Mast Cells in Age-Related Neurodegeneration and Neuroinflammation
Of late, it is becoming clear that the dysfunction of immune cells of the central nervous system, such as microglia, is an important part of neurodegeneration. Growing degrees of cellular senescence in these cell populations, leading to inflammatory signaling, appears to be significant in the progression of Alzheimer's disease, for example. There are many distinct types of supporting cell in the brain, however. This short open access review paper discusses the evidence for dysfunction of the immune cells known as mast cells to be relevant to the progression of chronic inflammation and neurodegeneration in the aging brain.
Mast cells are "first responders" that become activated with exposure to a diverse array of stimuli, from allergens and antigens to neuropeptides, trauma, and drugs. Activated mast cells are multifunctional effector cells that exert a variety of both immediate and delayed actions.
Neuroinflammation, which is now recognized as a primary pathological component of diseases such as multiple sclerosis, is gaining acceptance as an underlying component of most, if not all, neurodegenerative diseases. Whereas past focus has predominantly centered on glial cells of the central nervous system, recently mast cells have emerged as potential key players in both neuroinflammation and neurodegenerative diseases. Mast cells are well positioned for such a role owing to their ability to affect both their microenvironment and neighboring cells including T cells, astrocytes, microglia, and neurons. The secretory granules of mast cells contain an arsenal of preformed/stored immunomodulators, neuromodulators, proteases, amines, and growth factors that enable complex cross-communication, which can be both unidirectional and bidirectional. Mast cells can also affect disruption/permeabilization of the blood-brain barrier and this has the potential for dramatically altering the neuroinflammatory state.
With respect to Alzheimer's disease (AD), Parkinson's disease (PD), ALS, and Huntington's disease (HD), mast cell perturbation of the blood-brain barrier appears to share a commonality. Moreover, mast cells have been found to home to sites of amyloid deposition in AD; and, an inhibitor of mast cell function was shown to reduce cognitive decline in AD patients. Mast cell interactions with neurons and glial cells have also been implicated in PD pathogenesis. Emerging evidence suggests that mast cell autocrine signaling may contribute to ALS: The mast cell chemoattractant, IL-15, is elevated in the serum and cerebrospinal fluid of ALS patients; and, mast cells expressing IL-17 have been found in the spinal cord of ALS patients. Plasma levels of cytokines (IL-6, IL-8), known to affect mast cell activation, have been correlated with functional scores in HD patients suggesting the possible involvement of mast cells in the pathogenesis of HD.