{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T10:59:25Z","timestamp":1792407565376,"version":"4.4.0"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T00:00:00Z","timestamp":1635465600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T00:00:00Z","timestamp":1635465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["S1311009"],"award-info":[{"award-number":["S1311009"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008732","name":"Uehara Memorial Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008732","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Central nervous system (CNS)-mediated symptoms, such as fatigue, depression, and hyperalgesia, are common complications among patients with rheumatoid arthritis (RA). However, it remains unclear how the peripheral pathology of RA spreads to the brain. Accumulated evidence showing an association between serum cytokine levels and aberrant CNS function suggests that humoral factors participate in this mechanism. In contrast to the well-known early responses of microglia (CNS-resident immune cells) in the area postrema [AP; a brain region lacking a blood\u2013brain barrier (BBB)] to experimental inflammation, microglial alterations in the AP during chronic inflammation like RA remain unclear. Therefore, to determine whether microglia in the AP can react to persistent autoimmune-arthritis conditions, we analyzed these cells in a mouse model of collagen-induced arthritis (CIA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Microglial number and morphology were analyzed in the AP of CIA and control mice (administered Freund\u2019s adjuvant or saline). Immunostaining for ionized calcium-binding adaptor molecule-1 was performed at various disease phases: \u201cpre-onset\u201d [post-immunization day (PID) 21], \u201cestablishment\u201d (PID 35), and \u201cchronic\u201d (PID 56 and 84). Quantitative analyses of microglial number and morphology were performed, with principal component analysis used to classify microglia. Interleukin-1\u03b2 (IL-1\u03b2) mRNA expression was analyzed by multiple fluorescent in situ hybridization and real-time polymerase chain reaction. Behavioral changes were assessed by sucrose preference test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Microglia in the AP significantly increased in density and exhibited changes in morphology during the establishment and chronic phases, but not the pre-onset phase. Non-subjective clustering classification of cell morphology (CIA, 1,256 cells; saline, 852 cells) showed that the proportion of highly activated microglia increased in the CIA group during establishment and chronic phases. Moreover, the density of IL-1\u03b2-positive microglia, a hallmark of functional activation, was increased in the AP. Sucrose preferences in CIA mice negatively correlated with IL-1\u03b2 expression in brain regions containing the AP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings demonstrate that microglia in the AP can sustain their activated state during persistent autoimmune arthritis, which suggests that chronic inflammation, such as RA, may affect microglia in brain regions lacking a BBB and have various neural consequences.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13075-021-02657-x","type":"journal-article","created":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T12:02:33Z","timestamp":1635508953000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Sustained microglial activation in the area postrema of collagen-induced arthritis mice"],"prefix":"10.1186","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1297-6137","authenticated-orcid":false,"given":"Takayuki","family":"Matsushita","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Otani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohsuke","family":"Oto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukari","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daitaro","family":"Kurosaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fusao","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,29]]},"reference":[{"issue":"1","key":"2657_CR1","doi-asserted-by":"publisher","first-page":"2243","DOI":"10.1038\/s41467-018-04648-0","volume":"9","author":"A Schrepf","year":"2018","unstructured":"Schrepf A, Kaplan CM, Ichesco E, Larkin T, Harte SE, Harris RE, et al. A multi-modal MRI study of the central response to inflammation in rheumatoid arthritis. Nat Commun. 