MMP-9 expression and activity, and increase capillary density to reduce fibrotic remodeling. IL-33, which is released by stressed cardiomyocytes and fibroblasts, but can also be produced by mast cells, has been shown to protect cardiomyocytes and fibroblasts from death under hypoxic conditions. This results in decreased inflammation and reduction in fibrosis. VEGF, which promotes angiogenesis and recapillarization of the cardiac tissue, is associated with reduced fibrosis and is another mast cell product. Finally, CXCL10 has been shown to inhibit fibroblast migration into the myocardium and delay differentiation to the pro-fibrotic myofibroblast phenotype. Figure created in BioRender.