title: Boosting regulatory T cells limits neuroinflammation in permanent cortical stroke.
abstract: Inflammatory mechanisms contribute substantially to secondary tissue injury after brain ischemia. Regulatory T cells (Tregs) are key endogenous modulators of postischemic neuroinflammation. We investigated the potential of histone deacetylase inhibition (HDACi) to enhance Treg potency for experimental stroke in mice. HDACi using trichostatin A increased the number of Tregs and boosted their immunosuppressive capacity and interleukin (IL)-10 expression. In vivo treatment reduced infarct volumes and behavioral deficits after cortical brain ischemia, attenuated cerebral proinflammatory cytokine expression, and increased numbers of brain-invading Tregs. A similar effect was obtained using tubastatin, a specific inhibitor of HDAC6 and a key HDAC in Foxp3 regulation. The neuroprotective effect of HDACi depended on the presence of Foxp3(+) Tregs, and in vivo and in vitro studies showed that the anti-inflammatory cytokine IL-10 was their main mediator. In summary, modulation of Treg function by HDACi is a novel and potent target to intervene at the center of neuroinflammation. Furthermore, this novel concept of modulating endogenous immune mechanisms might be translated to a broad spectrum of diseases, including primary neuroinflammatory and neurodegenerative disorders.
authors.affiliation: Department of Neurology, University of Heidelberg, 69120 Heidelberg, Germany, Department of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany, Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, 53105 Bonn, Germany, Laboratory for Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and German Centre for Cardiovascular Research, Heidelberg University Research Center for Cardiomyopathies and Arrhythmias-From Genes to Translation, Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany, and Laboratory of Endocrinology and Genomics, CHUQ Research Center and Department of Molecular Medicine, Laval University, Québec City, Québec G1V 4G2, Canada.
authors.forename: Arthur
authors.initials: A
authors.lastname: Liesz
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Na
authors.forename: Günter J
authors.initials: GJ
authors.lastname: Hämmerling
authors.forename: Natalio
authors.initials: N
authors.lastname: Garbi
authors.forename: Simone
authors.initials: S
authors.lastname: Karcher
authors.forename: Eva
authors.initials: E
authors.lastname: Mracsko
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
authors.forename: Serge
authors.initials: S
authors.lastname: Rivest
authors.forename: Roland
authors.initials: R
authors.lastname: Veltkamp
mesh_terms: D000818:Animals; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D016753:Interleukin-10 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020521:Stroke / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C556062:IL10 protein, mouse; D016753:Interleukin-10; C012589:trichostatin A