Role of classical pro- and anti-inflammatory mediators in ischemic stroke. Beyond neuroimmunomodulation

Sammanfattning: Stroke is a leading cause of death and long-term neurological deficits worldwide, and no effective treatment is available for the vast majority of the stroke patients. A rapid and persistent activation of multiple and dynamic inflammatory and immune cascades, in and outside the brain, occurs after stroke. These cascades are believed to affect the progression of the cerebral damage, as well as neural plasticity and functional recovery, but the underlying molecular and cellular determinants remain unclear. The proteins macrophage migration inhibitory factor (MIF) and interferon (IFN)-β are potent regulators of inflammation and immunity, and hence were hypothesized to play a role in stroke pathobiology. Ischemic stroke, the most common form stroke, often results from the occlusion of the middle cerebral artery (MCA), which can be modelled in rodents. Housing rats subjected to permanent MCAo in an enriched environment, a paradigm that improves sensory-motor function without altering infarct volume, resulted in a down-regulation of MIF around the infarct core, when compared to housing rats in standard cages. Moreover, disruption of the MIF-encoding gene in mice led to both a smaller cerebral infarct volume and a better sensory-motor function during the first week after transient MCAo. Within 3 h to 72 h after MCAo, MIF accumulated in neurons of the penumbra and later peri-infarct region, and pharmacological inhibition of MIF in isolated cerebrocortical neurons conferred protection against ischemia-induced death. Furthermore, abrogation of MIF in mice resulted in a higher galectin-3, a marker of macrophages/microglia, immunoreactivity within the cerebral infarct core but did not affect further hallmarks of the inflammatory and immune response during the first week post-tMCAo. By contrast, deletion of Ifn-β in mice resulted in major alterations of the inflammatory/immune response, including an increase in the number of putative macrophages in the brain and of B cells in the blood and a decrease in plasma interleukins 1β and 5, two days after tMCAo. However, it failed to contribute critically to the behavioural performance of mice over the first week after tMCAo. Overall, MIF may promote neuronal death and repress the recovery of neurological function after stroke. The results further suggest a role for neuronal MIF in the pathogenesis of stroke, and that the observed MIF-mediated effects might be independent of its pro-inflammatory action. The endogenous expression of IFN-β modulates/ameliorates the inflammatory/immune response, but it does not affect sensory-motor deficits during the first week post-stroke. Future studies will further address the mode(s) of action of MIF and IFN-β in cerebral ischemia.