Selective CB2 receptor activation attenuates neuroinflammation and preserves immune responsiveness after photothrombotic stroke

Ischemic stroke triggers neuroinflammation that can drive CNS injury-induced immunodepression syndrome (CIDS), a peripheral immunosuppressive state associated with increased infection risk. The endocannabinoid system, particularly cannabinoid receptor type 2 (CB2), represents a promising immunomodulatory target because of its anti-inflammatory actions and limited psychoactive liability. In this study, we investigated whether CB2 receptor activation confers neuroprotection and preserves systemic immune responsiveness in a murine photothrombotic stroke (PTS) model. Male C57BL/6 mice underwent PTS or sham surgery and were treated before stroke induction with the non-selective CB1/CB2 agonist WIN-55212, receptor antagonists, the selective CB2 agonist HU-308, or vehicle. Neurological deficits, infarct volume, cerebral inflammatory gene expression, and intestinal leukocyte-endothelial interactions following lipopolysaccharide (LPS) challenge were assessed using Neuroscore, TTC staining, RT-qPCR, and intravital microscopy. SIM-A9 microglia were used to evaluate the effects of HU-308 on viability and cytokine release under inflammatory conditions. PTS induced a CIDS-like phenotype characterized by reduced baseline leukocyte rolling and a markedly blunted leukocyte adhesion response following LPS challenge. Non-selective cannabinoid receptor activation improved neurological scores and reduced infarct size, while CB2 blockade abolished this protection. Selective CB2 activation with HU-308 reduced infarct volume, improved neurological outcome, and suppressed stroke-associated TNF and IL-6 expression in the ischemic hemisphere. In vitro, HU-308 reduced TNF release from LPS-stimulated microglia, while IL-4 enhanced microglial viability and IL-10 production. Importantly, HU-308 preserved leukocyte adhesion after LPS challenge following stroke, suggesting maintained peripheral immune responsiveness. These findings identify CB2 receptor activation as a promising neuroimmune strategy that limits acute stroke injury while attenuating the development of CIDS.