Triggering Receptor Expressed on Myeloid Cells-2 Correlates to Hypothermic Neuroprotection in Ischemic Stroke

Hypothermia is neuroprotective against many acute neurological insults, including ischemic stroke. We and others have previously shown that protection by hypothermia is partially associated with an anti-inflammatory effect. Phagocytes are thought to play an important role in the clearance of necrotic debris, paving the way for endogenous repair mechanisms to commence, but the effect of cooling and phagocytosis has not been extensively studied. Triggering receptor expressed on myeloid cells-2 (TREM2) is a newly identified surface receptor shown to be involved in phagocytosis. In this study, we examined the effect of therapeutic hypothermia on TREM2 expression. Mice underwent permanent middle cerebral artery occlusion (MCAO) and were treated with one of the two cooling paradigms: one where cooling (30 degrees C) began at the onset of MCAO (early hypothermia [eHT]) and another where cooling began 1 hour later (delayed hypothermia [dHT]). In both groups, cooling was maintained for 2 hours. A third group was maintained at normothermia (NT) as a control (37 degrees C). Mice from the NT and dHT groups had similar ischemic lesion sizes and neurological performance, but the eHT group showed marked protection as evidenced by a smaller lesion size and less neurological deficits up to 30 days after the insult. Microglia and macrophages increased after MCAO as early as 3 days, peaked at 7 days, and decreased by 14 days. Both hypothermia paradigms were associated with decreased numbers of microglia and macrophages at 3 and 7 days, with greater decreases in the early paradigm. However, the proportion of the TREM2-positive microglia/macrophages was actually increased among the eHT group at day 7. eHT showed a long-term neurological benefit, but neuroprotection did not correlate to immune suppression. However, hypothermic neuroprotection was associated with a relative increase in TREM2 expression, and suggests that TREM2 may serve a beneficial role in brain ischemia.