Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis.
While there is a strong evidence for neural tissue destruction mediated by adaptive autoimmune responses, it is still debated how innate immune responses contribute to neuroinflammatory and neurodegenerative diseases such as multiple sclerosis and Alzheimer's disease. Recently, it was shown that loss-of-function mutations of the innate microglial immune receptor triggering receptor expressed on myeloid cells-2 (TREM2) led to a chronic neurodegenerative disease, named Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). PLOSL is a recessively inherited disease characterized by early onset adult dementia associated with bone cysts. Since microglial cells are the major TREM2-producing cell type in the central nervous system (CNS), they appear to be plausible candidates for the neurodegenerative pathogenesis of PLOSL. Indeed, TREM2 of microglia fulfils important function of tissue debris clearance and resolution of latent inflammatory reactions. Absence of TREM2 expression on microglia impairs their capacity to phagocytose cell membrane debris and increases their gene transcription of pro-inflammatory cytokines. The disease PLOSL and the finding that TREM2 of microglia is required for tissue debris clearance provide prototypic molecular evidence that dysfunctional innate immunity can be disease causative leading to a chronic neurodegenerative process.
Neumann
Harald
H
Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University Bonn LIFE & BRAIN Center and Hertie-Foundation, Sigmund-Freud-Str. 25, 53127 Bonn, Germany. hneuman1@uni-bonn.de
Takahashi
Kazuya
K
D000818:Animals; D002490:Central Nervous System / Q000166:cytology*; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000276:immunology; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D017628:Microglia / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*
D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human