Mast Cell Mediated Pathophysiology in Atherosclerotic Disease

Atherosclerosis is a chronic inflammatory disorder characterised by lipid accumulation, immune cell infiltration and progressive arterial wall remodelling. Mast cells, long recognised for their role in allergy, have emerged as pivotal contributors to plaque development and destabilisation. These tissue‐resident granulocytes accumulate within the intimal and perivascular regions of developing lesions, where they release a repertoire of bioactive mediators—histamine, neutral proteases (tryptase, cathepsin G), cytokines and chemokines. Proteolytic enzymes degrade extracellular matrix proteins and modify low‐density lipoprotein (LDL), promoting lipid retention and foam‐cell formation. Mast‐cell‐derived chemokines enhance recruitment of neutrophils and monocytes, while growth factors stimulate neovascularisation, generating fragile microvessels prone to intraplaque haemorrhage. Further, mast cells form extracellular traps that exacerbate local inflammation and thrombosis. Emerging evidence implicates mast‐cell pH regulation via IgE‐mediated activation of macrophage Na⁺/H⁺ exchanger 1 (NHE1) in lesion acidification, while acute psychological stress triggers mast‐cell degranulation, raising systemic interleukin-6 levels and precipitating plaque rupture. Collectively, these insights underscore mast cells as orchestrators of lesion progression and instability, highlighting opportunities for targeted modulation of their activation and mediator release as novel therapeutic strategies and for non‐invasive imaging of vulnerable plaques.

Research from Nature Portfolio

Work on macrophage Na⁺/H⁺ exchanger 1 (NHE1) revealed that IgE engagement of FcεRI complexes with NHE1 to induce extracellular acidification in atherosclerotic lesions, promoting foam‐cell apoptosis and lesion growth. Deficiency of NHE1 or FcεRI in bone‐marrow‐derived cells reduced acidification and plaque burden in Apoe⁻/⁻ mice, and non‐invasive pH‐sensitive fluorescence tomography visualised acidic foci in live animals, offering a novel imaging approach to identify unstable plaques. In parallel, studies of acute stress in Apoe⁻/⁻ mice demonstrated that single‐episode restraint activates perivascular mast cells, elevates circulating interleukin-6 and corticosterone, and increases intraplaque haemorrhage. Mast cell‐deficient mice showed no stress‐induced plaque bleedings, confirming the central role of mast cells in translating psychological stress into structural plaque destabilisation.

Mast Cell Mediated Pathophysiology in Atherosclerotic Disease publication trend

The graph below shows the total number of articles in mast cell mediated pathophysiology in atherosclerotic disease across all publications each year (not limited to Nature Index journals).

Technical terms

Mast cell: A tissue‐resident immune cell containing cytoplasmic granules rich in histamine, proteases and cytokines, involved in both allergic responses and inflammatory processes within atherosclerotic plaques.

Atherosclerotic plaque: A focal lesion in the arterial wall composed of lipids, immune cells, smooth muscle cells and extracellular matrix, whose rupture or erosion leads to acute cardiovascular events.

Foam cell: A lipid‐laden macrophage or smooth muscle cell that forms after internalising modified LDL, contributing to the fatty streak and necrotic core of plaques.

Neovascularisation: The formation of new microvessels within the plaque, often driven by mast‐cell‐derived growth factors, which can lead to intraplaque haemorrhage.

FcεRI: The high‐affinity receptor for immunoglobulin E on mast cells and basophils, whose cross‐linking by IgE complexes triggers degranulation and mediator release.

Na⁺/H⁺ exchanger 1 (NHE1): A pH‐regulating transmembrane protein activated by IgE‐FcεRI signalling in macrophages, leading to extracellular acidification within the plaque microenvironment.

References

1. Cellular and Molecular Mechanisms of Mast Cells in Atherosclerotic Plaque Progression and Destabilization. Clinical Reviews in Allergy & Immunology (2024).
2. Mast Cells as Potential Accelerators of Human Atherosclerosis—From Early to Late Lesions. International Journal of Molecular Sciences (2019).
3. Na+-H+ exchanger 1 determines atherosclerotic lesion acidification and promotes atherogenesis. Nature Communications (2019).
4. Flow Cytometry-Based Characterization of Mast Cells in Human Atherosclerosis. Cells (2019).
5. Stress-induced mast cell activation contributes to atherosclerotic plaque destabilization. Scientific Reports (2019).