Characterizing the Role of C-C Chemokine Receptor Type 5 (CCR5) in Stroke Recovery

Stroke is the leading cause of long-term adult disability and it is the 5th leading cause of death in the United States. This costs the U.S government approximately $33 billion each year (Centers for Disease Control and Prevention [CDC], 2017). There are no medical treatments that promote stroke recovery. The best recovery results after a stroke involve neuro-rehabilitation therapies, which are heavily reliant on the brain’s ability to learn and relearn following a stroke. Previous studies have shown that molecules associated with learning and memory regulate stroke recovery. Recently, C-C chemokine receptor type 5 (CCR5), an inflammatory response G-protein coupled receptor and co-receptor for HIV-1, has been shown to play a prominent role in regulating learning and memory processes. Based on this, we tested the effects of CCR5 knock down on stroke recovery using a well-established measure of forelimb function-asymmetric forelimb task and found that animals that received CCR5 knockdown following a stroke showed early and sustained motor recovery compared to stroke only and control AAV and stroke groups. To determine cellular events through which CCR5 knock down leads to post-stroke recovery, we primarily focused on changes in glial activation mediated through CCR5 knock down. By quantifying immunoreactivity in post-stroke microglia and astrocytes using IBA1 and GFAP respectively, standard markers of their reactivity, we found that CCR5 knockdown led to a reduction in GFAP immunoreactivity at 7 days in the peri-infarct cortex but did not significantly alter astrocytic immunoreactivity at 2 months and microglial immunoreactivity at 7 days or 2 months post-stroke. This implies that recovery mediated through CCR5 knockdown may be influenced by an early reduction in astrocytic reactivity in the peri-infarct region after stroke. Next, we examined FDA-approved antiretroviral drugand CCR5 antagonist, maraviroc (Selzentry, Pfizer), as a pharmacological agent for stroke recovery. Animals that received maraviroc treatment or stroke and vehicle were tested for stroke recovery using a function-asymmetric forelimb task. Animals that received stroke and maraviroc treatment showed improved recovery on this task compared to stroke and vehicle or stroke alone groups. Based on its effect on improved motor recovery, we determined if CCR5 knockdown promotes recovery through reducing infarct size. We quantified infarct area in animals that received stroke, stroke and maraviroc treatment; and stroke and CCR5 knockdown; and found that infarct area from the different groups did not significantly differ. This shows that CCR5 knockdown does not promote recovery through tissue repair, suggesting complex signaling pathways through which CCR5 signals to dampen stroke recovery.