Acute, low-grade inflammation elevates white matter sensitivity to ischemia

Abstract Ischemic brain injuries, including stroke, are highly prevalent neurological diseases. Acute, low-grade inflammation, often resulting from peripheral infection, is a recognised risk factor. White matter axons, and their supporting glia, are susceptible to both ischemic and neuroinflammatory injury. The mechanisms behind ischemic and severe inflammatory injury in white matter are well established. However, the white matter response to acute, low-grade inflammation, and how this can interact with co-morbidities such as cerebral ischemia are yet to be examined. Here, we examine the response of white matter to acute, low-grade inflammation and the downstream effects this had on sensitivity of ischemia. Ex vivo mouse optic nerve and corpus callosum, central white matter tracts, tolerated acute, low-grade inflammation (110-minutes, 0.1μg/ml LPS), with preserved action potential conduction, limited microglial activation and no axo-myelinic damage. Exposure to these conditions elevated indicators of stress in oligodendrocytes which, when exposed to ischemic conditions (30 minutes oxygen-glucose deprivation), impaired their ability to maintain healthy myelin. There was a resulting increase in axo-myelinic damage and functional decline associated with ischemic conditions compared to white matter that had not been pre-exposed to LPS. Microglial depletion or dampening microglial responses with the clinically available drug minocycline eliminated the elevated sensitivity of white matter to ischemic injury associated with acute, low-grade inflammation. We demonstrate that acute, low-grade neuroinflammation primes white matter for heightened vulnerability to ischemic injury through microglial-mediated mechanisms. These findings provide a mechanistic explanation for the increased risk of ischemic brain injury observed during systemic inflammatory states and highlights microglial modulation as a clinical strategy to mitigate ischemic damage in susceptible patients.