Brain Foxp3+ regulatory T cells can be expanded by Interleukin-33 in mouse ischemic stroke

Background: Regulatory T (Treg) cells are known as immune regulators to decrease infarct volume and improve outcomes after ischemic stroke. Thus, the strategies for increasing Treg cells in ischemic brain may have the beneficial effects on stroke. In this study, we aim to examine the effect of Interleukin-33 (IL-33) on Treg cell expansion in mouse model of ischemic stroke. Methods: Mice were subjected to 30 min of middle cerebral artery occlusion (MCAO) followed by 24 h, 48 h of 72 h of reperfusion. Recombinant mouse IL-33 (2 mu g) was pre-treated intracerebroventricularly at 30 min prior to MCAO. The percentage of Treg cells in ischemic brain, related cytokines and transcription factors, the levels of ST2 receptor, amphiregulin (AREG), and epidermal growth factor receptor (EGFR) were measured. Results: IL-33 treatment can increase the number of Foxp3(+) Treg cells in the ischemic brain and the levels of IL-10 and TGF- beta 1 in serum and brain tissues at MCAO 48 h and 72 h, but not at MCAO 24 h. In the Treg cells separated from ischemic brain tissue following MCAO treated by IL-33, the expression level of ST2 receptor was up-regulated. In addition, IL-33 may increase the mRNA level of transcription factor Foxp3. Correspondingly, IL-33 treatment also elevated the levels of AREG and EGFR at MCAO 48 h and 72 h. Conclusion: We speculated that intracerebroventricular IL-33 can activate the downstream Foxp3 via ST2 receptor to increase Treg proportions in the ischemic brain. The elevated Treg cells produce AREG to activate EGFR located in neurons, which contribute to better outcomes.