Systemic treatment with a selective TNFR2 agonist alters the central and peripheral immune responses and transiently improves functional outcome after experimental ischemic stroke

Estrid Thougaard; Pernille Vinther Nielsen; Amalie Forsberg; Victoria Phuong; Aitana Martínez Velasco; Agnieszka Wlodarczyk; Harald Wajant; Isabell Lang; Jens D Mikkelsen; Bettina Hjelm Clausen; Roberta Brambilla; Kate Lykke Lambertsen

doi:10.1016/j.jneuroim.2023.578246

Systemic treatment with a selective TNFR2 agonist alters the central and peripheral immune responses and transiently improves functional outcome after experimental ischemic stroke

J Neuroimmunol. 2023 Dec 15:385:578246. doi: 10.1016/j.jneuroim.2023.578246. Epub 2023 Nov 17.

Affiliations

¹ Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense C, Denmark. Electronic address: [email protected].
² Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense C, Denmark; Department of Neurology, Odense University Hospital, J.B. Winsløwsvej 4, 5000 Odense C, Denmark. Electronic address: [email protected].
³ Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark. Electronic address: [email protected].
⁴ Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark. Electronic address: [email protected].
⁵ Neurobiology Research Unit, University Hospital Rigshospitalet, Inge Lehmanns Vej 6, 2100 Copenhagen, Denmark.
⁶ Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense C, Denmark. Electronic address: [email protected].
⁷ Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacher Straße 6, Würzburg 97080, Germany. Electronic address: [email protected].
⁸ Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacher Straße 6, Würzburg 97080, Germany. Electronic address: [email protected].
⁹ Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; Neurobiology Research Unit, University Hospital Rigshospitalet, Inge Lehmanns Vej 6, 2100 Copenhagen, Denmark; Department of Neuroscience, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark. Electronic address: [email protected].
¹⁰ Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense C, Denmark. Electronic address: [email protected].
¹¹ Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense C, Denmark; The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Lois Pope LIFE Center, Miami, FL 33136, USA. Electronic address: [email protected].
¹² Neurobiology Research, Department of Molecular Medicine, University of Southern Denmark, J. B. Winsløwsvej 21 st, 5000 Odense C, Denmark; BRIDGE - Brain Research - Inter Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, J.B. Winsløwsvej 19, 5000 Odense C, Denmark; Department of Neurology, Odense University Hospital, J.B. Winsløwsvej 4, 5000 Odense C, Denmark. Electronic address: [email protected].

PMID: 37988839
DOI: 10.1016/j.jneuroim.2023.578246

Abstract

Ischemic stroke often leaves survivors with permanent disabilities and therapies aimed at limiting detrimental inflammation and improving functional outcome are still needed. Tumor necrosis factor (TNF) levels increase rapidly after ischemic stroke, and while signaling through TNF receptor 1 (TNFR1) is primarily detrimental, TNFR2 signaling mainly has protective functions. We therefore investigated how systemic stimulation of TNFR2 with the TNFR2 agonist NewSTAR2 affects ischemic stroke in mice. We found that NewSTAR2 treatment induced changes in peripheral immune cell numbers and transiently affected microglial numbers and neuroinflammation. However, this was not sufficient to improve long-term functional outcome after stroke in mice.

Keywords: Cytokines; Ischemic stroke; Microglia; Neuroinflammation; Peripheral immune cells; TNFR2 agonist.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Inflammation / pathology
Ischemic Stroke*
Mice
Mice, Inbred C57BL
Receptors, Tumor Necrosis Factor, Type I
Receptors, Tumor Necrosis Factor, Type II*
Tumor Necrosis Factor-alpha / metabolism

Substances

NewSTAR2
Receptors, Tumor Necrosis Factor, Type I
Receptors, Tumor Necrosis Factor, Type II
Tumor Necrosis Factor-alpha