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.

Keywords: PI3K; inflammation; microglia; neurodegeneration; signaling pathway.

Figure 1

The PI3K-Akt signaling pathway. The PI3K-Akt pathway is involved in some crucial cellular processes including protein synthesis and cell proliferation and survival. The PI3K/Akt pathway is activated by factors that initiate the PI3K signaling pathway via intermediate molecules (IRS), playing an important regulatory role in many cellular survival pathways. The pathway can be activated by a variety of signals, including growth factors (GF), LPS, and insulin (INS), targeting several downstream molecules. This activation is able to modulate cell activities, including cell proliferation, glucose metabolism, cell survival, cell cycle, protein synthesis, and neuronal morphology and plasticity.

Figure 2

M1/M2 microglia balance depending on PI3K inhibition/activation. Pro-inflammatory microglia (M1) release pro-inflammatory cytokines, which promote neuroinflammation, depending on damage severity and duration. Microglia are able to switch to the anti-inflammatory (M2) phenotype, leading to neuroprotection. The switch and balancing between the M1/M2 phenotype can be regulated by modulating PI3K inhibition/activation.