Editors' ChoiceInflammation

sTREM2 and neuroinflammation

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Sci. Signal.  14 Mar 2017:
Vol. 10, Issue 470, eaan1468
DOI: 10.1126/scisignal.aan1468

The soluble form of the innate immune receptor TREM2 promotes microglial survival and inflammatory responses in the brain.

TREM2 (triggering receptor expressed on myeloid cells 2) is a transmembrane innate immune receptor of the immunoglobulin family, which is found on microglia in the central nervous system. This receptor also undergoes proteolytic cleavage to generate a soluble form (sTREM2), the abundance of which is increased in the cerebrospinal fluid of patients with Alzheimer’s disease (AD). Furthermore, the R47H and R62H mutations in TREM2 are associated with a statistically significant increase in the risk for developing AD. Zhong et al. found that sTREM2 promoted the survival of mouse microglia in vitro by blocking apoptosis when the cells were deprived of GM-GSF, a cytokine that promotes viability. sTREM2 also promoted the expression of genes encoding proinflammatory cytokines in cultured microglia. The ability of sTREM2 to promote microglial survival depended on signaling by the kinase Akt, whereas proinflammatory cytokine production depended on activation of the transcription factor nuclear factor κB. Compared with the wild-type protein, the R47H and R62H TREM2 mutant proteins were less effective at promoting microglial survival or stimulating cytokine production. Last, when administered to the hippocampi of either wild-type or TREM2-deficient mice, sTREM2 stimulated inflammatory cytokine production and induced morphological changes in the microglia consistent with activation. Together, these data indicate that sTREM2 promotes microglial survival and inflammatory responses and suggest that sTREM2 may be a potential target in therapies for AD.

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