TREM2 in CNS homeostasis and neurodegenerative disease.
Myeloid-lineage cells accomplish a myriad of homeostatic tasks including the recognition of pathogens, regulation of the inflammatory milieu, and mediation of tissue repair and regeneration. The innate immune receptor and its adaptor protein—triggering receptor expressed on myeloid cells 2 (TREM2) and DNAX-activating protein of 12 kDa (DAP12)—possess the ability to modulate critical cellular functions via crosstalk with diverse signaling pathways. As such, mutations in TREM2 and DAP12 have been found to be associated with a range of disease phenotypes. In particular, mutations in TREM2 increase the risk for Alzheimer's disease and other neurodegenerative disorders. The leading hypothesis is that microglia, the resident immune cells of the central nervous system, are the major myeloid cells affected by dysregulated TREM2-DAP12 function. Here, we review how impaired signaling by the TREM2-DAP12 pathway leads to altered immune responses in phagocytosis, cytokine production, and microglial proliferation and survival, thus contributing to disease pathogenesis.
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Painter.meghan@mayo.edu.
Meghan M
MM
Painter
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Atagi.Yuka@mayo.edu.
Yuka
Y
Atagi
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Liu.chiachen@mayo.edu.|Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, 361102, China. Liu.chiachen@mayo.edu.
Chia-Chen
CC
Liu
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Rademakers.Rosa@mayo.edu.
Rosa
R
Rademakers
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, 361102, China. xuh@sanfordburnham.org.
Huaxi
H
Xu
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Fryer.John@mayo.edu.|Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Fryer.John@mayo.edu.
John D
JD
Fryer
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Bu.Guojun@mayo.edu.|Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian, 361102, China. Bu.Guojun@mayo.edu.|Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Bu.Guojun@mayo.edu.
Guojun
G
Bu
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002490:Central Nervous System / Q000473:pathology / Q000502:physiology*; D016207:Cytokines / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D007113:Immunity, Innate; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D017628:Microglia / Q000473:pathology / Q000502:physiology*; D008954:Models, Biological; D009154:Mutation; D022423:Myeloid Cells / Q000473:pathology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000276:immunology / Q000503:physiopathology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D012038:Regeneration; D051193:Toll-Like Receptors / Q000502:physiology; D014945:Wound Healing
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; C110546:TYROBP protein, human; D051193:Toll-Like Receptors