{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:41:52Z","timestamp":1768516912901,"version":"3.49.0"},"posted":{"date-parts":[[2024,8,31]]},"group-title":"Neuroscience","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,8,31]],"date-time":"2024-08-31T00:00:00Z","timestamp":1725062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Animal models of stress and stress-related disorders are also associated with blood neutrophilia. The mechanistic relevance of this to symptoms or behavior is unclear. We used cytometry, immunohistochemistry, whole tissue clearing, and single-cell sequencing to characterize the meningeal immune response to chronic social defeat (CSD) stress in mice. We find that chronic, but not acute, stress causes meningeal neutrophil accumulation, and CSD increases neutrophil trafficking in vascular channels emanating from skull bone marrow (BM). Transcriptional analysis suggested CSD increases type I interferon (IFN-I) signaling in meningeal neutrophils. Blocking this pathway via the IFN-I receptor (IFNAR) protected against the anhedonic and anxiogenic effects of CSD stress, potentially through reduced infiltration of IFNAR\n                  <jats:sup>+<\/jats:sup>\n                  neutrophils into the meninges from skull BM. Our identification of IFN-I signaling as a putative mediator of meningeal neutrophil recruitment may facilitate development of new therapies for stress-related disorders.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One sentence summary<\/jats:title>\n                  <jats:p>Type I interferon sensing neutrophils accumulate in meninges of psychosocially stressed mice via skull bone marrow channels and are associated with the negative behavioral sequelae of stress; blockade of this pathway inhibits neutrophil trafficking and improves behavioral outcomes.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.08.30.610447","type":"posted-content","created":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T04:05:11Z","timestamp":1725163511000},"source":"Crossref","is-referenced-by-count":1,"title":["Chronic social defeat stress induces meningeal neutrophilia via type I interferon signaling"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2636-0648","authenticated-orcid":false,"given":"Stacey L.","family":"Kigar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1939-7525","authenticated-orcid":false,"given":"Mary-Ellen","family":"Lynall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allison E.","family":"DePuyt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Atkinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia H.","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5662-3758","authenticated-orcid":false,"given":"Joshua D.","family":"Samuels","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9607-1721","authenticated-orcid":false,"given":"Nicole E.","family":"Eassa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9643-3457","authenticated-orcid":false,"given":"Chelsie N.","family":"Poffenberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael L.","family":"Lehmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel J.","family":"Listwak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ferenc","family":"Livak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdel G.","family":"Elkahloun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3340-9828","authenticated-orcid":false,"given":"Menna R.","family":"Clatworthy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8955-8283","authenticated-orcid":false,"given":"Edward T.","family":"Bullmore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2228-4238","authenticated-orcid":false,"given":"Miles","family":"Herkenham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024090322401100000_2024.08.30.610447v1.1","first-page":"9","article-title":"Elevated Inflammation Levels in Depressed Adults With a History of Childhood Maltreatment","volume":"65","year":"2008","journal-title":"Arch. Gen. Psychiatry"},{"key":"2024090322401100000_2024.08.30.610447v1.2","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.jpsychires.2017.03.015","article-title":"Gene expression in blood of children and adolescents: Mediation between childhood maltreatment and major depressive disorder","volume":"92","year":"2017","journal-title":"J. Psychiatr. Res"},{"key":"2024090322401100000_2024.08.30.610447v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2006.09.006"},{"key":"2024090322401100000_2024.08.30.610447v1.4","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/j.bbi.2020.02.010","article-title":"Inflammatory