Inhibition of γδ T Cells Alleviates Blood-Brain Barrier in Cardiac Arrest and Cardiopulmonary Resuscitation in Mice.

Abstract

Ischemia/reperfusion (I/R) injury is the leading cause of death following cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). γδT cells are suggested to aggravate blood-brain barrier (BBB) injury in various pathological processes. We herein investigate the effects of γδT cells inhibitor (UC7-13D5) against I/R injury post-CA/CPR. C57BL/6 mice were subjected to CA through injection of KCL (70 μL of 0.5mol/L) and cessation of mechanical ventilation followed by CPR. Flow cytometry was performed to measure the proportion of CD3-positive cells after intraperitoneal injection of 200μg UC7-13D5 at 6h, 24h, and 48h post-resuscitation into mice. Neurological scores and modified neurological severity scores were assessed to examine neurological functions. Brain edema was estimated via brain water content measurements. Immunohistochemistry of caspase-3 and immunofluorescence staining of claudin-1, ZO-1 and CD31 were performed to detect neuronal apoptosis, BBB integrity and angiogenesis. Microvascular morphology in the cortical area was assessed via H&E staining. Oxidative stress was determined by measuring malondialdehyde, myeloperoxidase, xanthine oxidase, superoxide dismutase, and glutathione peroxidase activities. Western blotting was performed to measure the protein levels of Nuclear factor-E2-related factor 2 (Nrf2) and Heme oxygenase-1 (HO-1). UC7-13D5 effectively depleted γδT cells. Inhibition of γδT cells improved neurological deficits and reduced brain edema post-CA/CPR. γδT cells depletion attenuated neuronal apoptosis, BBB disruption and oxidative stress and promoted angiogenesis following CA/CPR. Inhibition of γδT cells facilitated the activation of the Nrf2/HO-1 pathway in CA/CPR-induced mice. Inhibition of γδT cells alleviates neurological deficits and cerebral edema in mice with CA/CPR by inhibiting neuronal apoptosis, BBB disruption and oxidative stress, and promoting angiogenesis via activation of the Nrf2/HO-1 pathway.