Inflammatory Responses Mediate Brain-heart Interaction And Brain-derived Microparticles Aggravate Brain Injury

Background and Objective: Abundant clinical and experimental evidence indicate that stroke may induce cardiac dysfunction which increases post stroke mortality and morbidity.Secondary cardiac dysfunction resulting from stroke may increase with age.Here,we investigated the effects of inflammatory responses as underlying mediators of cardiac dysfunction after stroke in adult mice.After brain injury,a large number of brain-derived microparticles(BDMP)are released into the peripheral circulation system.These brain-derived microparticles can cause nervous system inflammation and aggravating brain damage.Lactadherin can bind to anionic phospholipids and extracellular matrix to promote BDMP clearance.We investigated whether BDMP can affect neurological inflammation caused by stroke,and whether Lactadherin treatment can reduce neurological inflammation induced by BDMP,thereby improving stroke functional outcome.Methods:(1)Adult(8-9 months)male C57BL/6 mice were subjected to photothrombotic stroke model.To test whether immunoresponse to stroke leads to cardiac dysfunction,splenectomy was performed prior to stroke.To evaluate cardiac function,echocardiography was performed on 3 and 28 days after stroke.Immunohistochemistry,flow cytometry,PCR and ELISA were used to investigate mechanisms of brain-heart interaction.(2)Middle aged(8–9 months old)male C57BL/6J mice were subjected to photothrombotic stroke model,and BDMPs were extracted from ischemic brain 24 h after d MCAo by ultracentrifugation.Adult male C57BL/6J mice were subjected to d MCAo and treated via tail vein injection at 3 h after stroke with: A)+PBS;B)+BDMPs;C)+Lactadherin;D)+BDMP+Lactadherin.A battery of neurological function tests were performed and mice sacrificed for immunostaining at 14 days after stroke.Blood plasma was used for Western blot assay Results:(1)We found marginal cardiac dysfunction at acute phase and significant cardiac dysfunction at chronic phase of stroke.Cardiac function at 28 days after stroke is significantly worse than cardiac function assessed at 3 days after stroke.Stroke significantly increases macrophage infiltration into the heart and increases interleukin IL-1β,IL-6,TGF-β,monocyte chemotactic protein-1(MCP-1),and macrophage-associated inflammatory cytokine levels in the heart as well as induces cardiac-fibrosis and hypertrophy.Splenectomy prior to stroke significantly reduces monocyte and macrophage infiltration into heart,decreases inflammatory factor expression in the heart,decreases cardiac hypertrophy and fibrosis,as well as significantly improves cardiac function compared to non-splenectomized middle aged mice subject to stroke.(2)Treatment of Stroke with BDMP significantly increases lesion volume,neurological deficits,blood brain barrier(BBB)leakage,microglial activation,inflammatory cell infiltration into brain,inflammatory factor expression in brain,increases axon/white matter(WM)damage identified by decreased axon and myelin density,and increases inflammatory factor expression in the plasma when compared to PBS treated stroke mice;Lactaherin treatment significantly reduced lesion volume,promoted neurological recovery,reduced inflammatory cell infiltration and expression of inflammatory factors.Conclusions:(1)Our results suggest that ischemic stroke can induce chronic heart function damage without primary heart disease.Splenectomy can not only reduce the neurological function deficits caused by ischemic stroke,but also reduce the infiltration of immune cells into the heart tissue and the expression of inflammatory factors in the heart,thereby alleviating cardiac dysfunction and cardiac remodeling after ischemic stroke.Adult mice with cerebral ischemic stroke can induce chronic cardiac insufficiency,and secondary immune response may lead to cardiac insufficiency after stroke Cerebral ischemic stroke in adult mice induces chronic cardiac dysfunction and secondary immune response may contribute to post stroke cardiac dysfunction.The infract volume is significantly correlated with the severity of cardiac function damage.(2)BDMP promotes neuroinflammation and aggravates brain injury after ischemic stroke.Lactadherin exerts anti-inflammatory effects and improves the clearance of MPs to reduce neurological deficits caused by stroke and BDMP.