The Role of S100A8/A9 in Autoimmune Eye Diseases: From Pathogenesis to Targeted Therapy.

The S100 proteins are a group of calcium-binding proteins that are widely expressed in vertebrates and participate in various biological and pathological processes, including cell proliferation, differentiation, inflammation, infection, and autoimmunity. S100A8 and S100A9, members of the S100 family that predominantly exist as heterodimers (S100A8/A9), are primarily localized in myeloid cells such as neutrophils, monocytes, and dendritic cells (DCs). Accumulating studies have identified S100A8/A9 as critical damage-associated molecular patterns (DAMPs) or alarmins. Upon engagement with their receptors, S100A8/A9 can drive the production of cytokines, chemokines, and adhesion factors, thereby initiating and amplifying immune responses. Current literature reports that S100A8/A9 is upregulated in various autoimmune diseases, and targeted inhibition of S100A8/A9 holds significant therapeutic potential for these diseases. Recently, emerging studies have demonstrated a close association between S100A8/A9 and the pathogenesis of autoimmune eye diseases. Elucidating the signaling pathways mediated by S100A8/A9 is critical for the prevention and treatment of these ocular disorders. Therefore, we here summarize the biological characteristics of S100A8/A9 and their roles in the onset and progression of three autoimmune eye diseases, including autoimmune uveitis, Sjögren's dry eye disease (SjDED), and thyroid-associated ophthalmopathy (TAO), with particular emphasis on their utility as diagnostic biomarkers. Furthermore, we discuss current therapeutic strategies targeting S100A8/A9 and propose promising future research directions for S100A8/A9 interventions in autoimmune eye diseases.