Mast Cells in Neuroimmune Interactions: Mechanisms, Pathophysiological Roles, and Therapeutic Implications

Mast cells (MCs) are versatile immune cells that play a key role in neuroimmune interactions due to their strategic localization in barrier tissues and perineuronal sites, including the meninges, choroid plexus, thalamus, hypothalamus, and hippocampus within the central nervous system (CNS), as well as peripheral sites such as the skin, gastrointestinal tract, and dorsal root ganglia. They rapidly release stored and newly synthesized mediators, including histamine, tryptase, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), substance P, and prostaglandins, which regulate nerve signaling, vascular function, and inflammation. This review presents a framework integrating MC differentiation with distinct CNS microenvironments to explain their neuroprotective and toxic roles. The anatomical and molecular basis of MC-neuron interaction is discussed, with emphasis on bidirectional signaling via neuropeptides, neurotransmitters, and cytokines. MC functions in the CNS are highlighted, including neuroprotection through synaptic plasticity and BBB integrity under homeostatic conditions, as well as neurotoxicity, where aberrant activation promotes BBB breakdown, microglial priming, and neuroinflammatory cascades. Furthermore, the roles in which mast cell dysfunction is implicated in neurodegenerative and psychiatric disorders are examined, including Alzheimer's disease (AD), where amyloid-β triggers MC degranulation, Parkinson's disease (PD), where α-synuclein induces MC activation, multiple sclerosis (MS), autism, anxiety, and depression, as well as peripheral neuroimmune conditions affecting the skin, gut-brain axis, and pain. Current and emerging mast cell-targeted therapies, including stabilizers, histamine receptor blockers, tryptase inhibitors, and anti-IgE biologics, are discussed, along with future challenges in mast cell-based neuroimmunological treatment.