This R01 application aims to investigate novel roles of CD147 in stroke-induced peripheral immune dysfunction and stroke pathology. Recent studies, including our own, favor an important notion that stroke-induced peripheral immune dysfunction not only predisposes patients to post-stroke infections (particularly pneumonia) but also contributes to secondary brain damage by exacerbating and perpetuating inflammatory response in the post-ischemic brain. The spleen has emerged as a novel target that mediates the peripheral immune response after stroke. Based on the novel findings discussed in the Preliminary Studies section, we propose the central hypothesis that CD147 acts as a novel key regulator of the splenic response to focal cerebral ischemia and that contributes importantly to secondary brain damage after stroke. Specifically, we propose that spleen monocytes play a critical role in stroke- mediated brain injury through a novel CD147 mechanism.
Specific Aim 1 will test the hypothesis that CD147 contributes importantly to ischemic inflammation and brain injury and thus therapeutic blockade of CD147 provides neurovascular protection in ischemic stroke.
Aim 1 a: We will investigate whether therapeutic targeting of CD147 provides neurovascular protection in ischemic stroke. Anti-CD147 function-blocking antibodies will be given by intravenous injection at clinically relevant time points.
Aim 1 b: We will investigate the cellular and molecular mechanisms by which CD147 contributes to stroke injury, with a focus on examining brain leukocyte infiltration, BBB disruption, and the splenic inflammatory activation after stroke.
Aim 1 c: We will determine whether therapeutic targeting of CD147 has long-term beneficial effects on functional recovery after stroke.
Specific Aim 2 will test the hypothesis tha CD147 is a key mediator of the spleen's immune response and contribution to ischemic stroke through spleen inflammatory monocytes.
Aim 2 a: We will determine the cell-type specific expression of CD147 in the spleens of mice subjected to tMCAO and the role of CD147 in inflammatory activation of splenic immunocytes (particularly monocytes, T cells) after stroke.
Aim 2 b: By adoptive transfer of spleen monocytes into splenectomized mice, we will determine whether spleen inflammatory monocytes contribute importantly to stroke injury. To selectively target CD147 on spleen monocytes, siRNA knockdown technique will be used.
Aim 2 c: We will determine the effects of therapeutic targeting of CD147 on stroke-induced splenic atrophy and poststroke infections. These studies will reveal novel roles of CD147 in the spleen's immune response and contribution to cerebral ischemia, and the findings may have potential implications for developing novel treatments for stroke.
Stroke is the third leading cause of death in the U.S., and the most common cause of disability. CD147 is an important regulator of immune and inflammatory responses. In this application, we will pursue a focused investigation on the functional role of CD147 in the spleen's immune response and contribution to ischemic stroke in an attempt to develop novel treatments for stroke.