Long-Term Microgliosis Driven by Acute Systemic Inflammation.

Abstract

Severe sepsis, a systemic inflammatory response to infection, is an increasing cause of morbidity in intensive care units. During sepsis, the vasculature is profoundly altered, leading to release of microbial virulence factors and proinflammatory mediators to surrounding tissue, causing severe systemic inflammatory responses and hypoxic injury of multiple organs. To date, multiple studies have explored pathologic conditions in many vital organs, including lungs, liver, and kidneys. Although data suggest that sepsis is emerging as a key driver of chronic brain dysfunction, the immunological consequence of severe inflammatory responses in the brain remain poorly understood. In this study, we used C57BL/6 sepsis mouse models to establish a disease phenotype in which septic mice with various degrees of severity recover. In the early phases of sepsis, monocytes infiltrate the brain with significantly elevated proinflammatory cytokine levels. In recovered animals, monocytes return to vehicle levels, but the number of brain-resident microglia is significantly increased in the cortex, the majority of which remain activated. The increase in microglia number is mainly due to self-proliferation, which is completely abolished in CCR2 knockout mice. Collectively our data suggest that early monocyte infiltration causes permanent changes to microglia during sepsis, which may ultimately dictate the outcome of future infections and neuropathological diseases.