2018;9(1):2243.","journal-title":"Nat Commun"},{"issue":"12","key":"2657_CR2","doi-asserted-by":"publisher","first-page":"2136","DOI":"10.1093\/rheumatology\/ket169","volume":"52","author":"F Matcham","year":"2013","unstructured":"Matcham F, Rayner L, Steer S, Hotopf M. The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology. 2013;52(12):2136\u201348.","journal-title":"Rheumatology."},{"issue":"1","key":"2657_CR3","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1002\/acr.23243","volume":"70","author":"T Meade","year":"2018","unstructured":"Meade T, Manolios N, Cumming SR, Conaghan PG, Katz P. Cognitive Impairment in Rheumatoid Arthritis: A Systematic Review. Arthritis Care Res. 2018;70(1):39\u201352.","journal-title":"Arthritis Care Res"},{"key":"2657_CR4","doi-asserted-by":"crossref","unstructured":"Katz P. Fatigue in Rheumatoid Arthritis. Curr Rheumatol Rep. 2017;19(5):25.","DOI":"10.1007\/s11926-017-0649-5"},{"key":"2657_CR5","doi-asserted-by":"crossref","unstructured":"Saitou M, Noda K, Matsushita T, Ukichi T, Kurosaka D. Central sensitisation features are associated with neuropathic pain-like symptoms in patients with longstanding rheumatoid arthritis: a cross-sectional study using the central sensitisation inventory. Clin Exp Rheumatol. 2021. [Epub ahead of print].","DOI":"10.55563\/clinexprheumatol\/msy022"},{"issue":"5","key":"2657_CR6","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1080\/14397595.2017.1416940","volume":"28","author":"M Ishida","year":"2018","unstructured":"Ishida M, Kuroiwa Y, Yoshida E, Sato M, Krupa D, Henry N, et al. Residual symptoms and disease burden among patients with rheumatoid arthritis in remission or low disease activity: a systematic literature review. Mod Rheumatol. 2018;28(5):789\u201399.","journal-title":"Mod Rheumatol"},{"key":"2657_CR7","doi-asserted-by":"publisher","unstructured":"Michaud K, Pope J, van de Laar M, Curtis JR, Kannowski C, Mitchell S, et al. Systematic Literature Review of Residual Symptoms and an Unmet Need in Patients With Rheumatoid Arthritis. Arthritis Care Res. 2020. https:\/\/doi.org\/10.1002\/ACR.24369.","DOI":"10.1002\/ACR.24369"},{"key":"2657_CR8","doi-asserted-by":"crossref","unstructured":"Nerurkar L, Siebert S, McInnes IB, Cavanagh J. Rheumatoid arthritis and depression: an inflammatory perspective. Lancet Psychiatry. 2019;6(2):164\u201373.","DOI":"10.1016\/S2215-0366(18)30255-4"},{"issue":"1","key":"2657_CR9","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1002\/art.20747","volume":"52","author":"RH Straub","year":"2005","unstructured":"Straub RH, Dhabhar FS, Bijlsma JWJ, Cutolo M. How psychological stress via hormones and nerve fibers may exacerbate rheumatoid arthritis. Arthritis Rheum. 2005;52(1):16\u201326.","journal-title":"Arthritis Rheum"},{"issue":"1","key":"2657_CR10","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/sj.npp.1301574","volume":"33","author":"C Pittenger","year":"2008","unstructured":"Pittenger C, Duman RS. Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms. Neuropsychopharmacol. 2008;33(1):88\u2013109.","journal-title":"Neuropsychopharmacol"},{"key":"2657_CR11","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1186\/s12891-016-1011-1","volume":"17","author":"F Matcham","year":"2016","unstructured":"Matcham F, Ali S, Irving K, Hotopf M, Chalder T. Are depression and anxiety associated with disease activity in rheumatoid arthritis? A prospective study. BMC Musculoskelet Disord. 