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Cited by 180TGF-β signaling in diseasesNeuroinflammation and Neurodegeneration MechanismsCell Adhesion Molecules Research

A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System

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Qin, Yan, Garrison, Brian S., Ma, Wenjiang, Wang, Rui, Jiang, Aiping, Li, Jing, Mistry, Meeta, Bronson, Roderick T. +7 more·2018·Cell
DOI 10.1016/j.cell.2018.05.027PMC PMC6089614
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Abstract

Extracellular proTGF-β is covalently linked to "milieu" molecules in the matrix or on cell surfaces and is latent until TGF-β is released by integrins. Here, we show that LRRC33 on the surface of microglia functions as a milieu molecule and enables highly localized, integrin-αVβ8-dependent TGF-β activation. Lrrc33-/- mice lack CNS vascular abnormalities associated with deficiency in TGF-β-activating integrins but have microglia with a reactive phenotype and after 2 months develop ascending paraparesis with loss of myelinated axons and death by 5 months. Whole bone marrow transplantation results in selective repopulation of Lrrc33-/- brains with WT microglia and halts disease progression. The phenotypes of WT and Lrrc33-/- microglia in the same brain suggest that there is little spreading of TGF-β activated from one microglial cell to neighboring microglia. Our results suggest that interactions between integrin-bearing cells and cells bearing milieu molecule-associated TGF-β provide localized and selective activation of TGF-β.

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  • Activated microglia can secrete pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β, IL-18) or anti-inflammatory cytokines (e.g., IL-4, IL-10, TGF-β) depending on the dose, frequency, and context of stimulation.

    “Activated microglia can either secrete pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-18 or anti-inflammatory cytokines such as IL-4, IL-10, and transforming growth factor (TGF)-β depending on the dose, frequency, and context of the stimulation.4–7”

    From Tubular human brain organoids to model microglia-mediated neuroinflammation (2021) · cites this paper as [5]

    The Introduction states that TGF-β1 is constitutively expressed in microglia, and the Discussion describes localized activation of microglia-associated TGF-β1. The paper does not establish the claimed pro- and anti-inflammatory cytokine secretion patterns or their dependence on stimulation dose, frequency, and context. No page numbers are available in our copy. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Upon stimulation by factors such as TLR ligands, Aβ aggregates, complement factors, or opioids, microglia can shift from a homeostatic state to an activated state.

    “Upon stimulation by factors such as toll-like receptor (TLR) ligands, β-amyloid (Aβ) aggregates, complement factors, or opioids, microglia can shift from homeostatic state to an activated state.”

    From Tubular human brain organoids to model microglia-mediated neuroinflammation (2021) · cites this paper as [5]

    The Results section (“Abnormalities in microglia, macrophages, and TGF-β1 in Lrrc33−/− mice”; page not provided) reports that loss of Lrrc33 gave microglia an activated, reactive-like phenotype compared with wild-type microglia. The paper does not identify TLR ligands, Aβ aggregates, complement factors, or opioids as stimuli for that shift; it discusses deficient TGF-β signaling instead. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Qin, Y., Garrison, B. S., Ma, W., Wang, R., Jiang, A., Li, J., Mistry, M., Bronson, R. T., Santoro, D., Franco, C., Robinton, D. A., Stevens, B., Rossi, D. J., Lu, C., & Springer, T. A.
Affiliations
  • Boston Children's Hospital (US)
  • Harvard University (US)
Corresponding author
  • Lu, Chafen
  • Springer, Timothy A.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2018-06
Volume
174
Issue
1
Pages
156-171.e16
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2018.05.027
PMC
PMC6089614
OpenAlex
W2808287878
Cited by
180
References
10
Citations by year
2026: 14 · 2025: 23 · 2024: 26 · 2023: 13 · 2022: 24 · 2021: 28 · 2020: 27 · 2019: 22 · 2018: 3
FWCI
7.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (AR067288)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Keywords
TGF-beta activation, microglia, integrin αvβ8, latent TGF-beta, paraparesis, bone marrow transplantation, microglial repopulation
MeSH terms
Animals, Axons, Brain, Carrier Proteins, Cells, Cultured, Macrophages, Mice, Inbred C57BL, Nervous System, Phylogeny, Protein Binding, Protein Precursors, Integrins, Bone Marrow Transplantation, Transforming Growth Factor beta, Mutagenesis, Site-Directed, Microglia, Mice, Knockout, Neurodegenerative Diseases, Mice, Kaplan-Meier Estimate

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