Abstract
Rare sequence variants in the microglial cell surface receptor TREM2 have been shown to increase the risk for Alzheimer’s disease (AD). Disease-linked TREM2 mutations seem to confer a partial loss of function, and increasing TREM2 cell surface expression and thereby its function(s) might have therapeutic benefit in AD. However, druggable targets that could modulate microglial TREM2 surface expression are not known. To identify such targets, we conducted a screen of small molecule compounds with known pharmacology using human myeloid cells, searching for those that enhance TREM2 protein at the cell surface. Inhibitors of the kinases MEK1/2 displayed the strongest and most consistent increases in cell surface TREM2 protein, identifying a previously unreported pathway for TREM2 regulation. Unexpectedly, inhibitors of the downstream effector ERK kinases did not have the same effect, suggesting that noncanonical MEK signaling regulates TREM2 trafficking. In addition, siRNA knockdown experiments confirmed that decreased MEK1 and MEK2 were required for this recruitment. In iPSC-derived microglia, MEK inhibition increased cell surface TREM2 only modestly, so various cytokines were used to alter iPSC microglia phenotype, making cells more sensitive to MEK inhibitor-induced TREM2 recruitment. Of those tested, only IFN-gamma priming prior to MEK inhibitor treatment resulted in greater TREM2 recruitment. These data identify the first known mechanisms for increasing surface TREM2 protein and TREM2-regulated function in human myeloid cells and are the first to show a role for MEK1/MEK2 signaling in TREM2 activity.
Highlights
Interest in microglial biology in neurodegenerative disease has intensified since genome-wide association studies revealed multiple microglia-specific gene risk variants for Alzheimer’s disease (AD)
In this study we show that it is possible to double cell surface triggering receptor expressed on myeloid cells-2 (TREM2) protein on human myeloid cells, the largest magnitude of increase in cell surface TREM2 that has been described
There is a wealth of knowledge from TREM2-deficient mice, but far less is known about human myeloid cell responses to TREM2 perturbations, and we chose to limit our work to human cells
Summary
Interest in microglial biology in neurodegenerative disease has intensified since genome-wide association studies revealed multiple microglia-specific gene risk variants for Alzheimer’s disease (AD). Validation of these compounds by an orthogonal methodology, flow cytometry, involving treating THP1 cells with MEK1/2 inhibitor trametinib at the doses indicated followed by immunostaining, revealed a similar effect (Fig. 2C). One ERK inhibitor increased surface TREM2, with an EC50 of 1 μM (Table 1); this compound inhibits ERK2 enzyme with an IC50 value
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