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

Abstract

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°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°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.

TREM2-Ligand Interactions in Health and Disease

“…These findings suggest a more general defect in activation [64–66]. Other studies examining the role of TREM2 in stroke have found increased expression following ischemic attack [39, 67, 68]. As in the other cases, these studies found that Trem2 deficiency decreased inflammation, impaired microglial activation, and resulted in a failure of microglia to cluster at scar tissue [39, 67].…”

Still cooling after all these years: Meta-analysis of pre-clinical trials of therapeutic hypothermia for acute ischemic stroke

“…We used the normalized mean difference of all treatment effects to allow pooling and statistical comparisons, but this approach ignores critical differences in methodology among the trials. 7 Perhaps reflecting investigator awareness that shallower target temperatures require longer durations, treatment duration was longer if target temperature was higher than 34 C and this introduces an obvious bias into our meta-regression since temperature and duration were not independent; further randomized investigations of target depth, treatment delay, and duration must be completed. Although investigated in a limited number of studies, additional presumed neuro-protective therapy administered concomitant with TH did not provide better functional or histological outcomes compared with TH alone.…”

The role of the microglia in acute CNS injury

“…Protection by hypothermia has been shown to be related, in part, to inhibiting microglial activation and reducing elaboration of many pro-inflammatory immune molecules (Yenari and Han 2012; Han et al 2002). However, as mentioned above, hypothermic neuroprotection has also been associated with the upregulation of the pro-phagocytic molecule, TREM2 (Kawabori et al 2013). …”

“…Conversely, loss of TREM2 impairs phagocytosis and promotes inflammation (Takahashi et al 2005). In a model of neuroprotection by therapeutic hypothermia, our group found that while therapeutic cooling led to decreased activated microglia and other pro-immune responses, TREM2 was actually increased on microglia of brains protected from ischemia, suggesting that TREM2 was correlated to improved stroke outcome (Kawabori et al 2013). Thus, some phagocytic pathways of microglia may potentiate damage, while other pathways may ameliorate it.…”