Targeting S100A8/A9: a molecular gateway to oral inflammation, microglial activation and neuroinflammation.

S100A8 and S100A9 are critical members of the S100 protein family with diverse immunoregulatory functions, serving as important mediators of neuroimmune communication and key links between inflammation, microglial activation, and neurodegenerative processes. S100A8 and S100A9 are abundantly expressed in neutrophils, monocytes, and other immune cells and are rapidly released during inflammatory responses. Once extracellular, S100A8/A9 interacts with cell-surface pattern-recognition receptors, including TLR4 and RAGE, triggering downstream NF-κB and MAPK signaling cascades that drive pro-inflammatory cytokine production. S100A8/A9 has also been implicated in activating the intracellular NLRP3 inflammasome sensor/scaffold, a pro-inflammatory response associated with neuroinflammation. Growing evidence indicates that dysregulated S100A8/A9 expression contributes to both central and peripheral inflammatory pathologies and is elevated across multiple disease states. This review provides a comprehensive analysis of the S100A8/A9 signaling axis, examining its structural and functional roles in regulating microglial activation and neuroimmune crosstalk. It further explores the role of S100A8/A9 signaling in the pathogenesis of diverse inflammatory and neurodegenerative disorders, highlighting the underlying molecular mechanisms. By integrating current knowledge, this review highlights the therapeutic potential of targeting the S100A8/A9 to modulate neuroinflammation and facilitate the development of more effective interventions for neurodegenerative diseases.