Dual role of microglia in neuroinflammation and neurodegenerative diseases

Microglia are the principal innate immune cells of the central nervous system, playing cardinal roles in regulating immunity and mediating neuroinflammation - a chronic inflammatory response occurring in the brain and spinal cord. Microglia exhibit a dual role in this process: they can suppress neuroinflammation through anti-inflammatory polarization or inhibition of proinflammatory intracellular signaling, or conversely, they can exacerbate neuroinflammation via activation of proinflammatory pathways and phenotypes. This seemingly binary behavior is further complicated by a network of internal and external molecular effectors that influence microglial polarization and function, guiding them toward either neuroprotection or neurotoxicity. In this narrative review, we aimed to elucidate the dual role of microglia in neuroinflammation, particularly in the context of neurodegenerative diseases and other brain pathologies. Special emphasis is placed on the most recent findings related to key proteins such as TREM2 (triggering receptor expressed on myeloid cells 2) and HMGB1 (high mobility group box 1 protein). By examining the molecular mechanisms and pathways involving these proteins, we highlight promising therapeutic targets for modulating neuroinflammation and advancing developing novel treatment strategies for neurodegenerative and other brain-related disorders.