markers in depression: A meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls","volume":"87","year":"2020","journal-title":"Brain. Behav. Immun"},{"key":"2024090322401100000_2024.08.30.610447v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2007.05.026"},{"key":"2024090322401100000_2024.08.30.610447v1.6","doi-asserted-by":"publisher","DOI":"10.1159\/000201718"},{"key":"2024090322401100000_2024.08.30.610447v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2014.06.200"},{"key":"2024090322401100000_2024.08.30.610447v1.8","doi-asserted-by":"crossref","unstructured":"Magri, C. et al. Alterations observed in the interferon \u03b1 and \u03b2 signaling pathway in MDD patients are marginally influenced by cis-acting alleles. Sci. Rep. 11, 727 (2021).","DOI":"10.1038\/s41598-020-80374-2"},{"key":"2024090322401100000_2024.08.30.610447v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2013.161"},{"key":"2024090322401100000_2024.08.30.610447v1.10","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.pnpbp.2018.03.012","article-title":"Neutrophil\/lymphocyte ratio and platelet\/lymphocyte ratio in mood disorders: A meta-analysis","volume":"84","year":"2018","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"2024090322401100000_2024.08.30.610447v1.11","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.psychres.2018.08.007","article-title":"Increased neutrophil-lymphocyte ratios in depressive adolescents is correlated with the severity of depression","volume":"268","year":"2018","journal-title":"Psychiatry Res"},{"key":"2024090322401100000_2024.08.30.610447v1.12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M405883200"},{"key":"2024090322401100000_2024.08.30.610447v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.11.055"},{"key":"2024090322401100000_2024.08.30.610447v1.14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2003603117"},{"key":"2024090322401100000_2024.08.30.610447v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3589"},{"key":"2024090322401100000_2024.08.30.610447v1.16","doi-asserted-by":"crossref","unstructured":"Ao, T. et al. Local sympathetic neurons promote neutrophil egress from the bone marrow at the onset of acute inflammation. Int. Immunol. 10 (2020).","DOI":"10.1093\/intimm\/dxaa025"},{"key":"2024090322401100000_2024.08.30.610447v1.17","doi-asserted-by":"publisher","DOI":"10.1080\/10615806.2015.1005078"},{"key":"2024090322401100000_2024.08.30.610447v1.18","first-page":"185","article-title":"Peripheral Blood Cell-Stratified Subgroups of Inflamed Depression","volume":"88","year":"2019","journal-title":"Biol. Psychiatry"},{"key":"2024090322401100000_2024.08.30.610447v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/nature18626"},{"key":"2024090322401100000_2024.08.30.610447v1.20","doi-asserted-by":"crossref","unstructured":"Ribeiro, M. et al. Meningeal \u03b3\u03b4 T cell\u2013derived IL-17 controls synaptic plasticity and short-term memory. Sci. Immunol. 4, (2019).","DOI":"10.1126\/sciimmunol.aay5199"},{"key":"2024090322401100000_2024.08.30.610447v1.21","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.bbi.2021.08.002","article-title":"B-cells are abnormal in psychosocial stress and regulate meningeal myeloid cell activation","volume":"97","year":"2021","journal-title":"Brain. Behav. Immun"},{"key":"2024090322401100000_2024.08.30.610447v1.22","doi-asserted-by":"crossref","unstructured":"Lehmann, M. L. et al. Decoding microglia responses to psychosocial stress reveals blood-brain barrier breakdown that may drive stress susceptibility. Sci. Rep. 8, 11240 (2018).","DOI":"10.1038\/s41598-018-28737-8"},{"key":"2024090322401100000_2024.08.30.610447v1.23","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.bbi.2022.01.011","article-title":"CCR2 monocytes repair cerebrovascular damage caused by chronic social defeat stress","volume":"101","year":"2022","journal-title":"Brain. Behav. Immun"},{"key":"2024090322401100000_2024.08.30.610447v1.24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0069822"},{"key":"2024090322401100000_2024.08.30.610447v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01487-1"},{"key":"2024090322401100000_2024.08.30.610447v1.26","doi-asserted-by":"crossref","unstructured":"Herisson, F. et al. Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat. Neurosci. 