S100B is a calcium-binding protein concentrated in astrocytes in the Central Nervous System. It is regarded to act as a Damage-Associated Molecular Pattern molecule (for review, 1) and, in this respect, it has also been shown to actively participate in neuroinflammatory processes accompanying Experimental Automimmune Encephalomyelitis (EAE), a recognized animal model for Multiple Sclerosis. In fact both inhibition of S100B activity using pentamidine and of S100B astrocytic synthesis using arundic acid ameliorated clinical and pathologic parameters of the disease (2-4). This study further goes in detail on the role of S100B, and in particular of astrocytic S100B in these neuroinflammatory processes. First, S100B gene was ablated in mice. In fact both clinical and pathologic parameters ameliorated in S100B KO mice when EAE was induced. Then we focused on astrocytes. When S100B synthesis was inhibited in astrocytes isolated from EAE animals using arundic acid, the expression of proinflammatory molecules, such as Tumor Necrosis Factor alpha, was reduced. The present results further individuate astrocytic S100B as a key factor and, as a consequence, a potential therapeutic target for EAE neuroinflammatory processes.1.Michetti F et al. Int J Mol Sci. 2023 May 31;24(11):9605. doi: 10.3390/ijms24119605.2.Di Sante G et al.Cells. 2020 Mar 18;9(3):748. doi: 10.3390/cells9030748.3.Camponeschi C et al. Int J Mol Sci. 2021 Dec 17;22(24):13558. doi: 10.3390/ijms2224135584.Barros, C etal Brain Communications 2022, 4, fcac076, doi:10.1093/braincomms/fcac076.