Stroke is a multiphasic process, and the initial ischemic phase is followed by secondary injury and repair from post-stroke inflammation that unfolds over an extended time period. Because strategies targeting neuroprotection and cerebral blood flow have a narrow time window of efficacy, the post-stroke inflammatory response represents a translationally accessible phase in stroke evolution where intervention may improve functional recovery. Myeloid-lineage cells, notably resident microglia and infiltrating macrophages, perform important and beneficial functions after stroke, including clearance of toxic debris and elaboration of growth and anti-inflammatory factors; however, these cells also can produce toxic reactive oxygen species, cytokines, and proteases. Therefore, microglia and macrophages can have beneficial but also toxic effects after stroke. In recent studies examining the in vivo function of the PGE2 EP2 receptor in microglia and macrophages, we have determined that cell-specific ablation of myeloid-lineage EP2 signaling is significantly beneficial in vivo, and reduces toxic inflammation, enhances immune cell trafficking and clearance of toxic substances, and leads to elaboration of trophic factors in models of innate immune inflammation. Because the early post-stroke inflammatory phase exhibits many of the characteristics of an innate immune response, we hypothesize that post-stroke, microglia and macrophage EP2 signaling will assume similar characteristics, and ablation of EP2 in myeloid cells in this setting will have significant and beneficial effects by enhancing phagocytosis of toxic debris and generating beneficial trophic factors. In this proposal, we will use a validated conditional knockout genetic approach to selectively ablate EP2 in macrophages and microglia as well as pharmacological strategies to test these hypotheses. We will test whether functional recovery can be enhanced and accelerated with inactivation of inflammatory EP2 signaling post stroke. The proposed studies should help advance our understanding of microglial-macrophage biology post-stroke, and validate new approaches targeting EP2 signaling pathway after stroke.
Stroke is a major cause of morbidity and mortality. We have identified a prostaglandin receptor that has important pro-inflammatory and toxic properties that if inhibited may attenuate the injurious aspects of the post-stroke inflammatory response, and result in improved stroke recovery. The research objective of this proposal is to examine the functions of this receptor in a model of cerebral ischemia.
