Abstract WP286: Post-Stroke Immune Suppression is Mediated by Bioactive Lipids

Ischemic stroke patients frequently develop systemic immune suppression that predisposes them to life-threatening infections. Although this dysfunction has been recognized for decades, the mechanisms linking brain injury to impaired leukocyte responses remain poorly defined. We hypothesized that circulating lipids with immunosuppressive potential drive systemic immune paralysis after stroke, reducing antimicrobial activity and increasing infection risk. We examined leukocyte function in both acute ischemic stroke patients and mice subjected to 60-minutes of transient middle cerebral artery occlusion (tMCAO). Peripheral mononuclear blood cells isolated from ischemic stroke patients during the first week of hospitalization exhibited significantly diminished uptake and killing capacity (N= 53, p<0.05) when exposed to Staphylococcus aureus or zymosan bioparticles, confirming the profound effects of stroke on immune suppression. These results were replicated in mice using the tMCAO model. To assess the functional effects of circulating lipids after stroke, plasma was isolated from young adult C57Bl/6 male sham and tMCAO mice at 3-days post-stroke. Splenocytes from young adult naïve male C57Bl/6 mice were incubated ex vivo under three conditions (N=5 per group): PBS control, stroke plasma, or de-lipidated stroke plasma using Cleanascite. Lipid-rich stroke plasma increased lipid uptake in splenic neutrophils, reflected by elevated LipiBlue MFI (p<0.0001). In addition, phagocytosis of E. coli was significantly suppressed (p<0.001), and fewer neutrophils engulfed Staphylococcus aureus (p<0.05), indicating diminished uptake and reduced frequency of responding cells. Furthermore, antigen processing capacity was impaired, shown by reduced OVA-DQ fluorescence (p<0.0001). Importantly, de-lipidation of stroke plasma restored function across all measures: preventing neutrophil lipid accumulation, impaired bacterial clearance (p<0.05), and diminished antigen processing (p<0.01). Similar findings were seen in vivo after repeated infusions of de-lipidated stroke plasma, supporting the idea that lipids are key drivers of post-stroke immune suppression. In conclusion, ischemic stroke causes changes in circulating lipid composition, lipid accumulation and immune-regulatory potential that contributes to peripheral immune suppression. Importantly, these results suggest that lipid-mediated immune suppression after brain injury is a conserved biological phenomenon.