{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T02:42:47Z","timestamp":1781836967572,"version":"3.54.5"},"reference-count":78,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,18]],"date-time":"2023-03-18T00:00:00Z","timestamp":1679097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Education, University and Research","award":["2017XKJTLW_001"],"award-info":[{"award-number":["2017XKJTLW_001"]}]},{"name":"Italian Ministry of Education, University and Research","award":["2015KRYSJN"],"award-info":[{"award-number":["2015KRYSJN"]}]},{"name":"University of Calabria","award":["2017XKJTLW_001"],"award-info":[{"award-number":["2017XKJTLW_001"]}]},{"name":"University of Calabria","award":["2015KRYSJN"],"award-info":[{"award-number":["2015KRYSJN"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The identification of novel targets to modulate the immune response triggered by cerebral ischemia is crucial to promote the development of effective stroke therapeutics. Since tumour necrosis factor (TNF)-\u03b1-stimulated gene 6 (TSG-6), a hyaluronate (HA)-binding protein, is involved in the regulation of immune and stromal cell functions in acute neurodegeneration, we aimed to characterize its involvement in ischemic stroke. Transient middle cerebral artery occlusion (1 h MCAo, followed by 6 to 48 of reperfusion) in mice resulted in a significant elevation in cerebral TSG-6 protein levels, mainly localized in neurons and myeloid cells of the lesioned hemisphere. These myeloid cells were clearly infiltrating from the blood, strongly suggesting that brain ischemia also affects TSG-6 in the periphery. Accordingly, TSG-6 mRNA expression was elevated in peripheral blood mononuclear cells (PBMCs) from patients 48 h after ischemic stroke onset, and TSG-6 protein expression was higher in the plasma of mice subjected to 1 h MCAo followed by 48 h of reperfusion. Surprisingly, plasma TSG-6 levels were reduced in the acute phase (i.e., within 24 h of reperfusion) when compared to sham-operated mice, supporting the hypothesis of a detrimental role of TSG-6 in the early reperfusion stage. Accordingly, systemic acute administration of recombinant mouse TSG-6 increased brain levels of the M2 marker Ym1, providing a significant reduction in the brain infarct volume and general neurological deficits in mice subjected to transient MCAo. These findings suggest a pivotal role of TSG-6 in ischemic stroke pathobiology and underscore the clinical relevance of further investigating the mechanisms underlying its immunoregulatory role.<\/jats:p>","DOI":"10.3390\/ijms24065800","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T04:33:31Z","timestamp":1679286811000},"page":"5800","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Characterization of the Involvement of Tumour Necrosis Factor (TNF)-\u03b1-Stimulated Gene 6 (TSG-6) in Ischemic Brain Injury Caused by Middle Cerebral Artery Occlusion in Mouse"],"prefix":"10.3390","volume":"24","author":[{"given":"Chiara","family":"Di Santo","sequence":"first","affiliation":[{"name":"Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"La Russa","sequence":"additional","affiliation":[{"name":"Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosaria","family":"Greco","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, PV, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Persico","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, PV, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Zanaboni","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, Via Mondino 2, 27100 Pavia, PV, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8540-6218","authenticated-orcid":false,"given":"Giacinto","family":"Bagetta","sequence":"additional","affiliation":[{"name":"Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7513-3495","authenticated-orcid":false,"given":"Diana","family":"Amantea","sequence":"additional","affiliation":[{"name":"Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, CS, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S1474-4422(21)00252-0","article-title":"Global, regional, and national burden of stroke and its risk factors, 1990\u20132019: A systematic analysis for the Global Burden of Disease Study 2019","volume":"20","author":"Feigin","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1016\/S0140-6736(20)32163-2","article-title":"Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: Systematic review and meta-analysis of individual patient data","volume":"396","author":"Thomalla","year":"2020","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1056\/NEJMoa1813046","article-title":"Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke","volume":"380","author":"Ma","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1056\/NEJMoa0804656","article-title":"Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke","volume":"359","author":"Hacke","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1007\/s12975-020-00879-w","article-title":"Recanalization Therapy for Acute Ischemic Stroke with Large Vessel Occlusion: Where We Are and What Comes Next?","volume":"12","author":"Shafie","year":"2021","journal-title":"Transl. Stroke Res."