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Cited by 77Neuroinflammation and Neurodegeneration MechanismsBone Metabolism and DiseasesInflammasome and immune disorders

The TREM2-DAP12 signaling pathway in Nasu–Hakola disease: a molecular genetics perspective

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Humphrey, Mary Beth, Xing, Junjie, Titus, Amanda·2015·Research and Reports in Biochemistry
DOI 10.2147/rrbc.s58057PMC PMC4605443
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Abstract

Abstract: Nasu–Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a rare recessively inherited disease that is associated with early dementia and bone cysts with fractures. Here, we review the genetic causes of PLOSL with loss-of-function mutations or deletions in one of two genes, TYROBP and TREM2 , encoding for two proteins DNAX-activating protein 12 (DAP12) and triggering receptor expressed on myeloid cells-2 (TREM2). TREM2 and DAP12 form an immunoreceptor signaling complex that mediates myeloid cell, including microglia and osteoclasts, development, activation, and function. Functionally, TREM2-DAP12 mediates osteoclast multi-nucleation, migration, and resorption. In microglia, TREM2-DAP12 participates in recognition and apoptosis of neuronal debris and amyloid deposits. Review of the complex immunoregulatory roles of TREM2-DAP12 in the innate immune system, where it can both promote and inhibit pro-inflammatory responses, is given. Little is known about the function of TREM2-DAP12 in normal brain homeostasis or in pathological central nervous system diseases. Based on the state of the field, genetic testing now aids in diagnosis of PLOSL, but therapeutics and interventions are still under development. Keywords: polycystic, leukoencephalopathy, Alzheimer's, lipomembranous, dementia, microglia

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  • TREM2 expression is restricted to myeloid lineage, including dendritic cells and monocytes, as well as parenchymal macrophages residing in various tissues/organs, such as the lungs, bones and liver.

    “TREM2 expression is restricted to myeloid lineage, including dendritic cells and monocytes, as well as parenchymal macrophages residing in various tissues/organs, such as the lungs, bones and liver [4, 23]”

    From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [4]

    The “TREM2 and DAP12 expression” section says TREM2 is expressed in myeloid-lineage macrophages, osteoclasts and dendritic cells. It lists monocytes for DAP12, not TREM2, and does not establish TREM2 expression in resident macrophages of the lungs or liver. It also reports disputed evidence of expression in neurons and oligodendrocytes, so it does not establish that expression is restricted to the myeloid lineage. Page numbers were not provided in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • TREM2 and PLCγ2 signalling has been shown to regulate several immune functions in macrophages, promoting both pro- or anti-inflammatory responses, depending on cellular state and influence of the local environment.

    “TREM2 and PLCγ2 signalling has been shown to regulate several immune functions in macrophages, promoting both pro- or anti-inflammatory responses, depending on cellular state and influence of the local environment [4].”

    From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [4]

    The sections “TREM2 and DAP12 mediate innate immune responses” and “TREM2 and DAP12 intracellular signaling” describe immune activation and inhibition, including suppression of pro-inflammatory responses in macrophages. However, the paper identifies the pathway as TREM2–DAP12, mentions PLC-γ without specifying PLCγ2, and does not establish that TREM2–PLCγ2 signaling promotes both pro- and anti-inflammatory responses according to cellular state and local environment. Page numbers are not available in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • TREM2 and PLCγ2 are important for osteoclast development and function.

    “TREM2 and PLCγ2 are important for osteoclast development and function [4]”

    From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [4]

    The section “TREM2 and DAP12 mediate OC development and function” says TREM2 is important for osteoclast differentiation and bone-resorbing function. “TREM2 and DAP12 intracellular signaling” discusses PLC-γ as a downstream signaling component, but does not identify PLCγ2 specifically or establish its importance for osteoclast development and function. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Humphrey, M. B., Xing, J., & Titus, A.
Affiliations
University of Oklahoma Health Sciences Center (US)
ORCID
Venue
Research and Reports in Biochemistry
Publisher
Informa UK Limited
Published
2015-03
Volume
5
Pages
89
ISSN
2230-3154 (ISSN-L)
DOI
10.2147/rrbc.s58057
PMC
PMC4605443
OpenAlex
W2022794439
Cited by
77
References
16
Citations by year
2026: 4 · 2025: 6 · 2024: 9 · 2023: 4 · 2022: 8 · 2021: 12 · 2020: 8 · 2019: 3 · 2018: 8 · 2017: 10 · 2016: 4 · 2015: 1
FWCI
3.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Research and Reports in Biochemistry (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc)
  • PubMed Central (acceptedVersion, cc-by-nc)
  • DOAJ (DOAJ: Directory of Open Access Journals) (acceptedVersion)
  • Dove Medical Press (Taylor and Francis Group) (submittedVersion, other-oa)
Funders
National Institute of Dental and Craniofacial Research (R01DE019398)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
Nasu-Hakola disease, TREM2, DAP12, TYROBP, microglia, osteoclasts, bone cysts, dementia, loss-of-function mutations, genetic diagnosis, innate immunity, amyloid clearance, neuroinflammation

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