Abstract
Considered relevant during allergy responses, numerous observations have also identified mast cells (MCs) as critical effectors during the progression and modulation of several neuroinflammatory conditions, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). MC granules contain a plethora of constituents, including growth factors, cytokines, chemokines, and mitogen factors. The release of these bioactive substances from MCs occurs through distinct pathways that are initiated by the activation of specific plasma membrane receptors/channels. Here, we focus on hemichannels (HCs) formed by connexins (Cxs) and pannexins (Panxs) proteins, and we described their contribution to MC degranulation in AD, ALS, and harmful stress conditions. Cx/Panx HCs are also expressed by astrocytes and are likely involved in the release of critical toxic amounts of soluble factors—such as glutamate, adenosine triphosphate (ATP), complement component 3 derivate C3a, tumor necrosis factor (TNFα), apoliprotein E (ApoE), and certain miRNAs—known to play a role in the pathogenesis of AD, ALS, and other neurodegenerative disorders. We propose that blocking HCs on MCs and glial cells offers a promising novel strategy for ameliorating the progression of neurodegenerative diseases by reducing the release of cytokines and other pro-inflammatory compounds.
Highlights
Considered relevant during allergy responses, numerous observations have identified mast cells (MCs) as critical effectors during the progression and modulation of several neuroinflammatory conditions, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS)
Astrocytes located at amyloid plaque foci of hippocampal brain slices from APPswe/PS1dE9 mice, which presented elevated Cx43 HC activity, unexpectedly show unaltered gap junctional communication [93], contrasting with the reduced gap junctional communication found in cultured astrocytes under inflammatory conditions [51,94]
We show only a few membrane proteins,along alongwith withsome some bioactive substances secretion signaling mechanisms are critical for communicating proteins, bioactive substances andand secretion signaling mechanisms that that are critical for communicating with with neurons and glial cells and are involved in diverse neurodegenerative diseases, in Alzheimers disease neurons and glial cells and are involved in diverse neurodegenerative diseases, in Alzheimers disease and and amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). (B) Plasma membrane channels/receptors inamyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). (B) Plasma membrane channels/receptors include clude HCs, purinergic receptors (e.g., P2XR, P2YR), growth factor receptors
Summary
Mast cells (MCs) are resident immune cells from vascularized tissues that are closely associated with blood vessels, glia, and neurons. The maturation dependence of local factors has led to recognizing MCs heterogeneity in mammals, variable cell numbers, size, recognition of damage/pathogens, activation response, sensitivity to inhibitors, granule numbers, and content along the same body. In this context, two subtypes have been historically classified in rodents: connective tissue MCs (found in peritoneal cavity, lungs, and skin) and mucosal MCs (gastrointestinal tract and urinary bladder). For the latter case, after intracellular signals are generated, connexins (Cxs) (potentially mediated by Cx43 and/or Cx32) and Panx HCs are eventually activated. Degranulation without constitutive secretions has been demonstrated after complement peptides activation [42,43,44]
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