2016;17:155.","journal-title":"BMC Musculoskelet Disord"},{"issue":"2","key":"2657_CR12","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/mp.2016.167","volume":"23","author":"N Kappelmann","year":"2018","unstructured":"Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry. 2018;23(2):335\u201343.","journal-title":"Mol Psychiatry"},{"issue":"12","key":"2657_CR13","doi-asserted-by":"publisher","first-page":"3886","DOI":"10.1002\/art.37686","volume":"64","author":"DB Bas","year":"2012","unstructured":"Bas DB, Su J, Sandor K, Agalave NM, Lundberg J, Codeluppi S, et al. Collagen antibody\u2013induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency. Arthritis Rheum. 2012;64(12):3886\u201396.","journal-title":"Arthritis Rheum"},{"issue":"10","key":"2657_CR14","doi-asserted-by":"publisher","first-page":"5865","DOI":"10.1523\/JNEUROSCI.14-10-05865.1994","volume":"14","author":"C Abbadie","year":"1994","unstructured":"Abbadie C, Besson J, Calvino B. c-Fos expression in the spinal cord and pain-related symptoms induced by chronic arthritis in the rat are prevented by pretreatment with Freund adjuvant. J Neurosci. 1994;14(10):5865\u201371.","journal-title":"J Neurosci"},{"issue":"1","key":"2657_CR15","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s12974-021-02086-2","volume":"18","author":"P-H Lai","year":"2021","unstructured":"Lai P-H, Wang T-H, Zhang N-Y, Wu K-C, Yao C-CJ, Lin C-J. Changes of blood-brain-barrier function and transfer of amyloid beta in rats with collagen-induced arthritis. J Neuroinflammation. 2021;18(1):35.","journal-title":"J Neuroinflammation"},{"issue":"4","key":"2657_CR16","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1046\/j.1471-4159.2003.02097.x","volume":"87","author":"A Nadjar","year":"2003","unstructured":"Nadjar A, Combe C, Lay\u00e9 S, Tridon V, Dantzer R, Am\u00e9d\u00e9e T, et al. Nuclear factor \u03baB nuclear translocation as a crucial marker of brain response to interleukin-1. A study in rat and interleukin-1 type I deficient mouse. J Neurochem. 2003;87(4):1024\u201336.","journal-title":"J Neurochem"},{"issue":"6","key":"2657_CR17","doi-asserted-by":"publisher","first-page":"2657","DOI":"10.1152\/japplphysiol.00822.2001","volume":"92","author":"E-M Harr\u00e9","year":"2002","unstructured":"Harr\u00e9 E-M, Roth J, Pehl U, Kueth M, Gerstberger R, H\u00fcbschle T. Selected Contribution: Role of IL-6 in LPS-induced nuclear STAT3 translocation in sensory circumventricular organs during fever in rats. J Appl Physiol. 2002;92(6):2657\u201366.","journal-title":"J Appl Physiol"},{"issue":"2","key":"2657_CR18","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/S0306-4522(98)00368-6","volume":"89","author":"JP Konsman","year":"1999","unstructured":"Konsman JP, Kelley K, Dantzer R. Temporal and spatial relationships between lipopolysaccharide-induced expression of fos, interleukin-1 \u03b2 and inducible nitric oxide synthase in rat brain. Neuroscience. 1999;89(2):535\u201348.","journal-title":"Neuroscience."},{"issue":"1","key":"2657_CR19","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.jneumeth.2011.08.002","volume":"202","author":"S Miyata","year":"2011","unstructured":"Miyata S, Morita S. A new method for visualization of endothelial cells and extravascular leakage in adult mouse brain using fluorescein isothiocyanate. J Neurosci Methods. 2011;202(1):9\u201316.","journal-title":"J Neurosci Methods"},{"key":"2657_CR20","doi-asserted-by":"crossref","unstructured":"Oto Y, Takahashi Y, Kurosaka D, Kato F. Alterations of voluntary behavior in the course of disease progress and pharmacotherapy in mice with collagen-induced arthritis. Arthritis Res Ther. 2019;21(1):284.","DOI":"10.1186\/s13075-019-2071-z"},{"issue":"1","key":"2657_CR21","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1186\/s12891-016-1243-0","volume":"17","author":"H Ito","year":"2016","unstructured":"Ito H, Noda K, Yoshida K, Otani K, Yoshiga M, Oto Y, et al. Prokineticin 2 antagonist, PKRA7 suppresses arthritis in mice with collagen-induced arthritis. BMC Musculoskelet Disord. 