},{"key":"ref_6","unstructured":"Amantea, D., and Greco, R. (2022). Comprehensive Pharmacology, Elsevier."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Haupt, M., Gerner, S.T., B\u00e4hr, M., and Doeppner, T.R. (2022). Quest for Quality in Translational Stroke Research\u2014A New Dawn for Neuroprotection?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105381"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/S1474-4422(16)00114-9","article-title":"Neuroprotection in acute stroke: Targeting excitotoxicity, oxidative and nitrosative stress, and inflammation","volume":"15","author":"Chamorro","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"241","DOI":"10.3389\/fnins.2018.00241","article-title":"Paradigm Shift to Neuroimmunomodulation for Translational Neuroprotection in Stroke","volume":"12","author":"Amantea","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1161\/CIRCRESAHA.121.319994","article-title":"Immune Pathways in Etiology, Acute Phase, and Chronic Sequelae of Ischemic Stroke","volume":"130","author":"Endres","year":"2022","journal-title":"Circ. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Frank, D., Zlotnik, A., Boyko, M., and Gruenbaum, B.F. (2022). The Development of Novel Drug Treatments for Stroke Patients: A Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105796"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1172\/JCI135530","article-title":"Immune responses to stroke: Mechanisms, modulation, and therapeutic potential","volume":"130","author":"Iadecola","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"825834","DOI":"10.3389\/fimmu.2022.825834","article-title":"Ischemic Preconditioning Modulates the Peripheral Innate Immune System to Promote Anti-Inflammatory and Protective Responses in Mice Subjected to Focal Cerebral Ischemia","volume":"13","author":"Amantea","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"La Russa, D., Di Santo, C., Lizasoain, I., Moraga, A., Bagetta, G., and Amantea, D. (2022). Tumor necrosis factor (TNF)-\u03b1-stimulated gene 6 (TSG-6): A promising immunomodulatory target in acute neurodegenerative diseases. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021162"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6593","DOI":"10.4049\/jimmunol.151.11.6593","article-title":"TSG-6: A TNF-, IL-1-, and LPS-inducible secreted glycoprotein associated with arthritis","volume":"151","author":"Wisniewski","year":"1993","journal-title":"J. Immunol."},{"key":"ref_16","first-page":"6561","article-title":"NF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1","volume":"14","author":"Klampfer","year":"1994","journal-title":"Mol. Cell. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1083\/jcb.116.2.545","article-title":"A novel secretory tumor necrosis factor-inducible protein (TSG-6) is a member of the family of hyaluronate binding proteins, closely related to the adhesion receptor CD44","volume":"116","author":"Lee","year":"1992","journal-title":"J. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.2337\/db13-1658","article-title":"Hyaluronan and Hyaluronan-Binding Proteins Accumulate in Both Human Type 1 Diabetic Islets and Lymphoid Tissues and Associate with Inflammatory Cells in Insulitis","volume":"63","author":"Bogdani","year":"2014","journal-title":"Diabetes"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/j.1468-3083.2010.03792.x","article-title":"Characterization of hyaluronan and TSG-6 in skin scarring: Differential distribution in keloid scars, normal scars and unscarred skin","volume":"25","author":"Tan","year":"2011","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12433","DOI":"10.1074\/jbc.M112.342873","article-title":"Constitutive Expression of Inter-\u03b1-inhibitor (I\u03b1I) Family Proteins and Tumor Necrosis Factor-stimulated Gene-6 (TSG-6) by Human Amniotic Membrane Epithelial and Stromal Cells Supporting Formation of the Heavy Chain-Hyaluronan (HC-HA) Complex","volume":"287","author":"Zhang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19939","DOI":"10.1074\/jbc.M115.710673","article-title":"Tumor Necrosis Factor-stimulated Gene-6 (TSG-6) Is Constitutively Expressed in Adult Central Nervous System (CNS) and Associated with Astrocyte-mediated Glial Scar Formation following Spinal Cord Injury","volume":"291","author":"Lauer","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1242\/jcs.00407","article-title":"TSG-6: A multifunctional protein associated with inflammation","volume":"116","author":"Milner","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.matbio.2018.01.011","article-title":"TSG-6: A multifunctional protein with anti-inflammatory and tissue-protective properties","volume":"78\u201379","author":"Day","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"25745","DOI":"10.1074\/jbc.M313319200","article-title":"TSG-6 