21, 14 (2018).","DOI":"10.1038\/s41593-018-0213-2"},{"key":"2024090322401100000_2024.08.30.610447v1.27","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf7844"},{"key":"2024090322401100000_2024.08.30.610447v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.07.009"},{"key":"2024090322401100000_2024.08.30.610447v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.02.002"},{"key":"2024090322401100000_2024.08.30.610447v1.30","doi-asserted-by":"publisher","DOI":"10.1101\/792200"},{"key":"2024090322401100000_2024.08.30.610447v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22973-9"},{"key":"2024090322401100000_2024.08.30.610447v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01576-3"},{"key":"2024090322401100000_2024.08.30.610447v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01490-5"},{"key":"2024090322401100000_2024.08.30.610447v1.34","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1182\/blood.V39.3.301.301","article-title":"Alteration of the Cell Periphery During Granulocyte Maturation: Relationship to Cell Function","volume":"39","year":"1972","journal-title":"Blood"},{"key":"2024090322401100000_2024.08.30.610447v1.35","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-199812000-00021"},{"key":"2024090322401100000_2024.08.30.610447v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2008.08.010"},{"key":"2024090322401100000_2024.08.30.610447v1.37","doi-asserted-by":"crossref","first-page":"201","DOI":"10.4049\/jimmunol.137.1.201","article-title":"Phenotypic changes induced by interferon in resting T cells: major enhancement of Ly-6 antigen expression","volume":"137","year":"1986","journal-title":"J. Immunol"},{"key":"2024090322401100000_2024.08.30.610447v1.38","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15203"},{"key":"2024090322401100000_2024.08.30.610447v1.39","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41586-023-06993-7","article-title":"Identification of direct connections between the dura and the brain","volume":"627","year":"2024","journal-title":"Nature"},{"key":"2024090322401100000_2024.08.30.610447v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(95)90157-4"},{"key":"2024090322401100000_2024.08.30.610447v1.41","doi-asserted-by":"crossref","unstructured":"Aslanidis, A. et al. Activated microglia\/macrophage whey acidic protein (AMWAP) inhibits NF\u03baB signaling and induces a neuroprotective phenotype in microglia. J. Neuroinflammation 12, 77 (2015).","DOI":"10.1186\/s12974-015-0296-6"},{"key":"2024090322401100000_2024.08.30.610447v1.42","doi-asserted-by":"crossref","first-page":"e13470","DOI":"10.1111\/acel.13470","article-title":"Type I Interferon signaling controls the accumulation and transcriptomes of monocytes in the aged lung","volume":"20","year":"2021","journal-title":"Aging Cell"},{"key":"2024090322401100000_2024.08.30.610447v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2011.12.078"},{"key":"2024090322401100000_2024.08.30.610447v1.44","doi-asserted-by":"crossref","unstructured":"Kupa, L. D. V. K. et al. Role of Translocator 18 KDa Ligands in the Activation of Leukotriene B4 Activated G-Protein Coupled Receptor and Toll Like Receptor-4 Pathways in Neutrophils. Front. Pharmacol. 8, 766 (2017).","DOI":"10.3389\/fphar.2017.00766"},{"key":"2024090322401100000_2024.08.30.610447v1.45","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0212099"},{"key":"2024090322401100000_2024.08.30.610447v1.46","doi-asserted-by":"crossref","unstructured":"Trzeciak, A. et al. Neutrophil heterogeneity in complement C1q expression associated with sepsis mortality. Front. Immunol. 13, 965305 (2022).","DOI":"10.3389\/fimmu.2022.965305"},{"key":"2024090322401100000_2024.08.30.610447v1.47","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200154"},{"key":"2024090322401100000_2024.08.30.610447v1.48","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2022008834"},{"key":"2024090322401100000_2024.08.30.610447v1.49","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62636"},{"key":"2024090322401100000_2024.08.30.610447v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2020.05.030"},{"key":"2024090322401100000_2024.08.30.610447v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0086-2"},{"key":"2024090322401100000_2024.08.30.610447v1.52","doi-asserted-by":"crossref","unstructured":"Santos-Lima, B. , Pietronigro, E. C. , Terrabuio, E. , Zenaro, E. & Constantin, G . The role of neutrophils in the dysfunction of central nervous system barriers. Front. Aging Neurosci. 