Editors' ChoiceNEUROIMMUNOLOGY

Memorable cerebral inflammation

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Science Translational Medicine  09 May 2018:
Vol. 10, Issue 440, eaat8525
DOI: 10.1126/scitranslmed.aat8525

Abstract

Exposure to peripheral inflammation induces microglia to alter subsequent course of stroke and Alzheimer’s pathologies.

Inflammatory processes play a central role in neurological diseases, including stroke, Alzheimer’s disease, and brain tumors. The ability of immune cells to learn from previous experience and adapt their response, defined as immune memory, is classically associated with B- and T cell–mediated adaptive immunity. Recent surprising evidence, however, suggests innate immune cells may recognize and alter response to subsequent stimuli. In the brain, innate immune response is mainly carried out by microglia. Because microglial cells have been shown to possess extended life span, acquisition of immune memory by this cell type would persist for extended periods. Here Wendeln et al. studied microglial immune memory and its effects on the development of subsequent neuropathology.

The authors show that lipopolysaccharide (LPS) intraperitoneal injection in mice triggered two types of immune memories in the brain parenchyma depending on the intensity and duration of the inflammatory stimulus; a single LPS injection induced trained immunity, displayed as increased inflammatory cortical cytokines after subsequent insult. On the contrary, LPS treatment for four consecutive days induced tolerance, a drastic decrease of cortical inflammatory cytokines after a second insult.

Using mouse models of Alzheimer’s disease and stroke, they show that LPS-induced trained immunity worsened the pathology, whereas the induction of tolerance produced a less severe disease phenotype (though stroke exacerbation was muted). Molecular profiling revealed microglial epigenetic reprogramming mediating the training and tolerance paradigms.

The results presented here suggest that peripheral inflammation might have long-term effects on brain cells affecting the severity of neurological diseases. Further evaluation examining whether other cell types and/or more clinically relevant insults may still play a role in the modulation of neuropathology are warranted. Regardless, early peripheral inflammation and microglial response may now represent a risk factor and target in the treatment of a multitude of neurologic diseases.

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