2016;17(1):387.","journal-title":"BMC Musculoskelet Disord"},{"key":"2657_CR22","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.neuropharm.2018.04.023","volume":"137","author":"E Brown","year":"2018","unstructured":"Brown E, Mc Veigh CJ, Santos L, Gogarty M, M\u00fcller HK, Elfving B, et al. TNF\u03b1-dependent anhedonia and upregulation of hippocampal serotonin transporter activity in a mouse model of collagen-induced arthritis. Neuropharmacology. 2018;137:211\u201320.","journal-title":"Neuropharmacology."},{"issue":"2","key":"2657_CR23","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s00441-015-2207-7","volume":"363","author":"S Morita","year":"2016","unstructured":"Morita S, Furube E, Mannari T, Okuda H, Tatsumi K, Wanaka A, et al. Heterogeneous vascular permeability and alternative diffusion barrier in sensory circumventricular organs of adult mouse brain. Cell Tissue Res. 2016;363(2):497\u2013511.","journal-title":"Cell Tissue Res"},{"issue":"6","key":"2657_CR24","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1007\/s00401-010-0743-5","volume":"120","author":"S Sis\u00f3","year":"2010","unstructured":"Sis\u00f3 S, Jeffrey M, Gonz\u00e1lez L. Sensory circumventricular organs in health and disease. Acta Neuropathol. 2010;120(6):689\u2013705.","journal-title":"Acta Neuropathol"},{"issue":"3","key":"2657_CR25","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1038\/bmt.2012.244","volume":"48","author":"Y Kanda","year":"2013","unstructured":"Kanda Y. Investigation of the freely available easy-to-use software \u201cEZR\u201d for medical statistics. Bone Marrow Transplant. 2013;48(3):452\u20138.","journal-title":"Bone Marrow Transplant"},{"issue":"1","key":"2657_CR26","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1186\/s12974-017-0990-7","volume":"14","author":"JG Knoll","year":"2017","unstructured":"Knoll JG, Krasnow SM, Marks DL. Interleukin-1\u03b2 signaling in fenestrated capillaries is sufficient to trigger sickness responses in mice. J Neuroinflammation. 2017;14(1):219.","journal-title":"J Neuroinflammation"},{"key":"2657_CR27","doi-asserted-by":"crossref","unstructured":"Walker FR, Beynon SB, Jones KA, Zhao Z, Kongsui R, Cairns M, et al. Dynamic structural remodelling of microglia in health and disease: A review of the models, the signals and the mechanisms. Brain Behav Immun. 2014;37:1\u201314.","DOI":"10.1016\/j.bbi.2013.12.010"},{"key":"2657_CR28","doi-asserted-by":"crossref","unstructured":"Zhang L, Zhang J, You Z. Switching of the microglial activation phenotype is a possible treatment for depression disorder. Front Cell Neurosci. 2018;12:306.","DOI":"10.3389\/fncel.2018.00306"},{"issue":"11","key":"2657_CR29","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.3899\/jrheum.150478","volume":"42","author":"S Yilmaz-Oner","year":"2015","unstructured":"Yilmaz-Oner S, Ozen G, Can M, Atagunduz P, Direskeneli H, Inanc N. Biomarkers in Remission According to Different Criteria in Patients with Rheumatoid Arthritis. J Rheumatol. 2015;42(11):2066\u201370.","journal-title":"J Rheumatol"},{"issue":"6","key":"2657_CR30","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1111\/1756-185X.13529","volume":"22","author":"Y-C Li","year":"2019","unstructured":"Li Y-C, Chou Y-C, Chen H-C, Lu C-C, Chang D-M. Interleukin-6 and interleukin-17 are related to depression in patients with rheumatoid arthritis. Int J Rheum Dis. 2019;22(6):980\u20135.","journal-title":"Int J Rheum Dis"},{"issue":"2","key":"2657_CR31","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1111\/j.1756-185X.2011.01673.x","volume":"15","author":"Y Liu","year":"2012","unstructured":"Liu Y, Ho RC-M, Mak A. The role of interleukin (IL)-17 in anxiety and depression of patients with rheumatoid arthritis. Int J Rheum Dis. 2012;15(2):183\u20137.","journal-title":"Int J Rheum Dis"},{"issue":"1","key":"2657_CR32","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1186\/s12888-019-2087-6","volume":"19","author":"P Leff Gelman","year":"2019","unstructured":"Leff Gelman P, Mancilla-Herrera I, Flores-Ramos M, Saravia Takashima MF, Cruz Coronel FM, Cruz Fuentes C, et al. The cytokine profile of women with severe anxiety and depression during pregnancy. BMC Psychiatry. 