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Microglial activation, a prominent initiator of neuroinflammation, can be induced through lipopolysaccharide (LPS) treatment resulting in expression of the inducible form of nitric oxide synthase (iNOS), which produces nitric oxide (NO). NO post\u2010translationally modifies cysteine thiols through S\u2010nitrosylation, which can alter function of the target protein. Furthermore, packaging of these NO\u2010modified proteins into extracellular vesicles (EVs) allows for the exertion of NO signalling in distant locations, resulting in further propagation of the neuroinflammatory phenotype. Despite this, the NO\u2010modified proteome of activated microglial EVs has not been investigated. This study aimed to identify the protein post\u2010translational modifications NO signalling induces in neuroinflammation. EVs isolated from LPS\u2010treated microglia underwent mass spectral surface imaging using time of flight\u2010secondary ion mass spectrometry (ToF\u2010SIMS), in addition to iodolabelling and comparative proteomic analysis to identify post\u2010translation S\u2010nitrosylation modifications. ToF\u2010SIMS imaging successfully identified cysteine thiol side chains modified through NO signalling in the LPS treated microglial\u2010derived EV proteins. In addition, the iodolabelling proteomic analysis revealed that the EVs from LPS\u2010treated microglia carried S\u2010nitrosylated proteins indicative of neuroinflammation. These included known NO\u2010modified proteins and those associated with LPS\u2010induced microglial activation that may play an essential role in neuroinflammatory communication. Together, these results show activated microglia can exert broad NO signalling changes through the selective packaging of EVs during neuroinflammation.<\/jats:p>","DOI":"10.1002\/jev2.12455","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T02:48:35Z","timestamp":1718678915000},"source":"Crossref","is-referenced-by-count":12,"title":["Microglial activation induces nitric oxide signalling and alters protein S\u2010nitrosylation patterns in extracellular vesicles"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6554-4496","authenticated-orcid":false,"given":"Natasha","family":"Vassileff","sequence":"first","affiliation":[{"name":"The Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science La Trobe University  Bundoora Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5872-8983","authenticated-orcid":false,"given":"Jereme G.","family":"Spiers","sequence":"additional","affiliation":[{"name":"The Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science La Trobe University  Bundoora Victoria Australia"},{"name":"Clear Vision Research, Eccles Institute of Neuroscience, John Curtin School of Medical Research, College of Health and Medicine The Australian National University  Acton Australia"},{"name":"School of Medicine and Psychology, College of Health and Medicine The Australian National University  Acton Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Bamford","sequence":"additional","affiliation":[{"name":"Centre for Materials and Surface Science and Department of Mathematical and Physical Sciences La Trobe University  Bundoora Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan G. 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