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The current study reveals that trauma induces the augmented release of a transcriptionally distinct CD115<jats:sup>+<\/jats:sup>\/Ly6C<jats:sup>hi<\/jats:sup> monocyte population into the circulation of mice pre-exposed to clodronate depletion conditions. This phenomenon correlates with tissue protection, blood\u2013brain barrier stability, and cerebral blood flow improvement. Uniquely, this shifted the innate immune cell profile in the cortical milieu and reduced the expression of pro-inflammatory Il6, IL1r1, MCP-1, Cxcl1, and Ccl3 cytokines. Monocytes that emerged under these conditions displayed a morphological and gene profile consistent with a subset commonly seen during emergency monopoiesis. Single-cell RNA sequencing delineated distinct clusters of monocytes and revealed a key transcriptional signature of Ly6C<jats:sup>hi<\/jats:sup> monocytes enriched for <jats:italic>Apoe<\/jats:italic> and chitinase-like protein 3 (<jats:italic>Chil3<\/jats:italic>\/Ym1), commonly expressed in pro-resolving immunoregulatory monocytes, as well as granule genes <jats:italic>Elane<\/jats:italic>,<jats:italic> Prtn3<\/jats:italic>,<jats:italic> MPO<\/jats:italic>, and <jats:italic>Ctsg<\/jats:italic> unique to neutrophil-like monocytes. The predominate shift in cell clusters included subsets with low expression of transcription factors involved in monocyte conversion, <jats:italic>Pou2f2<\/jats:italic>, <jats:italic>Na4a1,<\/jats:italic> and a robust enrichment of genes in the oxidative phosphorylation pathway which favors an anti-inflammatory phenotype. Transfer of this monocyte assemblage into brain-injured recipient mice demonstrated their direct role in neuroprotection. These findings reveal a multifaceted innate immune response to brain injury and suggest targeting surrogate monocyte subsets may foster tissue protection in the brain.<\/jats:p>","DOI":"10.1186\/s12974-024-03032-8","type":"journal-article","created":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T13:02:32Z","timestamp":1706965352000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Immunoregulatory and neutrophil-like monocyte subsets with distinct single-cell transcriptomic signatures emerge following brain injury"],"prefix":"10.1186","volume":"21","author":[{"given":"Erwin K.","family":"Gudenschwager Basso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman","family":"Soliman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"de Jager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoran","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Pridham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L.","family":"Olsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle H.","family":"Theus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,3]]},"reference":[{"issue":"3","key":"3032_CR1","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/nrneurol.2017.13","volume":"13","author":"DW Simon","year":"2017","unstructured":"Simon DW, et al. 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The\u00a0effects of sterile brain injury on their phenotypic identity and recruitment, under emergency conditions were studied at the single-cell level. Our work has uncovered a novel immunoregulatory state that may be sufficient to provide neuroprotection.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Significance statement"}},{"value":"The authors have declared that no conflict of interest exists. The authors declare no competing financial interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"41"}}