2019;19(1):104.","journal-title":"BMC Psychiatry"},{"issue":"34","key":"2657_CR33","doi-asserted-by":"publisher","first-page":"E7150","DOI":"10.1073\/pnas.1710519114","volume":"114","author":"JG Montoya","year":"2017","unstructured":"Montoya JG, Holmes TH, Anderson JN, Maecker HT, Rosenberg-Hasson Y, Valencia IJ, et al. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci. 2017;114(34):E7150\u20138.","journal-title":"Proc Natl Acad Sci"},{"key":"2657_CR34","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.jad.2018.12.037","volume":"246","author":"R Strawbridge","year":"2019","unstructured":"Strawbridge R, Hodsoll J, Powell TR, Hotopf M, Hatch SL, Breen G, et al. Inflammatory profiles of severe treatment-resistant depression. J Affect Disord. 2019;246:42\u201351.","journal-title":"J Affect Disord"},{"issue":"19","key":"2657_CR35","doi-asserted-by":"publisher","first-page":"9117","DOI":"10.1073\/pnas.89.19.9117","volume":"89","author":"S Kent","year":"1992","unstructured":"Kent S, Bluthe RM, Dantzer R, Hardwick AJ, Kelley KW, Rothwell NJ, et al. Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1. Proc Natl Acad Sci. 1992;89(19):9117\u201320.","journal-title":"Proc Natl Acad Sci"},{"issue":"2","key":"2657_CR36","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.4049\/jimmunol.179.2.1369","volume":"179","author":"K Yanaba","year":"2007","unstructured":"Yanaba K, Hamaguchi Y, Venturi GM, Steeber DA, St Clair EW, Tedder TF. B cell depletion delays collagen-induced arthritis in mice: arthritis induction requires synergy between humoral and cell-mediated immunity. J Immunol. 2007;179(2):1369\u201380.","journal-title":"J Immunol"},{"issue":"6","key":"2657_CR37","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/S0361-9230(98)00045-8","volume":"46","author":"HY Lee","year":"1998","unstructured":"Lee HY, Whiteside MB, Herkenham M. Area postrema removal abolishes stimulatory effects of intravenous interleukin-1\u03b2 on hypothalamic-pituitary-adrenal axis activity and c-fos mRNA in the hypothalamic paraventricular nucleus. Brain Res Bull. 1998;46(6):495\u2013503.","journal-title":"Brain Res Bull"},{"key":"2657_CR38","first-page":"79","volume":"6","author":"S Lee","year":"2010","unstructured":"Lee S, Zhao YQ, Ribeiro-da-Silva A, Zhang J. Distinctive response of CNS glial cells in oro-facial pain associated with injury, infection and inflammation. Mol Pain. 2010;6:79.","journal-title":"Mol Pain"},{"key":"2657_CR39","doi-asserted-by":"crossref","unstructured":"Litvin DG, Denstaedt SJ, Borkowski LF, Nichols NL, Dick TE, Smith CB, et al. Peripheral-to-central immune communication at the area postrema glial-barrier following bleomycin-induced sterile lung injury in adult rats. Brain Behav Immun. 2020;87:610\u201333.","DOI":"10.1016\/j.bbi.2020.02.006"},{"key":"2657_CR40","doi-asserted-by":"crossref","unstructured":"Dempsey E, Abautret-Daly \u00c1, Docherty NG, Medina C, Harkin A. Persistent central inflammation and region specific cellular activation accompany depression- and anxiety-like behaviours during the resolution phase of experimental colitis. Brain Behav Immun. 2019;80:616\u201332.","DOI":"10.1016\/j.bbi.2019.05.007"},{"issue":"6","key":"2657_CR41","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1002\/dneu.22571","volume":"78","author":"EM York","year":"2018","unstructured":"York EM, Bernier L-P, MacVicar BA. Microglial modulation of neuronal activity in the healthy brain. Dev Neurobiol. 2018;78(6):593\u2013603.","journal-title":"Dev Neurobiol"},{"key":"2657_CR42","doi-asserted-by":"crossref","unstructured":"Illes P, Rubini P, Ulrich H, Zhao Y, Tang Y. Regulation of Microglial Functions by Purinergic Mechanisms in the Healthy and Diseased CNS. Cells. 2020;9(5):1108.","DOI":"10.3390\/cells9051108"},{"key":"2657_CR43","doi-asserted-by":"publisher","first-page":"698","DOI":"10.3389\/fimmu.2018.00698","volume":"9","author":"KM Lenz","year":"2018","unstructured":"Lenz KM, Nelson LH. Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function. Front Immunol. 2018;9:698.","journal-title":"Front Immunol"},{"key":"2657_CR44","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.jneuroim.2017.10.008","volume":"331","author":"S Takagi","year":"2019","unstructured":"Takagi S, Furube E, Nakano Y, Morita M, Miyata S. Microglia are continuously activated in the circumventricular organs of mouse brain. J Neuroimmunol. 2019;331:74\u201386.","journal-title":"J Neuroimmunol"},{"issue":"1","key":"2657_CR45","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.jneumeth.2005.01.009","volume":"146","author":"Z Soltys","year":"2005","unstructured":"Soltys Z, Orzylowska-Sliwinska O, Zaremba M, Orlowski D, Piechota M, Fiedorowicz A, et al. Quantitative morphological study of microglial cells in the ischemic rat brain using principal component analysis. J Neurosci Methods. 2005;146(1):50\u201360.","journal-title":"J Neurosci Methods"},{"key":"2657_CR46","doi-asserted-by":"publisher","first-page":"472","DOI":"10.3389\/fncel.2019.00472","volume":"13","author":"M Fernandez-Arjona","year":"2019","unstructured":"Fernandez-Arjona M, Grondona JM, Fern\u00e1ndez-Llebrez P, Lopez-Avalos MD. Microglial morphometric parameters correlate with the expression level of IL-1\u03b2, and allow identifying different activated morphotypes. Front Cell Neurosci. 2019;13:472.","journal-title":"Front Cell Neurosci"},{"issue":"1","key":"2657_CR47","doi-asserted-by":"publisher","first-page":"2203","DOI":"10.1038\/s41598-018-20643-3","volume":"8","author":"E Furube","year":"2018","unstructured":"Furube E, Kawai S, Inagaki H, Takagi S, Miyata S. Brain Region-dependent Heterogeneity and Dose-dependent Difference in Transient Microglia Population Increase during Lipopolysaccharide-induced Inflammation. Sci Rep. 2018;8(1):2203.","journal-title":"Sci Rep"},{"issue":"5","key":"2657_CR48","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1111\/j.1471-4159.2005.03100.x","volume":"93","author":"A Vall\u00e8s","year":"2005","unstructured":"Vall\u00e8s A, Mart\u00ed O, Armario A. Mapping the areas sensitive to long-term endotoxin tolerance in the rat brain: A c-fos mRNA study. J Neurochem. 2005;93(5):1177\u201388.","journal-title":"J Neurochem"},{"key":"2657_CR49","doi-asserted-by":"crossref","unstructured":"Kim SH, Hadley SH, Maddison M, Patil M, Cha B, Kollarik M, et al. Mapping of Sensory Nerve Subsets within the Vagal Ganglia and the Brainstem Using Reporter Mice for Pirt, TRPV1, 5-HT3, and Tac1 Expression. eNeuro. 2020;7(2):ENEURO.0494\u201319.","DOI":"10.1523\/ENEURO.0494-19.2020"},{"issue":"3","key":"2657_CR50","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/S0304-3940(00)01031-4","volume":"285","author":"AM Van Dam","year":"2000","unstructured":"Van Dam AM, Bol JGJM, Gaykema RPA, Goehler LE, Maier SF, Watkins LR, et al. Vagotomy does not inhibit high dose lipopolysaccharide-induced interleukin-1\u03b2 immunoreactivity in rat brain and pituitary gland. Neurosci Lett. 2000;285(3):169\u201372.","journal-title":"Neurosci Lett"},{"issue":"1","key":"2657_CR51","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1002\/jnr.10253","volume":"69","author":"YB Lee","year":"2002","unstructured":"Lee YB, Nagai A, Kim SU. Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res. 2002;69(1):94\u2013103.","journal-title":"J Neurosci Res"},{"key":"2657_CR52","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.brainres.2007.06.016","volume":"1162","author":"C Becskei","year":"2007","unstructured":"Becskei C, Grabler V, Edwards GL, Riediger T, Lutz TA. Lesion of the lateral parabrachial nucleus attenuates the anorectic effect of peripheral amylin and CCK. Brain Res. 2007;1162:76\u201384.","journal-title":"Brain Res"},{"issue":"5","key":"2657_CR53","first-page":"R906","volume":"260","author":"IL Bernstein","year":"1991","unstructured":"Bernstein IL, Taylor EM, Bentson KL. TNF-induced anorexia and learned food aversions are attenuated by area postrema lesions. Am J Phys. 1991;260(5):R906\u201310.","journal-title":"Am J Phys"},{"issue":"3","key":"2657_CR54","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1002\/jcsm.12169","volume":"8","author":"T Borner","year":"2017","unstructured":"Borner T, Arnold M, Ruud J, Breit SN, Langhans W, Lutz TA, et al. Anorexia-cachexia syndrome in hepatoma tumour-bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC-1\/GDF15. J Cachexia Sarcopenia Muscle. 