Modulates the Interaction between Hyaluronan and Cell Surface CD44","volume":"279","author":"Lesley","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2048","DOI":"10.2337\/db12-0931","article-title":"TSG-6 Produced by hMSCs Delays the Onset of Autoimmune Diabetes by Suppressing Th1 Development and Enhancing Tolerogenicity","volume":"62","author":"Kota","year":"2013","journal-title":"Diabetes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"25675","DOI":"10.1074\/jbc.M111.247395","article-title":"The Inflammation-associated Protein TSG-6 Cross-links Hyaluronan via Hyaluronan-induced TSG-6 Oligomers","volume":"286","author":"Baranova","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1182\/blood-2010-12-327353","article-title":"Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2\/NF-\u03baB signaling in resident macrophages","volume":"118","author":"Choi","year":"2011","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"30481","DOI":"10.1074\/jbc.M114.568154","article-title":"Incorporation of Pentraxin 3 into Hyaluronan Matrices Is Tightly Regulated and Promotes Matrix Cross-linking","volume":"289","author":"Baranova","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"29642","DOI":"10.1074\/jbc.M113.477422","article-title":"Inter-\u03b1-inhibitor Impairs TSG-6-induced Hyaluronan Cross-linking","volume":"288","author":"Baranova","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"23465","DOI":"10.1074\/jbc.M114.557447","article-title":"Umbilical Cord Mesenchymal Stem Cells Suppress Host Rejection","volume":"289","author":"Gesteira","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/978-1-4939-1714-3_42","article-title":"Analysis of the Heavy-Chain Modification and TSG-6 Activity in Pathological Hyaluronan Matrices","volume":"1229","author":"Lauer","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"175909142110106","DOI":"10.1177\/17590914211010628","article-title":"Human Umbilical Cord Mesenchymal Stem Cells-Secreted TSG-6 Is Anti-Inflammatory and Promote Tissue Repair After Spinal Cord Injury","volume":"13","author":"Liao","year":"2021","journal-title":"ASN Neuro"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1007\/s11064-021-03375-1","article-title":"Tumor Necrosis Factor-stimulated Gene-6 (TSG-6) Secreted by BMSCs Regulates Activated Astrocytes by Inhibiting NF-\u03baB Signaling Pathway to Ameliorate Blood Brain Barrier Damage After Intracerebral Hemorrhage","volume":"46","author":"Tang","year":"2021","journal-title":"Neurochem. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1186\/s12974-018-1279-1","article-title":"TSG-6 attenuates inflammation-induced brain injury via modulation of microglial polarization in SAH rats through the SOCS3\/STAT3 pathway","volume":"15","author":"Li","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.nbd.2013.06.017","article-title":"Administration of TSG-6 improves memory after traumatic brain injury in mice","volume":"59","author":"Watanabe","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Roura, S., Mongui\u00f3-Tortajada, M., Munizaga-Larroud\u00e9, M., Clos-Sansalvador, M., Franquesa, M., Rosell, A., and Borr\u00e0s, F.E. (2020). Potential of Extracellular Vesicle-Associated TSG-6 from Adipose Mesenchymal Stromal Cells in Traumatic Brain Injury. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186761"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1038\/aps.2012.199","article-title":"Mesenchymal stem cells transplantation suppresses inflammatory responses in global cerebral ischemia: Contribution of TNF-\u03b1-induced protein 6","volume":"34","author":"Lin","year":"2013","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/1742-2094-10-106","article-title":"Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury","volume":"10","author":"Zhang","year":"2013","journal-title":"J. Neuroinflamm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1093\/brain\/awl139","article-title":"Changes in hyaluronan production and metabolism following ischaemic stroke in man","volume":"129","year":"2006","journal-title":"Brain"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"713379","DOI":"10.3389\/fimmu.2022.713379","article-title":"Plasma Concentration of Tumor Necrosis Factor-Stimulated Gene-6 as a Novel Diagnostic and 3-Month Prognostic Indicator in Non-Cardioembolic Acute Ischemic Stroke","volume":"13","author":"Qu","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_41","first-page":"113","article-title":"Suppression of inflammatory damage to the brain after global cerebral ischemia by transplanted mesenchymal stem cells via secretion of TSG-6","volume":"21","author":"Lin","year":"2016","journal-title":"Neurol. Asia"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.neulet.2016.09.032","article-title":"Neuroprotective effect of mesenchymal stem cell through complement component 3 downregulation after transient focal cerebral ischemia in mice","volume":"633","author":"Jung","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1016\/S0002-9440(10)63018-0","article-title":"Anti-Inflammatory