Intraparenchymal B cell therapy protects neurological function and modulates local neuroinflammation in experimental hemorrhagic stroke.

Abstract

Intracerebral hemorrhage (ICH) is a devastating subtype of stroke, with a 5-year mortality of up to 70 %. Disease-modifying treatments to improve neurological outcomes in ICH survivors represent a critical unmet need. Neuroinflammation contributes significantly to ongoing secondary brain injury and long-term morbidity in ICH. We and others have shown that B cells are potent modulators of the inflammatory response, capable of acquiring a regulatory phenotype within injured microenvironments. Here, we investigated the effects of a single intraparenchymal application of mature naïve splenic B lymphocytes in a murine model of collagenase-induced ICH. In vivo tracking of luciferase-expressing B cells showed that the exogenous cells remained localized at the delivery site for up to 2 weeks. Delayed intraparenchymal B cell application at 24 h post-ICH was associated with acute neuroprotection of motor function in wire grip and rotarod assays and significant cognitive neuroprotection at 30 days post-injury in a Y maze paradigm. B cell administration was associated with reduced inflammasome activation at the injury site, diminished infiltration of CD8cytotoxic T cells in the injured hemisphere, and a regulatory shift in cytokine production in infiltrating monocytes/macrophages and natural killer cells. Systemically, modest increases in inflammatory cytokines and in regulatory markers were observed in myeloid cells in the spleen of animals treated with B cells intraparenchymally. These findings support intraparenchymal delivery of naïve B lymphocytes as a promising cell-based therapy for ICH, capable of facilitating functional neuroprotection via dynamic immunomodulation of adjacent immune populations.