Review
Mast Cells in Neuroimmune Interactions

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Highlights

Mast cells, while best known for their role in allergic inflammation, have diverse physiologic roles including innate defense against infection, modulation of adaptive immunity, angiogenesis, and tissue homeostasis.

Mast cells and neurons are closely aligned, anatomically and functionally, throughout the body.

Mast cell activity is modulated by neurotransmitters, allowing them to act as conduits for peripheral and central nervous system control of inflammation, immunity, hemodynamics, and tissue remodeling.

Mast cells act as components of the somatosensory system, responding to environmental cues and relaying signals to the nervous system resulting in changes in neural activity, sensitivity, and phenotype.

Mast cells localize to a specific brain region and play a role in normative behavior. There is also growing evidence that aberrant brain mast cell function may contribute to neurodegenerative, neurodevelopmental, and mood disorders.

A major aspect of the regulatory function of mast cells appears to be their role as intermediaries between the nervous and immune systems. Mast cells are activated by neurotransmitters allowing neural control of innate and adaptive immunity. Conversely, mast cells secrete mediators including neurotransmitters and neurotrophic factors that directly influence nerves, causing acute activation and/or long-lasting changes in excitability and phenotype. While some basic mechanisms underlying mast cell–nerve communication are well-established, the full extent to which this relationship influences health and disease is unclear. Future studies of mast cell–nerve interactions may provide greater understanding of how immune and nervous systems coordinate multiple aspects of homeostatic control, and will potentially offer therapeutic targets in both immune and neurological disorders.

Section snippets

The Mast Cell: A Neuroimmune Archetype

The nervous and immune systems play critical roles in regulating processes required for maintaining physiological homeostasis, responding to acute stressors, and protecting against external threats. The functions of these two adaptive systems are often considered independently as evidenced by the distinct scientific disciplines of neuroscience and immunology. However, in reality, homeostasis and host defense require orchestrated responses involving constant communication between nervous and

An Overview of Mast Cells

Mast cells are long-lived tissue resident cells of hematopoietic origin (i.e., they derive from hematopoietic stem cells, which give rise to blood cells). While most recognized as the major effector cells of immunoglobulin E (IgE)-mediated allergic inflammation, mast cells play important roles in diverse physiological and pathological processes.

From an evolutionary perspective, cells with mast cell-like characteristics predate the emergence of the chordates >500 million years ago [8]. However,

Anatomical Relationships between Mast Cells and Neurons

The close spatial relationship between mast cells and peripheral myelinated and unmyelinated nerves has been known for over 30 years and has been identified in essentially every tissue examined 33, 34. Mast cells are found in particularly high numbers in tissues innervated by small caliber sensory A-delta and C-fibers responsible for pain transmission, and these anatomic associations between mast cells and nerves are even more evident at sites of inflammation 35, 36.

While studies suggest that

Mast Cell Modulation of Neural Function

The somatosensory system is a prime example of the mast cell–nerve functional unit in action. Mast cells are important first responders in protective pain responses that provoke withdrawal from noxious environmental stimuli. The activation of mast cells, in response to immunologic, chemical, or physical stimuli and the consequent release of molecules that actuate/sensitize nociceptors directly contributes to pain sensation [43]. In allergic inflammation, it is proposed that IgE-mediated mast

Neural Regulation of Mast Cells

Mast cells express receptors for a range of neurotransmitters, and consequently can be modulated by them. These neurotransmitters include: classical neurotransmitters such as acetylcholine [58]; neuropeptides such as substance P, CGRP, vasoactive intestinal peptide, and neurotensin [59]; and the gaseous neurotransmitters nitric oxide and hydrogen sulfide 60, 61 (Figure 2). The effects of these diverse neurotransmitters on mast cell function vary from direct activation to enhancement or

Mast Cells and the Brain

Mast cell–nerve interactions are not restricted to the periphery, as mast cells are also present, albeit in lower overall numbers, in the brain [82]. The combination of mast cell plasticity and the unique environment of the central nervous system leads to a very distinct brain mast cell phenotype. For example, under normal conditions brain parenchymal mast cells lack expression of both the high affinity IgE receptor, FcεRI [83], and receptors for the major mast cell survival factor, SCF [84],

Concluding Remarks

The functional relationship between mast cells and nerves can be seen as an archetype of neuroimmune communication. Nerve-mast cell interactions regulate, or are suggested to regulate, a plethora of physiological and pathophysiological responses (Figure 3). However, while interactions between mast cells and all branches of the nervous system have been documented for decades, the full extent to which such interactions influence health and disease is still obscure (see Outstanding Questions).

Acknowledgements

This work was funded by grants from the Office of Naval Research (N00014-14-1-0787) and the Natural Sciences and Engineering Research Council of Canada.

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