Abstract TMP35: CD200-CD200R1 Inhibitory Signaling Attenuates Neuroinflammation and Reduces Behavioral Deficits Following Ischemic Stroke

Abstract

Introduction: In ischemic stroke, central nervous system homeostasis is dysregulated, leading to a significant inflammatory response, cell death, and impaired neuronal survival. The immune-inhibitory CD200-CD200 Receptor 1 signaling axis is a key regulator of inflammation and CNS homeostasis. We investigated the role of CD200R1-mediated signaling in stroke by evaluating the effects of its genetic deletion on inflammation and neurological outcome. Methods: Juvenile (10-12 wks) male transgenic CD200R1 knockout and WT littermate control (C57BL/6) mice were subjected to 60-min of reversible right middle cerebral artery occlusion and evaluated at day 3 and 7. Microglia activation and infiltration of peripheral leukocytes were examined by flow cytometry. Behavioral outcome was assessed by open field and rotarod test. Results: Early after ischemia (72 hrs), CD200R1 KO mice had no differences in stroke outcome measures compared to wildtype controls. However, significantly more infiltrating monocytes were found in the ischemic brain of CD200R1 KO mice. Monocyte function was uniquely affected by CD200R1-deficiency and resulted in dysregulated polarization. Unlike their WT counterparts, which eventually de-escalated the brain’s inflammatory response to stroke, microglia and monocyte activation persisted out to 7 days in CD200R1 KO mice, and was accompanied by a delayed, but significantly augmented lymphocyte response. At this timepoint, CD200R1 KO mice displayed severe weight loss, greater neurological deficits, impaired motor function, and had poorer survival rates compared to their WT counterparts. Interestingly, we found that microglia did not express appreciable levels of CD200R1 surface protein. Instead, CD200R1 was exclusively expressed on infiltrating monocytes and lymphocytes after stroke. Conclusion: Due to its expression on activated peripheral immune cells after stroke, CD200R1 may be a potentially valuable translational target that can inhibit leukocyte transmigration and thus, dampen the overall amplitude of the inflammatory response. This study defines an essential role for CD200-CD200R1 signaling in down-regulating the neuroinflammatory response in the ischemic brain to facilitate post-acute behavioral recovery.