Mast Cells in the Brain: Enduring Mysteries, Emerging Roles

Mast cells are heterogeneous, tissue-resident immune sentinels best known for their roles in allergy and peripheral inflammation. The discovery of mast cells within the meninges and brain parenchyma over a century ago raised enduring questions regarding their function in the central nervous system (CNS), their ontogeny, and distinction from peripheral counterparts. Brain mast cells are sparse and predominantly located in perivascular niches rather than forming dense aggregates, a feature that has made them difficult to study. Nevertheless, accumulating evidence implicates mast cells in diverse aspects of CNS physiology and pathology, including regulation of blood-brain barrier (BBB) permeability and neurovascular function, as well as immune surveillance in contexts of infection and injury. The ability of mast cells to communicate with neighboring glial and neuronal networks suggests potential roles in modulating neural activity, development, and behavior, although this dimension remains incompletely understood. Much of the foundational literature predates advanced immunological tools, contributing to persistent misconceptions regarding the identity and significance of brain mast cells. In this review, we outline the history of research investigating this enigmatic aspect of mast cell biology, clarifying what is known, what remains speculative, and how emerging insights may help redefine the boundaries between classical immunology and neuroscience.