and Chondroprotective Effect of TSG-6 (Tumor Necrosis Factor-\u03b1-Stimulated Gene-6) in Murine Models of Experimental Arthritis","volume":"159","author":"Kamath","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"51068","DOI":"10.1074\/jbc.M205121200","article-title":"The Link Module from Human TSG-6 Inhibits Neutrophil Migration in a Hyaluronan- and Inter-\u03b1-inhibitor-independent Manner","volume":"277","author":"Getting","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.expneurol.2016.03.005","article-title":"Tumor necrosis factor-inducible gene 6 protein: A novel neuroprotective factor against inflammation-induced developmental brain injury","volume":"279","author":"Bertling","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3233\/JAD-180797","article-title":"Increased Hyaluronan and TSG-6 in Association with Neuropathologic Changes of Alzheimer\u2019s Disease","volume":"67","author":"Reed","year":"2019","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1161\/01.STR.32.4.1020","article-title":"Use of Suppression Subtractive Hybridization for Differential Gene Expression in Stroke","volume":"32","author":"Wang","year":"2001","journal-title":"Stroke"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1046\/j.1471-4159.2002.01225.x","article-title":"CD44 deficiency in mice protects brain from cerebral ischemia injury","volume":"83","author":"Wang","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5522291","DOI":"10.1155\/2021\/5522291","article-title":"BMSCs Regulate Astrocytes through TSG-6 to Protect the Blood-Brain Barrier after Subarachnoid Hemorrhage","volume":"2021","author":"Wan","year":"2021","journal-title":"Mediat. Inflamm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.3389\/fphar.2019.01432","article-title":"The Potassium SK Channel Activator NS309 Protects Against Experimental Traumatic Brain Injury Through Anti-Inflammatory and Immunomodulatory Mechanisms","volume":"10","author":"Chen","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.jacbts.2016.07.008","article-title":"Atheroprotective Effects of Tumor Necrosis Factor\u2013Stimulated Gene-6","volume":"1","author":"Watanabe","year":"2016","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"153838","DOI":"10.1016\/j.prp.2022.153838","article-title":"Tumor necrosis factor-stimulated gene-6-a new serum identification marker to identify severe and symptomatic carotid artery stenosis","volume":"232","author":"Tian","year":"2022","journal-title":"Pathol.-Res. Pract."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"104986","DOI":"10.1016\/j.jstrokecerebrovasdis.2020.104986","article-title":"TSG-6 Attenuates Oxidative Stress-Induced Early Brain Injury in Subarachnoid Hemorrhage Partly by the HO-1 and Nox2 Pathways","volume":"29","author":"Li","year":"2020","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1189\/jlb.0608345","article-title":"Coregulation in human leukocytes of the long pentraxin PTX3 and TSG-6","volume":"86","author":"Maina","year":"2009","journal-title":"J. Leukoc. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41423-019-0204-6","article-title":"Cell\u2013cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models","volume":"16","author":"Li","year":"2019","journal-title":"Cell Mol. Immunol."},{"key":"ref_56","first-page":"E8151","article-title":"TNF\u03b1-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury","volume":"50","author":"Mittal","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"114139","DOI":"10.1016\/j.expneurol.2022.114139","article-title":"Exosomes from LPS-preconditioned bone marrow MSCs accelerated peripheral nerve regeneration via M2 macrophage polarization: Involvement of TSG-6\/NF-\u03baB\/NLRP3 signaling pathway","volume":"356","author":"Li","year":"2022","journal-title":"Exp. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"13724","DOI":"10.1073\/pnas.1008117107","article-title":"Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties","volume":"107","author":"Bartosh","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/jid.2013.328","article-title":"TSG-6 Released from Intradermally Injected Mesenchymal Stem Cells Accelerates Wound Healing and Reduces Tissue Fibrosis in Murine Full-Thickness Skin Wounds","volume":"2","author":"Qi","year":"2014","journal-title":"J. Invest. Dermatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.brainres.2010.11.071","article-title":"IkappaB-alpha expression following transient focal cerebral ischemia is modulated by nitric oxide","volume":"1372","author":"Greco","year":"2011","journal-title":"Brain Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"S34","DOI":"10.1177\/0271678X20932870","article-title":"Transcriptomic characterization of microglia activation in a rat model of ischemic stroke","volume":"40","author":"Deng","year":"2020","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1038\/s41401-021-00746-w","article-title":"Neuronal