Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke

DOI

10.1016/j.immuni.2021.04.022

Authors

• Ligen Shi, Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
• Zeyu Sun, Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
• Wei Su, Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
• Fei Xu, Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA.
• Di Xie, Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
• Qingxiu Zhang, Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
• Xuejiao Dai, Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
• Kartik Iyer, Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
• T Kevin Hitchens, Animal Imaging Center and Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15203, USA.
• Lesley M. Foley, Animal Imaging Center and Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15203, USA.
• Sicheng Li, Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
• Donna B. Stolz, Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA 15213, USA.
• Kong Chen, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
• Ying Ding, Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15213, USA.
• Angus W. Thomson, Starzl Transplantation Institute, Department of Surgery and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
• Rehana K. Leak, Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA.
• Jun Chen, Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA.
• Xiaoming Hu, Pittsburgh Institute of Brain Disorders and Recovery and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA. Electronic address: hux2@upmc.edu.

Document Type

Journal Article

Publication Date

7-13-2021

Publication Title

Immunity

Volume

54

Issue

7

First Page

1527

Last Page

1.54E+11

Keywords

microglia, oligodendrocytes, osteopontin, regulatory T cells, stroke recovery, white matter

Abstract

The precise mechanisms underlying the beneficial effects of regulatory T (Treg) cells on long-term tissue repair remain elusive. Here, using single-cell RNA sequencing and flow cytometry, we found that Treg cells infiltrated the brain 1 to 5 weeks after experimental stroke in mice. Selective depletion of Treg cells diminished oligodendrogenesis, white matter repair, and functional recovery after stroke. Transcriptomic analyses revealed potent immunomodulatory effects of brain-infiltrating Treg cells on other immune cells, including monocyte-lineage cells. Microglia depletion, but not T cell lymphopenia, mitigated the beneficial effects of transferred Treg cells on white matter regeneration. Mechanistically, Treg cell-derived osteopontin acted through integrin receptors on microglia to enhance microglial reparative activity, consequently promoting oligodendrogenesis and white matter repair. Increasing Treg cell numbers by delivering IL-2:IL-2 antibody complexes after stroke improved white matter integrity and rescued neurological functions over the long term. These findings reveal Treg cells as a neurorestorative target for stroke recovery.

Open Access

OA

Preprint

Link to Free Text

Repository Citation

Shi, L., Sun, Z., Su, W., Xu, F., Xie, D., Zhang, Q., Dai, X., Iyer, K., Hitchens, T. K., Foley, L. M., Li, S., Stolz, D. B., Chen, K., Ding, Y., Thomson, A. W., Leak, R. K., Chen, J., & Hu, X. (2021). Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke. Immunity, 54 (7), 1527-1.54E+11. https://doi.org/10.1016/j.immuni.2021.04.022