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Recent evidences showed that systemic inflammation induces increasing cell infiltration within meninges and perivascular spaces in the brain parenchyma, triggering resident microglial and astrocytic activation. The anti\u2010inflammatory enzyme A20, also named TNF associated protein 3 (TNFAIP3), is considered a central gatekeeper in inflammation and peripheral immune system regulation through the inhibition of NF\u2010kB. The TNFAIP3 locus is genetically associated to MS and its transcripts is downregulated in blood cells in treatment\u2010na\u00efve MS patients. Recently, several evidences in mouse models have led to hypothesize a function of A20 also in the CNS. Thus, here we aimed to unveil a possible contribution of A20 to the CNS human MS pathology. By immunohistochemistry\/immunofluorescence and biomolecular techniques on <jats:italic>post\u2010mortem<\/jats:italic> brain tissue blocks obtained from control cases (CC) and progressive MS cases, we demonstrated that A20 is present in CC brain tissues in both white matter (WM) regions, mainly in few parenchymal astrocytes, and in grey matter (GM) areas, in some neuronal populations. Conversely, in MS brain tissues, we observed increased expression of A20 by perivascular infiltrating macrophages, resident\u2010activated astrocytes, and microglia in all the active and chronic active WM lesions. A20 was highly expressed also in the majority of active cortical lesions compared to the neighboring areas of normal\u2010appearing grey matter (NAGM) and control GM, particularly by activated astrocytes. We demonstrated increased A20 expression in the active MS plaques, particularly in macrophages and resident astrocytes, suggesting a key role of this molecule in chronic inflammation.<\/jats:p>","DOI":"10.1111\/bpa.12906","type":"journal-article","created":{"date-parts":[[2020,10,14]],"date-time":"2020-10-14T07:25:37Z","timestamp":1602660337000},"page":"283-296","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Overexpression of the ubiquitin\u2010editing enzyme A20 in the brain lesions of Multiple Sclerosis patients: moving from systemic to central nervous system inflammation"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2317-2564","authenticated-orcid":false,"given":"Simona","family":"Perga","sequence":"first","affiliation":[{"name":"Neuroscience Institute Cavalieri Ottolenghi (NICO) Orbassano Italy"},{"name":"Neurobiology Unit Neurology \u2013 CReSM (Regional Referring 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