Background and Purpose: ST2, a member of the interleukin 1 receptor family, and its ligand interleukin 33 (IL-33) play critical roles in immune regulation and inflammatory responses. The engagement of ST2 has been shown to reduce myocardial infarction and preserve heart function. Recent study documented an increase in blood ST2 expression after stroke. The exact roles of ST2 in the ischemic brain injury, however, are not explored.
Methods: C57/BL6 wild type and ST2 knockout mice were subjected to 60-minute transient cerebral ischemia (tMCAO). The expression of ST2 and IL-33 in the ischemic brain was measured at different time points after tMCAO using RT-PCR. Brain infarct was quantified using TTC staining and MAP2 immunostaing. Neurobehavioral tests were performed up to 14 days after tMCAO. Differences of immune cell components in blood, spleen, bone marrow and brain between wild type and ST2 knockout mice were assessed by flow cytometry analysis. For experiments with ST2 activation, IL-33 was injected intraperitoneally(i.p.) or intracerebroventricularly (i.c.v.) into wide type mice right after the induction of tMCAO.
Results: In wild type mice, the mRNA expression of ST2 in the ischemic brainexhibited a delayed elevation 7d after tMCAO, while the mRNA expression of IL-33 was transiently increased 1d after tMCAO. The deficiency of ST2 resulted in enlarged infarct volume 3d after tMCAO and aggravated neurological deficits lasted out to 14d. The worsened stroke outcome was accompanied by dramatic changes in the number of Th1, Th2 and regulatory T cells in the spleen, bone marrow and brain. Further study showed that either i.p. or i.c.v. injection of IL-33 at the time of reperfusion attenuated the severity of brain infarct in wide type mice, suggesting that both systemic and central activation of ST2 could protect against acute ischemic brain injury.
Conclusions: ST2/IL-33 signaling plays an essential role in restricting acute ischemic brain injury. Such protective effect of ST2/IL-33 involves both immune regulation in the peripheral immune system and a direct protection within the central nervous system. Our study may provide a new therapeutic target for stroke treatment.