Microglia Mediated Neuroinflammation: Focus on PI3K Modulation

Abstract

Immune activation in the central nervous system involves mostly microglia in response to pathogen invasion or tissue damage, which react, promoting a self-limiting inflammatory response aimed to restore homeostasis. However, prolonged, uncontrolled inflammation may result in the production by microglia of neurotoxic factors that lead to the amplification of the disease state and tissue damage. In particular, specific inducers of inflammation associated with neurodegenerative diseases activate inflammatory processes that result in the production of a number of mediators and cytokines that enhance neurodegenerative processes. Phosphoinositide 3-kinases (PI3Ks) constitute a family of enzymes regulating a wide range of activity, including signal transduction. Recent studies have focused attention on the intracellular role of PI3K and its contribution to neurodegenerative processes. This review illustrates and discusses recent findings about the role of this signaling pathway in the modulation of microglia neuroinflammatory responses linked to neurodegeneration. Finally, we discuss the modulation of PI3K as a potential therapeutic approach helpful for developing innovative therapeutic strategies in neurodegenerative diseases.

The Anti-Neuroinflammatory Role of Anthocyanins and Their Metabolites for the Prevention and Treatment of Brain Disorders

“…During this intracellular signaling cascade, a number of intermediate molecules activate PI3K which, in turn, promotes Akt activation. The phosphorylation of Akt regulates several target proteins implicated in various biological activities, including cell survival, apoptosis, protein synthesis and inflammatory responses [ 92 ]. The PI3K/Akt signaling pathway also involves the contribution of mammalian target of rapamycin (mTOR) protein kinase which increments Akt activity and/or stimulates NF-κB activity, promoting the upregulation of inflammatory genes [ 91 ].…”

“…The PI3K/Akt signaling pathway also involves the contribution of mammalian target of rapamycin (mTOR) protein kinase which increments Akt activity and/or stimulates NF-κB activity, promoting the upregulation of inflammatory genes [ 91 ]. The downregulation of PI3K/Akt-dependent signaling pathways, that culminates in the activation of target proteins such as NF-κB, mTOR or FOXO1, has been related to the inhibition of LPS-induced neuroinflammation [ 92 , 93 , 94 ]. Therefore, these signaling pathways appear to be relevant as therapeutic targets for microglia-mediated neuroinflammation.…”

Mesenchymal Stem Cells Regulate Activation of Microglia Cells to Improve Hippocampal Nerve Damage of Heat Stroke Rats

“…Microglia cells are widely distributed in the CNS and play roles of nutrition, support, antigen presentation and tissue repair in CNS. They are also the main mediators of CNS immune response and play a crucial role in the pathological and physiological processes of the CNS (8)(9)(10)(11). We found that microglial cell activation in the hippocampal vulnerable areas of heat stroke rats was signi cant in early stage (day 1) and middle stage (day 7 and 14), and signi cantly decreased in late stage (day 28).…”

“…In addition to high fever, ischemia, hypoxia and other factors, central nervous system (CNS) in ammatory response also plays an important role in the occurrence and development of heat-stroke-caused brain injury, and the level of such response is signi cantly correlated with nervous system injury, angioedema and neuron death (7). The occurrence and development of CNS in ammatory response are closely related to the microglia, which are widely distributed in the CNS and are involved in the nutrition, support, antigen presentation and tissue repair in the CNS (8)(9)(10)(11). Microglia are also the main medium of CNS immune response and play a crucial role in the pathological and physiological processes of the CNS (8)(9)(10)(11).…”

Extracellular Vesicles miRNA Cargo for Microglia Polarization in Traumatic Brain Injury

“…Microglia, the resident immune cells of the brain, are involved in both essential physiological functions and in pathological conditions of the CNS [ 19 , 20 , 21 ]. Their true origin has been the subject of debate, since previous evidence suggested that microglia differentiate in the bone marrow from embryonic hematopoietic precursor cells.…”