14, 965169 (2022).","DOI":"10.3389\/fnagi.2022.965169"},{"key":"2024090322401100000_2024.08.30.610447v1.53","unstructured":"Otxoa-de-Amezaga, A . Microglial cell loss after ischemic stroke favors brain neutrophil accumulation. Acta Neuropathol. (Berl .) 21 (2019)."},{"key":"2024090322401100000_2024.08.30.610447v1.54","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1091\/mbc.E19-02-0126","article-title":"Spindle\u2013F-actin interactions in mitotic spindles in an intact vertebrate epithelium","volume":"30","year":"2019","journal-title":"Mol. Biol. Cell"},{"key":"2024090322401100000_2024.08.30.610447v1.55","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.bbi.2024.06.011","article-title":"CD177 on neutrophils engages stress-related behavioral changes in male mice","volume":"120","year":"2024","journal-title":"Brain. Behav. Immun"},{"key":"2024090322401100000_2024.08.30.610447v1.56","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0329-4"},{"key":"2024090322401100000_2024.08.30.610447v1.57","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/gps.5444","article-title":"Comparison of poststroke depression between acute ischemic and hemorrhagic stroke patients","volume":"36","year":"2021","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"2024090322401100000_2024.08.30.610447v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3223(02)01348-3"},{"key":"2024090322401100000_2024.08.30.610447v1.59","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.neuint.2017.06.009","article-title":"Type-I interferon signalling through IFNAR1 plays a deleterious role in the outcome after stroke","volume":"108","year":"2017","journal-title":"Neurochem. Int"},{"key":"2024090322401100000_2024.08.30.610447v1.60","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1172\/JCI133737","article-title":"Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease","volume":"130","year":"2020","journal-title":"J. Clin. Invest"},{"key":"2024090322401100000_2024.08.30.610447v1.61","doi-asserted-by":"crossref","unstructured":"Elser, H. et al. Association of Early-, Middle-, and Late-Life Depression With Incident Dementia in a Danish Cohort. JAMA Neurol. 80, 949 (2023).","DOI":"10.1001\/jamaneurol.2023.2309"},{"key":"2024090322401100000_2024.08.30.610447v1.62","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2011.361"},{"key":"2024090322401100000_2024.08.30.610447v1.63","doi-asserted-by":"publisher","DOI":"10.1001\/archpsyc.1994.03950010008002"},{"key":"2024090322401100000_2024.08.30.610447v1.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.jadohealth.2016.06.012"},{"key":"2024090322401100000_2024.08.30.610447v1.65","doi-asserted-by":"crossref","unstructured":"Takahashi, A. et al. Establishment of a repeated social defeat stress model in female mice. Sci. Rep. 7, 12838 (2017).","DOI":"10.1038\/s41598-017-12811-8"},{"key":"2024090322401100000_2024.08.30.610447v1.66","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2017.259"},{"key":"2024090322401100000_2024.08.30.610447v1.67","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.neubiorev.2020.02.025","article-title":"The role of physical trauma in social stress-induced immune activation","volume":"113","year":"2020","journal-title":"Neurosci. Biobehav. Rev"},{"key":"2024090322401100000_2024.08.30.610447v1.68","doi-asserted-by":"crossref","unstructured":"Faust, N. , Varas, F. , Kelly, L. M. , Heck, S. & Graf, T . Insertion of enhanced green fluorescent protein into the lysozyme gene creates mice with green fluorescent granulocytes and macrophages. Blood 96, 8 (2000).","DOI":"10.1182\/blood.V96.2.719"},{"key":"2024090322401100000_2024.08.30.610447v1.69","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"2024090322401100000_2024.08.30.610447v1.70","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.085"},{"key":"2024090322401100000_2024.08.30.610447v1.71","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.07.056"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.08.30.610447","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:58:26Z","timestamp":1768460306000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.08.30.610447"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,31]]},"references-count":71,"URL":"https:\/\/doi.org\/10.1101\/2024.08.30.610447","relation":{},"subject":[],"published":{"date-parts":[[2024,8,31]]},"subtype":"preprint"}}