Dark side of glial talk: Role of neuroinflammation in neurodegeneration

Communication between astrocytes and microglia establishes a basis for maintaining cellular homeostasis, metabolic processes, and injury response in the central nervous system. Activation of astrocytes and microglia is a major initial phase of the response of the organism to pathogenic conditions that facilitate immune response causing neuroinflammation. The neuroprotective effects of neuroinflammation manifest in various contexts, including trauma, aging, and neurodegeneration. However, chronic glial reactivity can become a source of progressive central nervous system damage and suppress neuroprotective functions, ultimately exacerbating neurodegenerative diseases. In this scenario, signal transduction by glial cells, combined with mitochondrial dysfunction, leads to the establishment of a self-sustaining cycle of inflammation and metabolic stress. Modulating glial reactivity, correcting mitochondrial impairments, and targeting immune signaling pathways may offer a potential therapeutic strategy. Such interventions could involve suppressing excessive mitochondrial fission and targeting key molecular pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells, mammalian target of rapamycin, and immune receptors such as triggering receptor expressed on myeloid cells 2. The primary goal of such approach would not be complete suppression of neuroinflammation but rather the restoration of balance between pro-and anti-inflammatory programs, promoting the transition of glial cells toward neuroprotective phenotypes that slow neurodegenerative progression.