Therapeutic hypothermia, or cooling of the body or brain for the purposes of preserving organ viability, is one of the most robust neuroprotectants at both the preclinical and clinical levels. Although therapeutic hypothermia has been shown to improve outcome from related clinical conditions, the significance in ischemic stroke is still under investigation. Numerous pre-clinical studies of therapeutic hypothermia has suggested optimal cooling conditions, such as depth, duration, and temporal therapeutic window for effective neuroprotection. Several studies have also explored mechanisms underlying the mechanisms of neuroprotection by therapeutic hypothermia. As such, it appears that cooling affects multiple aspects of brain pathophysiology, and regulates almost every pathway involved in the evolution of ischemic stroke. This multifaceted mechanism is thought to contribute to its strong neuroprotective effect. In order to carry out this therapy in optimal clinical settings, methodological and pathophysiological understanding is crucial. However, more investigation is still needed to better understand the underlying mechanisms of this intervention, and to overcome clinical barriers which seem to preclude the routine use therapeutic hypothermia in stroke. This article is part of the Special Issue entitled 'Cerebral Ischemia'.

AQP4, aquaporin-4BBB, blood-brain barrierIba1, ionized calcium-binding adapter molecule 1ICA, internal carotid arteryICAM-1, intracellular adhesion molecule-1I/R, ischemia/reperfusionMCAO, middle cerebral artery occlusionMMP-9, matrix metalloproteinase-9.

Triggering receptor expressed on myeloid cells-2 (TREM2) is an innate immune receptor that promotes phagocytosis by myeloid cells such as microglia and macrophages. We previously showed that TREM2 deficiency worsened outcomes from experimental stroke and impeded phagocytosis. However, myeloid cells participating in stroke pathology include both brain resident microglia and circulating macrophages. We now clarify whether TREM2 on brain microglia or circulating macrophages contribute to its beneficial role in ischemic stroke by generating bone marrow (BM) chimeric mice. BM chimera mice from TREM2 knockout (KO) or wild type (Wt) mice were used as donor and recipient mice. Mice were subjected to experimental stroke, and neurological function and infarct volume were assessed. Mice with intact TREM2 in brain microglia showed better neurological recovery and reduced infarct volumes, compared with mice lacking microglial TREM2. Myeloid cell activation and numbers of phagocytes were decreased in mice lacking brain TREM2, compared with mice with intact brain TREM2. These results suggest that TREM2 expression is important for post-stroke recovery, and that TREM2 expression on brain resident microglia is more essential to this recovery, than that of circulating macrophages. These findings might suggest a new therapeutic target for cerebrovascular diseases.