The splenic response to ischemic stroke: what have we learned from rodent models?

The majority of promising experimental compounds have failed in clinical trials, highlighting the need for novel approaches to treat stroke. Much research has been devoted to elucidating the signaling pathways involved in delayed neuroinflammation that can be targeted at clinically relevant time points. The field of stroke research has benefited from experiments characterizing the temporal expression profiles of candidate cytokines, chemokines, matrix metalloproteinases, and other putative pro-inflammatory molecules. Yet, these data have offered only a glimpse into the complex pathological sequelae and have not advanced the treatment of neuropathies. Upon recognition that peripheral immune cell activation is involved in penumbral expansion, the spleen has emerged as a novel target that mediates the peripheral immune response and promotes pro-inflammatory injury. Although the precise mechanisms have yet to be elucidated, accumulated evidence demonstrates that focal cerebral ischemia alters cytokine, chemokine, and immune cell profiles in the spleen. Additionally, removal of this peripheral lymphoid organ is neuroprotective, and the efficacy of several protective therapies has been linked to actions at the level of the spleen. Future experiments aimed at identifying the splenic lymphocyte populations that respond to ischemic stroke, as well as their signaling mechanisms, are critical in developing novel therapies.