Modulating the post-stroke inflammatory response to improve outcome in models of cerebral ischemia ABSTRACT Stroke is a multiphasic process, with an initial ischemic phase followed by secondaryprogression of injury from inflammatory responses.Following ischemia, microglia and macrophages accumulate in the ischemic area and produce inflammatory mediators and chemokines that initially recruit peripheral macrophages, neutrophils, dendritic cells, and later T and B cells. This post-stroke inflammatory response is both beneficial and injurious, as multiple and simultaneous immune pathways in distinct immune cell populations generate both beneficial and maladaptive immune responses. Because the time window of intervention of thrombolytic strategies is limited after onset of ischemia, and because attempts at neuroprotection after stroke have not shown positive results, the post-stroke inflammatory response represents an attractive target for intervention to reduce brain injury and accelerate functional recovery. The identification of specific immune pathways activated after stroke that could be modulated therefore represents an opportunity to improve and accelerate recovery after stroke. In previous studies, we have focused on the beneficial effects of inhibiting COX-2/PGE2 inflammatory signaling through the myeloid PGE2 EP2 receptor. In these studies, we identified Triggering Receptor Expressed on Myeloid cells-1, or TREM1, as highly regulated by inflammatory PGE2 EP2 signaling. TREM1 is an inflammatory membrane receptor that is expressed only on myeloid lineage cells and is unique in its function as an amplifier of maladaptive inflammatory responses. Our preliminary data suggest that this immune signaling cascade enhances innate immune responses after cerebral ischemia days after stroke. Using a combination of pharmacological and conditional knockout strategies, we propose to identify the mechanisms of action of TREM1 signaling after stroke and test the hypothesis that inhibition of this pathway in the days after stroke will enhance brain repair and accelerate recovery.
RO1 The research objective of this proposal is to examine whether modulation of toxic immune signaling pathways during the post-stroke inflammatory response will improve outcome after stroke in rodent model of cerebral ischemia. This work will hopefully lead to new insights and strategies into modulating the post-stroke immune response to improve recovery in patients with stroke.
