{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T06:53:17Z","timestamp":1747205597762,"version":"3.40.5"},"posted":{"date-parts":[[2021,10,12]]},"group-title":"In Review","reference-count":0,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T00:00:00Z","timestamp":1633996800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2021,7,23]]},"abstract":"<title>Abstract<\/title>\n        <p>Microglia, the \u2018resident immunocompetent cells\u2019 of the central nervous system (CNS), are key players in innate immunity, synaptic refinement and homeostasis. Dysfunctional microglia contribute heavily to creating a toxic inflammatory milieu, a driving factor in the pathophysiology of several CNS disorders. Therefore, strategies to modulate the microglial function are required to tackle exacerbated tissue inflammation. Carbon monoxide (CO), an endogenous gaseous molecule produced by the degradation of haem, has anti-inflammatory, anti-apoptotic, pro-homeostatic and cytoprotective roles, among others.ALF826A, a novel molybdenum-based CO-releasing molecule, was used for the assessment of neuron-microglia remote communication. Primary cultures of rat microglia and neurons, or the BV-2 microglial and CAD neuronal murine cell lines, were used to study the microglia-neuron interaction. An approach based on microglial-derived conditioned media in neuronal culture was applied.<bold> <\/bold>Medium derived from CO-treated microglia provided indirect neuroprotection against inflammation by limiting the lipopolysaccharide (LPS)-induced expression of reactivity markers (CD11b), the production of reactive oxygen species (ROS) and the secretion of inflammatory factors (TNF-\u03b1, nitrites). This consequently prevented neuronal cell death and maintained neuronal morphology In contrast, in the absence of inflammatory stimulus, conditioned media from CO-treated microglia improved neuronal morphological complexity, which is an indirect manner of assessing neuronal function. Likewise, the microglial medium also prevented neuronal cell death induced by pro-oxidant <italic>tert<\/italic>-Butyl hydroperoxide (<italic>t<\/italic>-BHP). ALF826 treatment reinforced microglia secretion of Interleukin-10 (IL-10) and adenosine, mediators that may protect against <italic>t<\/italic>-BHP stress in this remote communication model. Chemical inhibition of the adenosine receptors A<sub>2A<\/sub> and A<sub>1<\/sub> reverted the CO-derived neuroprotective effect, further highlighting a role for CO in regulating neuron-microglia communication <italic>via<\/italic> purinergic signalling.Our findings indicate that CO has a modulatory role on microglia-to-neuron communication, promoting neuroprotection in a non-cell autonomous manner. CO enhances the microglial release of neurotrophic factors and blocks exacerbated microglial inflammation. CO improvement of microglial neurotrophism under non-inflammatory conditions is here described for the first time.<\/p>","DOI":"10.21203\/rs.3.rs-745011\/v2","type":"posted-content","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T17:16:53Z","timestamp":1634145413000},"source":"Crossref","is-referenced-by-count":0,"title":["Carbon Monoxide Modulation of Microglia-neuron Communication: Anti-neuroinflammatory and Neurotrophic Role"],"prefix":"10.21203","author":[{"given":"Nuno L.","family":"Soares","sequence":"first","affiliation":[{"name":"NOVA Medical School, Universidade Nova de Lisboa"}]},{"given":"In\u00eas","family":"Paiva","sequence":"additional","affiliation":[{"name":"NOVA Medical School, Universidade Nova de Lisboa"}]},{"given":"Joana","family":"Bravo","sequence":"additional","affiliation":[{"name":"Instituto de Biologia Molecular e Cellular: Instituto de Biologia Molecular e Celular"}]},{"given":"Claudia S. F.","family":"Queiroga","sequence":"additional","affiliation":[{"name":"NOVA Medical School, Universidade Nova de Lisboa"}]},{"given":"Bernadete F.","family":"Melo","sequence":"additional","affiliation":[{"name":"NOVA Medical School, Universidade Nova de Lisboa"}]},{"given":"Silvia V.","family":"Conde","sequence":"additional","affiliation":[{"name":"NOVA Medical School, Universidade Nova de Lisboa"}]},{"given":"Carlos C.","family":"Rom\u00e3o","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica"}]},{"given":"Teresa","family":"Summavielle","sequence":"additional","affiliation":[{"name":"Universidade do Porto"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9415-3742","authenticated-orcid":false,"given":"Helena L.A.","family":"Vieira","sequence":"additional","affiliation":[{"name":"NOVA School of Science and Technology, Universidade Nova de Lisboa"}]}],"member":"297","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-745011\/v2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-745011\/v2.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T03:21:13Z","timestamp":1659064873000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-745011\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,12]]},"references-count":0,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-745011\/v2","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1007\/s12035-021-02643-z","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2021,10,12]]},"subtype":"preprint"}}