Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2

Abstract

Elimination of apoptotic neurons without inflammation is crucial for brain tissue homeostasis, but the molecular mechanism has not been firmly established. Triggering receptor expressed on myeloid cells-2 (TREM2) is a recently identified innate immune receptor. Here, we show expression of TREM2 in microglia. TREM2 stimulation induced DAP12 phosphorylation, extracellular signal–regulated kinase phosphorylation, and cytoskeleton reorganization and increased phagocytosis. Knockdown of TREM2 in microglia inhibited phagocytosis of apoptotic neurons and increased gene transcription of tumor necrosis factor α and nitric oxide synthase-2, whereas overexpression of TREM2 increased phagocytosis and decreased microglial proinflammatory responses. Thus, TREM2 deficiency results in impaired clearance of apoptotic neurons and inflammation that might be responsible for the brain degeneration observed in patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy/Nasu-Hakola disease.

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

“…Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune cell surface receptor that facilitates phagocytosis of apoptotic neurons and bacteria, thereby quenching inflammation (N'Diaye, et al, 2009,Takahashi, et al, 2005. Loss-of-function mutations in TREM2 occur in patients suffering from Nasu-Hakola disease, which is characterized by bone cysts and early-onset progressive dementia (Paloneva, et al, 2002).…”

“…TREM2 has been reported to function as a phagocytic receptor for neuronal debris and bacteria (N'Diaye, et al, 2009,Takahashi, et al, 2005. Therefore, it is conceivable that TREM2 may also facilitate the phagocytosis and clearance of extracellularly deposited protein aggregates, such as Aβ plaques.…”

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…TREM2 gene is located on chromosome 6p21.1 and encodes a 26-kDa transmembrane glycoprotein that consists of an extracellular immunoglobulin-like domain, a transmembrane domain, and a short cytoplasmic tail (Colonna 2003). It is an innate immune receptor expressed on the extracellular membrane of activated macrophages, osteoclast, immature dendritic cells, and microglia in the brain (Takahashi et al 2005). Its signaling capacity is carried out through forming a complex with the TYRO protein tyrosine kinase binding protein (TYROBP, also known as DAP12) (Paloneva et al 2002).…”

Microglial Activation in Stroke: Therapeutic Targets

“…Conversely, loss of TREM2 impairs phagocytosis and promotes inflammation. 119 Blockade of TREM2 using a monoclonal antibody in experimental autoimmune encephalomyelitis led to exacerbation of immune responses with increased demyelination and worsened neurological function. 129 Although it has not yet been reported in brain ischemia models, these findings suggest that TREM2 may similarly regulate microglial phagocytosis and inflammatory responses in postischemic brain.…”