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Dysregulation of \u201cOff\u201d signaling has been reported in both acute and chronic neuroinflammation; however, the influence of inflammatory mediators on this pathway remains underexplored. Here, we investigated whether chronic IL\u20106 or IL\u201010 overexpression modulates microglia\u2013neuron \u201cOff\u201d signaling after FNA, thereby accounting for the previously observed differences in facial motoneuron (FMN) survival and microglial reactivity in transgenic mouse models (GFAP\u2010IL6Tg and GFAP\u2010IL10Tg). To this end, we examined the expression of the neuronal \u201cOff\u201d ligands CD200, CX3CL1, CD47, and CD22, as well as their corresponding microglial \u201cOff\u201d receptors CD200R, CX3CR1, SIRP\u2010\u03b1, and CD45 in non\u2010lesioned and axotomized GFAP\u2010IL6Tg, GFAP\u2010IL10Tg, and WT mice across multiple time points. Our analyses revealed the dynamic regulation of \u201cOff\u201d signaling in both neurons and microglia during microgliosis and FMN phagocytosis and showed temporally restricted strain\u2010specific differences in CD47 expression across genotypes. Chronic IL\u20106 overproduction promoted a more phagocytic microglial phenotype, defined by downregulation of SIRP\u03b1 and CX3CR1 alongside upregulated CD45 in the microglial population. In contrast, chronic IL\u201010 overproduction did not alter the expression of microglial \u201cOff\u201d receptors but induced an IL\u201010 dependent accelerated upregulation of neuronal CD47. Our findings highlight the CD47\u2010SIRP\u03b1 axis as a key regulator of FMN death via microglial phagocytosis and emphasize IL\u201010's neuroprotective potential role through enhanced neuronal CD47 signaling. Overall, this work positions the CD47\u2010SIRP\u03b1 axis as a potential therapeutic target to mitigate neuroinflammation\u2010induced neuronal loss.<\/jats:p>","DOI":"10.1002\/glia.70242","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T04:15:39Z","timestamp":1792469739000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>CD47<\/scp>\n                    \u2013\n                    <scp>SIRP\u03b1<\/scp>\n                    Axis as a Target for Neuroprotection"],"prefix":"10.1002","volume":"74","author":[{"given":"Ariadna Regina","family":"G\u00f3mez\u2010L\u00f3pez","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Physiology and Immunology Institute of Neuroscience, Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9866-271X","authenticated-orcid":false,"given":"Gemma","family":"Manich","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Physiology and Immunology Institute of Neuroscience, Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"},{"name":"Department of Morphological Sciences Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0554-3832","authenticated-orcid":false,"given":"Clara","family":"Penas","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Physiology and Immunology Institute of Neuroscience, Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9454-0734","authenticated-orcid":false,"given":"Judit","family":"Pampalona","sequence":"additional","affiliation":[{"name":"Department of Morphological Sciences Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6513-0250","authenticated-orcid":false,"given":"N\u00e0dia","family":"Villacampa","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Physiology and Immunology Institute of Neuroscience, Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6631-4385","authenticated-orcid":false,"given":"Beatriz","family":"Almolda","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Physiology and Immunology Institute of Neuroscience, Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3104-620X","authenticated-orcid":false,"given":"Emilie","family":"Viennois","sequence":"additional","affiliation":[{"name":"INSERM U1149, Center of Research on Inflammation, Universit\u00e9 Paris Cit\u00e9  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1834-7822","authenticated-orcid":false,"given":"Santiago","family":"Rojas","sequence":"additional","affiliation":[{"name":"Department of Morphological Sciences Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1860-3980","authenticated-orcid":false,"given":"Berta","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Physiology and Immunology Institute of Neuroscience, Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernardo","family":"Castellano","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Physiology and Immunology Institute of Neuroscience, Universitat Aut\u00f2noma de Barcelona  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1006\/exnr.1997.6593"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.161.4.1853"},{"issue":"3","key":"e_1_2_12_4_1","first-page":"939","article-title":"Expression Changes of CX3CL1 and CX3CR1 Proteins in the Hippocampal CA1 Field of the Gerbil Following Transient Global Cerebral Ischemia","volume":"44","author":"Ahn J. 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