Treg Upregulation by Treadmill Training Accelerates Myelin Repair Post-Ischemia

Overview

Journal J Neuroimmune Pharmacol

Date 2025 Feb 10

PMID 39930306

Authors

Juan Zhong

Tao Liu

Yingxi He

Ying Zhu

Sen Li

Yuan Liu

Ce Yang

Lehua Yu

Lu Pan

Ying Yin

Botao Tan

Affiliations

Soon will be listed here.

Abstract

Regulatory T (Treg) cells contribute to white matter repair following ischemic stroke, but their limited availability in circulation restricts their therapeutic potential. Exercise, as a non-invasive and effective rehabilitation method, has been shown to restore Treg balance in diseases. This study explores the effects of treadmill training on Treg upregulation and its influence on myelin repair and functional recovery in rats with middle cerebral artery occlusion (MCAO). After four weeks of treadmill training, we analyzed the proportion of Treg cells (Tregs), FOXP3 expression, and oligodendrocyte-related protein levels using flow cytometry, immunofluorescence, and Western blotting. Myelin structure was examined with transmission electron microscopy (TEM), while motor coordination and balance were assessed using the fatigue rotarod and CatWalk analysis systems. To further explore the role of Tregs, the FOXP3 inhibitor P60 was used to inhibit Treg activity. The findings of our study indicate that training on a treadmill supports the maturation of oligodendrocytes, leads to an increase in myelin-associated proteins and the thickness of myelin, and promotes the recovery of motor function. Inhibition of Treg activity diminished these benefits, highlighting Tregs' key role in exercise-induced remyelination. These findings suggest that treadmill training facilitates myelin regeneration and functional recovery by upregulating Tregs, offering potential new strategies for stroke treatment.

References

Beers D, Henkel J, Zhao W, Wang J, Huang A, Wen S . Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain. 2011; 134(Pt 5):1293-314. PMC: 3097891. DOI: 10.1093/brain/awr074. View

Campbell D, Koch M . Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol. 2011; 11(2):119-30. PMC: 3289970. DOI: 10.1038/nri2916. View

Casares N, Rudilla F, Arribillaga L, Llopiz D, Riezu-Boj J, Lozano T . A peptide inhibitor of FOXP3 impairs regulatory T cell activity and improves vaccine efficacy in mice. J Immunol. 2010; 185(9):5150-9. DOI: 10.4049/jimmunol.1001114. View

Chang E, Argyelan M, Aggarwal M, Chandon T, Karlsgodt K, Mori S . The role of myelination in measures of white matter integrity: Combination of diffusion tensor imaging and two-photon microscopy of CLARITY intact brains. Neuroimage. 2016; 147:253-261. PMC: 5560594. DOI: 10.1016/j.neuroimage.2016.11.068. View

Chen K, Zheng Y, Wei J, Ouyang H, Huang X, Zhang F . Exercise training improves motor skill learning via selective activation of mTOR. Sci Adv. 2019; 5(7):eaaw1888. PMC: 6609215. DOI: 10.1126/sciadv.aaw1888. View

Dirnagl U, Klehmet J, Braun J, Harms H, Meisel C, Ziemssen T . Stroke-induced immunodepression: experimental evidence and clinical relevance. Stroke. 2007; 38(2 Suppl):770-3. DOI: 10.1161/01.STR.0000251441.89665.bc. View

Dombrowski Y, OHagan T, Dittmer M, Penalva R, Mayoral S, Bankhead P . Regulatory T cells promote myelin regeneration in the central nervous system. Nat Neurosci. 2017; 20(5):674-680. PMC: 5409501. DOI: 10.1038/nn.4528. View

Dorneles G, da Silva I, Boeira M, Valentini D, Fonseca S, Lago P . Cardiorespiratory fitness modulates the proportions of monocytes and T helper subsets in lean and obese men. Scand J Med Sci Sports. 2019; 29(11):1755-1765. DOI: 10.1111/sms.13506. View

Feigin V, Norrving B, George M, Foltz J, Roth G, Mensah G . Prevention of stroke: a strategic global imperative. Nat Rev Neurol. 2016; 12(9):501-12. PMC: 8114177. DOI: 10.1038/nrneurol.2016.107. View

10.

Fernandes P, Oliveira L, Bruggemann T, Sato M, Olivo C, Arantes-Costa F . Physical Exercise Induces Immunoregulation of TREG, M2, and pDCs in a Lung Allergic Inflammation Model. Front Immunol. 2019; 10:854. PMC: 6532549. DOI: 10.3389/fimmu.2019.00854. View

11.

Gelderblom M, Leypoldt F, Steinbach K, Behrens D, Choe C, Siler D . Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke. 2009; 40(5):1849-57. DOI: 10.1161/STROKEAHA.108.534503. View

12.

Hori S, Nomura T, Sakaguchi S . Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003; 299(5609):1057-61. DOI: 10.1126/science.1079490. View

13.

Joisten N, Kummerhoff F, Koliamitra C, Schenk A, Walzik D, Hardt L . Exercise and the Kynurenine pathway: Current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training. Exerc Immunol Rev. 2020; 26:24-42. View

14.

Kamel H, Iadecola C . Brain-immune interactions and ischemic stroke: clinical implications. Arch Neurol. 2012; 69(5):576-81. PMC: 3586409. DOI: 10.1001/archneurol.2011.3590. View

15.

Kastrup A, Groschel K, Ringer T, Redecker C, Cordesmeyer R, Witte O . Early disruption of the blood-brain barrier after thrombolytic therapy predicts hemorrhage in patients with acute stroke. Stroke. 2008; 39(8):2385-7. DOI: 10.1161/STROKEAHA.107.505420. View

16.

Kleinschnitz C, Kraft P, Dreykluft A, Hagedorn I, Gobel K, Schuhmann M . Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. Blood. 2012; 121(4):679-91. PMC: 3790947. DOI: 10.1182/blood-2012-04-426734. View

17.

Koliamitra C, Javelle F, Joisten N, Shimabukuro-Vornhagen A, Bloch W, Schenk A . Do Acute Exercise-Induced Activations of the Kynurenine Pathway Induce Regulatory T-Cells on the Long-Term? - A Theoretical Frame Work Supported by Pilot Data. J Sports Sci Med. 2019; 18(4):669-673. PMC: 6873119. View

18.

Kruger K, Lechtermann A, Fobker M, Volker K, Mooren F . Exercise-induced redistribution of T lymphocytes is regulated by adrenergic mechanisms. Brain Behav Immun. 2007; 22(3):324-38. DOI: 10.1016/j.bbi.2007.08.008. View

19.

Kruger K, Alack K, Ringseis R, Mink L, Pfeifer E, Schinle M . Apoptosis of T-Cell Subsets after Acute High-Intensity Interval Exercise. Med Sci Sports Exerc. 2016; 48(10):2021-9. DOI: 10.1249/MSS.0000000000000979. View

20.

Lee J, Hamanaka G, Lo E, Arai K . Heterogeneity of microglia and their differential roles in white matter pathology. CNS Neurosci Ther. 2019; 25(12):1290-1298. PMC: 6887901. DOI: 10.1111/cns.13266. View