The PI3K/AKT/mTOR Pathway Is a Major Intracellular Regulator of Mast Cells Implicated in the Gut–Brain Axis and Mediates Inflammation

Abstract

Phosphoinositide 3-kinase beta (PI3Kβ), phosphatidylinositol (3,4,5)-trisphosphate (PIP3), and phosphatase and TENsin homolog (PTEN) play crucial roles in the remodelling of cell junctions during infection. Remodelling of epithelial and endothelial junctions is a physiological effect aimed at maintaining barrier integrity and enabling adaptive responses to physiological or pathological stimuli. The PI3K/Protein Kinase B (AKT)/mechanistic target of rapamycin (mTOR) signalling pathway, intestinal inflammation, and the gut–brain axis are elements interact with trophic and metabolic neurotransmitters, regulating metabolism, synaptic plasticity, neuronal survival, and protein translation. It has been documented that in mast cells (MCs), activated via FcεRI or cKit, the PI3Kβ pathway induces AKT and activates mechanistic target of rapamycin complex 1 (mTORC1) through protein phosphorylation. Inhibitors of mTORC1 reduce cytokine production and MC chemotaxis, as well as growth and survival. PI3K/AKT/mTORC1 regulates key MC functions such as degranulation, mediator production, development, and migration. MCs are important immune cells in the gut–brain axis, modulating intestinal permeability and neuroinflammation and interacting with neurons. The PI3K/AKT/mTOR pathway is a central cellular signalling axis that has a strong bidirectional link with the gut microbiota. MCs may also contribute to gut–brain axis dysregulation by inducing systemic inflammatory responses. MC activation is mediated by immune signals that potentially activate the intracellular PI3K/AKT/mTOR pathways. When intestinal MCs are activated via PI3K/AKT/mTOR, they can release inflammatory mediators that alter intestinal permeability, activate enteric neurons, and induce neuroinflammation. Cytokines can activate the PI3K/AKT/mTOR pathway, causing the release of histamine, tryptase, interleukin (IL)-1, tumor necrosis factor (TNF), and IL-6, and can increase intestinal and blood–brain barrier (BBB) permeability. The primary goal of this article is to demonstrate that the PI3K/AKT/mTOR pathway is a central hub linking MC activity, inflammation, and gut–brain communication, and to discuss the potential clinical applications of this knowledge. Future prospects aim to translate current knowledge into concrete clinical applications, improving the diagnosis and treatment of complex diseases. We believe that this review presents novel elements and the potential to provide new perspectives in this field.