chemokine-like-factor 1 (CKLF1) up-regulation promotes M1 polarization of microglia in rat brain after stroke","volume":"43","author":"Zhou","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1186\/s12974-018-1323-1","article-title":"Sphingosine 1-phosphate receptor subtype 3 (S1P3) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization","volume":"15","author":"Gaire","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2021\/6688053","article-title":"Remote Limb Ischemic Postconditioning Protects against Ischemic Stroke via Modulating Microglia\/Macrophage Polarization in Mice","volume":"2021","author":"Han","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.bbrc.2019.03.202","article-title":"Caspase-1 inhibition mediates neuroprotection in experimental stroke by polarizing M2 microglia\/macrophage and suppressing NF-\u03baB activation","volume":"513","author":"Li","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"106176","DOI":"10.1016\/j.intimp.2019.106176","article-title":"Excess salt intake promotes M1 microglia polarization via a p38\/MAPK\/AR-dependent pathway after cerebral ischemia in mice","volume":"81","author":"Zhang","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1186\/s13287-019-1436-1","article-title":"TSG-6 in conditioned media from adipose mesenchymal stem cells protects against visual deficits in mild traumatic brain injury model through neurovascular modulation","volume":"10","author":"Jha","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"146422","DOI":"10.1016\/j.brainres.2019.146422","article-title":"Mesenchymal stem cells enhance microglia M2 polarization and attenuate neuroinflammation through TSG-6","volume":"1724","author":"Liu","year":"2019","journal-title":"Brain Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1177\/039463201102400320","article-title":"The protective role of catalase against cerebral ischemia in vitro and in vivo","volume":"24","author":"Armogida","year":"2011","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_70","first-page":"e100063","article-title":"Multi-center Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke (TRICS). Protocol of a multi-center, parallel group, randomized, preclinical trial in female and male rat and mouse from the Italian Stroke Organization (ISO) Basic","volume":"4","author":"Tettamanti","year":"2020","journal-title":"Br. Med. J. Open Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.ejphar.2016.09.030","article-title":"Poly(ADP-ribose) polymerase is not involved in the neuroprotection exerted by azithromycin against ischemic stroke in mice","volume":"791","author":"Petrelli","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.phrs.2015.10.009","article-title":"Activation of RXR\/PPAR\u03b3 underlies neuroprotection by bexarotene in ischemic stroke","volume":"102","author":"Certo","year":"2015","journal-title":"Pharmacol. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1161\/CIRCULATIONAHA.112.103051","article-title":"Targeting Mannose-Binding Lectin Confers Long-Lasting Protection With a Surprisingly Wide Therapeutic Window in Cerebral Ischemia","volume":"126","author":"Orsini","year":"2012","journal-title":"Circulation"},{"key":"ref_74","unstructured":"Paxinos, G., and Franklin, K.B.J. (2012). Paxinos and Franklin\u2019s The Mouse Brain in Stereotaxic Coordinates, Academic Press."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.neuroscience.2020.06.014","article-title":"Modulation of Cerebral Store-operated Calcium Entry-regulatory Factor (SARAF) and Peripheral Orai1 Following Focal Cerebral Ischemia and Preconditioning in Mice","volume":"441","author":"Frisina","year":"2020","journal-title":"Neuroscience"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.expneurol.2015.10.012","article-title":"Azithromycin protects mice against ischemic stroke injury by promoting macrophage transition towards M2 phenotype","volume":"275","author":"Amantea","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1007\/s12975-020-00851-8","article-title":"Characterization of CB2 receptor expression in peripheral blood monocytes of acute ischemic stroke patients","volume":"12","author":"Greco","year":"2021","journal-title":"Transl. Stroke Res."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Greco, R., Demartini, C., Zanaboni, A.M., Tumelero, E., Persico, A., Candeloro, E., Morotti, A., Amantea, D., and Tassorelli, C. (2021). CD163 as a potential biomarker of monocyte activation in ischemic stroke patients. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22136712"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5800\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:58:09Z","timestamp":1760122689000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5800"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,18]]},"references-count":78,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24065800"],"URL":"https:\/\/doi.org\/10.3390\/ijms24065800","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,18]]}}}