Microglia and CD206+ border-associated mouse macrophages maintain their embryonic origin during Alzheimer's disease

  1. Xiaoting Wu
  2. Takashi Saito
  3. Takaomi C Saido
  4. Anna M Barron
  5. Christiane Ruedl  Is a corresponding author
  1. Nanyang Technological University, Singapore
  2. Riken Center for Brain Science, Japan

Abstract

Brain microglia and border-associated macrophages (BAMs) display distinct spatial, developmental, and phenotypic features. Although at steady-state, the origins of distinct brain macrophages are well-documented, the dynamics of their replenishment in neurodegenerative disorders remain elusive, particularly for activated CD11c+ microglia and BAMs. In this study, we conducted a comprehensive fate-mapping analysis of murine microglia and BAMs and their turnover kinetics during Alzheimer's disease (AD) progression. We used a novel inducible AD mouse model to investigate the contribution of bone marrow cells to the pool of foetal-derived brain macrophages during the development of AD. We demonstrated that microglia remain a remarkably stable embryonic-derived population even during the progression of AD pathology, indicating that neither parenchymal macrophage subpopulation originates from, nor are replenished by, bone marrow (BM)-derived cells. At the border-associated brain regions, bona fide CD206+ BAMs are minimally replaced by BM-derived cells, and their turnover rates are not accelerated by AD. In contrast, all other myeloid cells are swiftly replenished by BM progenitors. This information further elucidates the turnover kinetics of these cells not only at steady-state, but also in neurodegenerative diseases, which is crucial for identifying potential novel therapeutic targets.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3 and 4 and supplementary figures

Article and author information

Author details

  1. Xiaoting Wu

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0281-8717
  2. Takashi Saito

    Laboratory for Proteolytic Neuroscience, Riken Center for Brain Science, Wako, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Takaomi C Saido

    Laboratory for Proteolytic Neuroscience, Riken Center for Brain Science, Wako, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Anna M Barron

    Nanyang Technological University, singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Christiane Ruedl

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    For correspondence
    ruedl@ntu.edu.sg
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5599-6541

Funding

Ministry of Education - Singapore (MOE AcRF Tier 1)

  • Christiane Ruedl

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Simon Yona, The Hebrew University of Jerusalem, Israel

Ethics

Animal experimentation: Mice were bred and maintained in a specific pathogen-free animal facility at the Nanyang Technological University (Singapore). All animal studies were carried out according to the recommendations of the National Advisory Committee for Laboratory Animal Research and ARF SBS/NIE 18081, and 19093 protocols were approved by the Institutional Animal Care and Use Committee of the Nanyang Technological University.

Version history

  1. Received: July 2, 2021
  2. Preprint posted: July 5, 2021 (view preprint)
  3. Accepted: October 4, 2021
  4. Accepted Manuscript published: October 5, 2021 (version 1)
  5. Version of Record published: October 18, 2021 (version 2)

Copyright

© 2021, Wu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,122
    views
  • 390
    downloads
  • 19
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Xiaoting Wu
  2. Takashi Saito
  3. Takaomi C Saido
  4. Anna M Barron
  5. Christiane Ruedl
(2021)
Microglia and CD206+ border-associated mouse macrophages maintain their embryonic origin during Alzheimer's disease
eLife 10:e71879.
https://doi.org/10.7554/eLife.71879

Share this article

https://doi.org/10.7554/eLife.71879

Further reading

    1. Cancer Biology
    2. Immunology and Inflammation
    Nicholas J Mullen, Surendra K Shukla ... Pankaj K Singh
    Research Article

    Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

    1. Immunology and Inflammation
    Hyereen Kang, Seong Woo Choi ... Myung-Shik Lee
    Research Article

    We studied lysosomal Ca2+ in inflammasome. Lipopolysaccharide (LPS) + palmitic acid (PA) decreased lysosomal Ca2+ ([Ca2+]Lys) and increased [Ca2+]i through mitochondrial ROS, which was suppressed in Trpm2-KO macrophages. Inflammasome activation and metabolic inflammation in adipose tissue of high-fat diet (HFD)-fed mice were ameliorated by Trpm2 KO. ER→lysosome Ca2+ refilling occurred after lysosomal Ca2+ release whose blockade attenuated LPS + PA-induced inflammasome. Subsequently, store-operated Ca2+entry (SOCE) was activated whose inhibition suppressed inflammasome. SOCE was coupled with K+ efflux whose inhibition reduced ER Ca2+ content ([Ca2+]ER) and impaired [Ca2+]Lys recovery. LPS + PA activated KCa3.1 channel, a Ca2+-activated K+ channel. Inhibitors of KCa3.1 channel or Kcnn4 KO reduced [Ca2+]ER, attenuated increase of [Ca2+]i or inflammasome activation by LPS + PA, and ameliorated HFD-induced inflammasome or metabolic inflammation. Lysosomal Ca2+ release induced delayed JNK and ASC phosphorylation through CAMKII-ASK1. These results suggest a novel role of lysosomal Ca2+ release sustained by ERlysosome Ca2+ refilling and K+ efflux through KCa3.1 channel in inflammasome activation and metabolic inflammation.