TREM2 activation reduces white matter injury via PI3K/Akt/GSK‐3β signalling after intracerebral haemorrhage

BACKGROUND: White matter injury (WMI) considerably exacerbates the prognosis following intracerebral haemorrhage (ICH). While the triggering receptor on myeloid cells 2 (TREM2) is recognized for its neuroprotective roles in a range of neurological disorders through the modulation of neuroinflammation, phagocytosis, promoting cell survival, its specific function in WMI after ICH has yet to be fully elucidated. METHODS: This study involved inducing ICH in mice through autologous blood injection. Neurological functions were tested via behavioural assessments and electrophysiological recordings. WMI was examined using immunofluorescence, Luxol fast blue staining, MRI and transmission electron microscopy. Microglia were isolated and analysed using real-time polymerase chain reaction (PCR). Microglia depletion was achieved with PLX3397, primary cultures of microglia and oligodendrocytes were investigated. RESULTS: The activation of TREM2 resulted in improved neurological outcomes after ICH, correlated with reduced WMI, demonstrated by decreased white matter loss in the corpus striatum, reduced damage to the nodes of Ranvier, and better preservation of myelin and white matter tract integrity. These neuroprotective effects were attributed to changes in microglial states mediated via the PI3K/Akt/GSK-3β signalling pathway. However, the neuroprotective advantages conferred by TREM2 activation were negated in TREM2 KO mice, either through microglia depletion or inhibition of PI3K. CONCLUSIONS: This research is the first to illustrate that TREM2 activation mitigates WMI following ICH through a microglia-dependent mechanism involving the PI3K/Akt/GSK-3β pathway. TREM2 represents a potential therapeutic target for ICH.