Triggering receptor expressed on myeloid cells-2 expression in the brain is required for maximal phagocytic activity and improved neurological outcomes following experimental stroke

Abstract

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.

P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis

“…Increasing evidence show that microglial phagocytosis plays a canonical role in neurological recovery after brain injury . Several pathways are involved in microglial phagocytosis after brain injury, including CD36, MerTK, MFG‐E8, TL4, and TREM2 . It is thought that microglial phagocytosis plays a positive role in debris clearance and reconstruction of neuronal networks in brain pathologies such as MS, ALS, trauma .…”

“…[13][14][15]35 Several pathways are involved in microglial phagocytosis after brain injury, including CD36, MerTK, MFG-E8, TL4, and TREM2. [13][14][15]36 It is thought that microglial phagocytosis plays a positive role in debris clearance and reconstruction of neuronal networks in brain pathologies such as MS, ALS, trauma. [37][38][39] Ischemic stroke causes massive cells death in the brain, and microglial phagocytosis is involved in the clearance of dead cell and debris.…”

Mesenchymal stem cell therapy alleviates the neuroinflammation associated with acquired brain injury

“…Activated microglia and astrocytes prolong inflammation into the chronic phase via continued secretion of cytokines, chemokines, and CAMs, thus attracting more peripheral macrophages and neutrophils through the leaky BBB and other novel deleterious microglial and downstream signaling pathways. [21][22][23] Neuronal loss and cerebral edema may result from this progressive inflammation, compromising brain structure and function. 9,[19][20][21] Similar to stroke, the CNS following TBI undergoes a brief, neuroprotective phase during the acute inflammatory response following initial insult, yet this prosurvival stage is inadequate to provide neuroprotection for lasting inflammation.…”

“…A compromised BBB and tissue damage of the parenchyma and cerebral vasculature is linked with the chronic neurodegenerative phase of stroke. 9,23 A weakened endothelial cell barrier promotes infiltration of serum proteins and immune cells, contributing to secondary BBB disruption and heightening the original injury induced by stroke. 15 This worsens physiological damage by elevating cerebral pressure and increasing secondary cell loss.…”

Cofilin-actin rod formation in experimental stroke is attenuated by therapeutic hypothermia and overexpression of the inducible 70 kD inducible heat shock protein (Hsp70)

“…A focal cerebral infarct was induced by permanent occlusion of the left distal middle cerebral artery (dMCAO) as previously described. [21,22] Briefly, a small craniotomy was made above the proximal segment of the middle cerebral artery (MCA), and the MCA was exposed after the dura was opened and retracted. The MCA was occluded by coagulation at the MCA segment just proximal to the olfactory branch.…”