Abstract
Mast cells (MCs) are the major effector cells of allergic responses and reside throughout the body, including in the brain and meninges. Previously, we showed in a mouse model of subclinical cow’s milk allergy that brain MC numbers were elevated in sensitized mice. However, the neurophysiological consequences of intracranial MC accumulation and activation are unclear. We hypothesized that centrally recruited MCs in sensitized mice could be activated by the allergen via the IgE/FcεRI mechanism and increase the blood–brain barrier (BBB) permeability to promote neuroinflammation. Furthermore, we suspected that repeated allergen exposure could sustain MC activation. To investigate our hypothesis, we sensitized C57BL6/J mice to a bovine whey allergen, β-lactoglobulin (BLG), and subsequently placed them on a whey-containing diet for two weeks. MC activity and associated changes in the brain were examined. BLG-sensitized mice showed mobility changes and depression-like behavior with significantly increased MC numbers and histamine levels in select brain regions. IgG extravasation and perivascular astrogliosis were also evident. Importantly, myelin staining revealed cortical demyelination in the BLG-sensitized mice, suggesting a potential neural substrate for their behavioral changes. Our findings support the ability of brain MCs to release histamine and other mediators to increase BBB permeability and facilitate neuroinflammatory responses in the brain.
Highlights
Mast cells (MCs) are innate immune cells with secretory granules rich in various bioactive substances, including histamine [1], proteases [1], growth factors [2,3,4], cytokines [5,6,7], and chemokines [8]
MCs are best studied in the context of type I hypersensitivity reactions, during which an allergen binds to specific IgE coupled with Fcε receptor I (FcεRI) on MC surfaces
Since we found that MCs had accumulated and been activated in the brains of the cow’s milk allergy (CMA) mice after repeated allergen exposure, we assessed whether histamine levels were elevated in the brain
Summary
Mast cells (MCs) are innate immune cells with secretory granules rich in various bioactive substances, including histamine [1], proteases [1], growth factors [2,3,4], cytokines [5,6,7], and chemokines [8]. MCs are best studied in the context of type I hypersensitivity reactions, during which an allergen binds to specific IgE coupled with Fcε receptor I (FcεRI) on MC surfaces. This interaction causes rapid crosslinking of the IgE–FcεRI complexes followed by exocytosis of the MC vesicles, known as degranulation [10]. Activation of MCs by these substances causes complete degranulation or more selective release and de novo production of cytokines, chemokines, and secreted factors [18,19], which in turn promote pathogen clearance [13,14], regulate adaptive immune responses [20], suppress tumors [21], facilitate wound healing [22], and stimulate angiogenesis [23,24]. MCs are important for homeostasis as well as in pathologic conditions such as infections, cancers, and injuries
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