Regulatory T cells increase after treatment with poly (ADP-ribose) polymerase-1 inhibitor in ischemic stroke patients

Abstract

Background: Regulatory T cells (Tregs) are thought to play a modulatory role in immune responses and to improve outcomes after ischemic stroke. Thus, various strategies for increasing Tregs in animal models of ischemic stroke have yielded successful results. The aim of this study was to examine the potential effect of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor on Treg proportion in stroke patients. Methods: Peripheral blood samples were collected from 12 ischemic stroke patients (within 72 h of stroke onset) and 5 healthy control subjects. Flow cytometry analyses and quantitative reverse transcription polymerase chain reactions (qRT-PCR) were performed on peripheral blood mononuclear cells (PBMCs) before and after treating them with PARP-1 inhibitor (3-AB; JPI-289 1 pm, JPI-289 10 mu m) for 24 h. Results: Treg proportions were significantly higher in healthy controls (median 2.8%, IQR 2.6-5.0%) than ischemic stroke patients (median 1.6%, IQR 1.25-2.2%) (p < 0.001). In the latter, Treg proportions were positively correlated with age (r = 0.595, p = 0.041), but not with infarct volume (r = 0.367, p = 0.241). After PARP-1 inhibitor treatment, Treg proportions among PBMCs increased in response to high dose (10 mu m) JPI-289 (median 2.3%, IQR 2.0-2.9%) as did Treg-associated transcription factors such as FoxP3 and CTLA-4 mRNA. PARP-1 inhibitor treatment also decreased pro-inflammatory cytokines (IFN-gamma, TNF-alpha, and IL-17) and increased anti-inflammatory cytokines (IL-4, IL-10, and TGF-beta 1). Conclusion Treg proportions are reduced in ischemic stroke patients and increased by treatment with high-dose PARP-1 inhibitor JPI-289. The PARP-1 inhibitor also had a possible anti-inflammatory effect on cytokine levels, and may ameliorate the outcome of ischemic stroke by up-regulating Tregs.