2017;8(3):417\u201327.","journal-title":"J Cachexia Sarcopenia Muscle"},{"issue":"1","key":"2657_CR55","doi-asserted-by":"publisher","first-page":"2722","DOI":"10.1038\/s41598-019-39490-x","volume":"9","author":"CR Boychuk","year":"2019","unstructured":"Boychuk CR, Smith KC, Peterson LE, Boychuk JA, Butler CR, Derera ID, et al. A hindbrain inhibitory microcircuit mediates vagally-coordinated glucose regulation. Sci Rep. 2019;9(1):2722.","journal-title":"Sci Rep"},{"key":"2657_CR56","doi-asserted-by":"crossref","unstructured":"MacDonald AJ, Holmes FE, Beall C, Pickering AE, Ellacott KL. Regulation of food intake by astrocytes in the brainstem dorsal vagal complex. Glia. 2020;68(6):1241\u201354.","DOI":"10.1002\/glia.23774"},{"issue":"10","key":"2657_CR57","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1007\/s10067-010-1524-1","volume":"29","author":"MA Crilly","year":"2010","unstructured":"Crilly MA, Macdonald AG, Williams DJ, Kumar V, Clark HJ. Constitutional symptoms at the onset of rheumatoid arthritis and subsequent arterial stiffness. Clin Rheumatol. 2010;29(10):1113\u20139.","journal-title":"Clin Rheumatol"},{"issue":"5","key":"2657_CR58","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1002\/jcsm.12320","volume":"9","author":"RCE Santo","year":"2018","unstructured":"Santo RCE, Fernandes KZ, Lora PS, Filippin LI, Xavier RM. Prevalence of rheumatoid cachexia in rheumatoid arthritis: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. 2018;9(5):816\u201325.","journal-title":"J Cachexia Sarcopenia Muscle"},{"issue":"2","key":"2657_CR59","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1006\/cimm.1996.0027","volume":"167","author":"KL Sewell","year":"1996","unstructured":"Sewell KL, Breedveld F, Furrie E, O'Brien J, Brinckerhoff C, Dynesius-Trentham R, et al. The effect of minocycline in rat models of inflammatory arthritis: correlation of arthritis suppression with enhanced T cell calcium flux. Cell Immunol. 1996;167(2):195\u2013204.","journal-title":"Cell Immunol"},{"key":"2657_CR60","doi-asserted-by":"crossref","unstructured":"Garcia S, Hartkamp LM, Malvar-Fernandez B, van Es IE, Lin H, Wong J, et al. Colony-stimulating factor (CSF) 1 receptor blockade reduces inflammation in human and murine models of rheumatoid arthritis. Arthritis Res Ther. 2016;18:75.","DOI":"10.1186\/s13075-016-0973-6"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-021-02657-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13075-021-02657-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-021-02657-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,14]],"date-time":"2023-01-14T03:56:37Z","timestamp":1673668597000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/s13075-021-02657-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,29]]},"references-count":60,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2657"],"URL":"https:\/\/doi.org\/10.1186\/s13075-021-02657-x","relation":{},"ISSN":["1478-6362"],"issn-type":[{"value":"1478-6362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,29]]},"assertion":[{"value":"24 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 October 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 October 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Manipulation of animals was approved by the Institutional Animal Care and Use Committee of Jikei University (Approval No. 2018-076). All experiments conformed to the Guidelines for Proper Conduct of Animal Experiments of the Science Council of Japan (2006).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"273"}}