Stroke is a leading cause of mortality and disability worldwide. Despite many successes in acute protection in preclinical animal models of stroke, it has not been effectively translated into clinical settings. The recurring translational failures indicate that strategies aimed at long-term survival and that promoting functional recovery may be a novel approach to treat stroke victims. Ischemic conditioning enhances endogenous protective tolerance mechanisms against full insults. Whereas applying ischemic conditioning prior to ischemia has limitations, its application after the ischemia, especially through remote limbs was implicated in improving cardiovascular disease outcome in humans. However, mechanisms underlying the benefits have not been defined. Because the application of ischemic conditioning in the limb is remote from the brain, we speculate involvement of circulating immune cells in this process. Infiltrating monocytes/macrophages (MMs) modulate stroke severity and disease progression. Mouse MM subsets are characterized by two distinct subsets; pro-inflammatory Ly6CHi and anti-inflammatory Ly6CLow subset. In our preliminary studies, we observed that mice subjected to PSLC exhibited an increased total number of monocytes in the blood at 3 days post-ischemia. The increase was accompanied by a significant decrease in anti-inflammatory Ly6CLow MMs in the blood, suggesting a potential post-stroke limb conditioning (PSLC)-induced conversion of anti-inflammatory Ly6CLow MM subset to pro-inflammatory Ly6CHi subset. In addition, the PSLC mice displayed better motor/gait functions without reducing infarct size. Based on these observations, we hypothesize that PSLC-induced changes in MM subsets promote functional recovery in chronic stroke. The goal of this proposal is to investigate the mechanism(s) by which peripheral immunity may be regulated by PSLC and how this contributes to recovery in chronic stroke. Successful execution of this proposal will provide insight to develop a potential immune-based strategy with high clinical relevance for patients with cardio and cerebrovascular diseases.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||07/01/2015 → 06/30/2017|