LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis

  1. Chi G Weindel
  2. Samantha L Bell
  3. Krystal J Vail
  4. Kelsi O West
  5. Kristin L Patrick
  6. Robert O Watson  Is a corresponding author
  1. Texas A&M Health Science Center, United States
  2. Texas A&M University College of Veterinary Medicine and Biomedical Sciences, United States

Abstract

The Parkinson's Disease (PD)-associated gene leucine-rich repeat kinase (LRRK2) has been studied extensively in the brain. However, several studies have established that mutations in LRRK2 confer susceptibility to mycobacterial infection, suggesting LRRK2 also controls immunity. We demonstrate that loss of LRRK2 in macrophages induces elevated basal levels of type I interferons (IFN) and interferon stimulated genes (ISGs) and causes blunted interferon responses to mycobacterial pathogens and cytosolic nucleic acid agonists. Altered innate immune gene expression in Lrrk2 knockout (KO) macrophages is driven by a combination of mitochondrial stresses, including oxidative stress from low levels of purine metabolites and DRP1-dependent mitochondrial fragmentation. Together, these defects promote mtDNA leakage into the cytosol and chronic cGAS engagement. While Lrrk2 KO mice can control Mycobacterium tuberculosis (Mtb) replication, they have exacerbated inflammation and lower ISG expression in the lungs. These results demonstrate previously unappreciated consequences of LRRK2-dependent mitochondrial defects in controlling innate immune outcomes.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1 and 5.

Article and author information

Author details

  1. Chi G Weindel

    Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Samantha L Bell

    Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Krystal J Vail

    Veterinary Pathobiology, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, College Station, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1964-7985
  4. Kelsi O West

    Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kristin L Patrick

    Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2442-4679
  6. Robert O Watson

    Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, Bryan, United States
    For correspondence
    robert.watson@tamu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4976-0759

Funding

Michael J. Fox Foundation for Parkinson's Research (M1801235)

  • Robert O Watson

National Institute of Allergy and Infectious Diseases (R21AI40004)

  • Robert O Watson

National Institute of General Medical Sciences (R35GM133720)

  • Kristin L Patrick

Parkinson's Disease Foundation

  • Chi G Weindel

National Institutes of Health (5T32OD011083-10)

  • Krystal J Vail

Michael J. Fox Foundation for Parkinson's Research (12185)

  • Robert O Watson

National Institute of Allergy and Infectious Diseases (1R01AI12551)

  • Robert O Watson

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

Ethics

Animal experimentation: This study followed the recommendations in the Guide for the Care and Use of Laboratory Animals by the National Research Council. All animals were housed, bred, and studied at Texas A&M Health Science Center using protocols reviewed and approved by the institutional animal care and use committee (IACUC) of Texas A&M University (protocol #2018-0125).

Copyright

© 2020, Weindel 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

  • 6,661
    views
  • 1,123
    downloads
  • 84
    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. Chi G Weindel
  2. Samantha L Bell
  3. Krystal J Vail
  4. Kelsi O West
  5. Kristin L Patrick
  6. Robert O Watson
(2020)
LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis
eLife 9:e51071.
https://doi.org/10.7554/eLife.51071

Share this article

https://doi.org/10.7554/eLife.51071

Further reading

    1. Immunology and Inflammation
    Jasmine Rowell, Ching-In Lau ... Tessa Crompton
    Research Article

    Here, we sequenced rearranged TCRβ and TCRα chain sequences in CD4+CD8+ double positive (DP), CD4+CD8- single positive (SP4) and CD4-CD8+ (SP8) thymocyte populations from the foetus and young adult mouse. We found that life-stage had a greater impact on TCRβ and TCRα gene segment usage than cell-type. Foetal repertoires showed bias towards 3’TRAV and 5’TRAJ rearrangements in all populations, whereas adult repertoires used more 5’TRAV gene segments, suggesting that progressive TCRα rearrangements occur less frequently in foetal DP cells. When we synchronised young adult DP thymocyte differentiation by hydrocortisone treatment the new recovering DP thymocyte population showed more foetal-like 3’TRAV and 5’TRAJ gene segment usage. In foetus we identified less influence of MHC-restriction on α-chain and β-chain combinatorial VxJ usage and CDR1xCDR2 (V region) usage in SP compared to adult, indicating weaker impact of MHC-restriction on the foetal TCR repertoire. The foetal TCRβ repertoire was less diverse, less evenly distributed, with fewer non-template insertions, and all foetal populations contained more clonotypic expansions than adult. The differences between the foetal and adult thymus TCR repertoires are consistent with the foetal thymus producing αβT-cells with properties and functions that are distinct from adult T-cells: their repertoire is less governed by MHC-restriction, with preference for particular gene segment usage, less diverse with more clonotypic expansions, and more closely encoded by genomic sequence.

    1. Immunology and Inflammation
    Donal J Cox, Sarah A Connolly ... Joseph Keane
    Research Article

    Airway macrophages (AM) are the predominant immune cell in the lung and play a crucial role in preventing infection, making them a target for host directed therapy. Macrophage effector functions are associated with cellular metabolism. A knowledge gap remains in understanding metabolic reprogramming and functional plasticity of distinct human macrophage subpopulations, especially in lung resident AM. We examined tissue-resident AM and monocyte-derived macrophages (MDM; as a model of blood derived macrophages) in their resting state and after priming with IFN-γ or IL-4 to model the Th1/Th2 axis in the lung. Human macrophages, regardless of origin, had a strong induction of glycolysis in response to IFN-γ or upon stimulation. IFN-γ significantly enhanced cellular energetics in both AM and MDM by upregulating both glycolysis and oxidative phosphorylation. Upon stimulation, AM do not decrease oxidative phosphorylation unlike MDM which shift to ‘Warburg’-like metabolism. IFN-γ priming promoted cytokine secretion in AM. Blocking glycolysis with 2-deoxyglucose significantly reduced IFN-γ driven cytokine production in AM, indicating that IFN-γ induces functional plasticity in human AM, which is mechanistically mediated by glycolysis. Directly comparing responses between macrophages, AM were more responsive to IFN-γ priming and dependent on glycolysis for cytokine secretion than MDM. Interestingly, TNF production was under the control of glycolysis in AM and not in MDM. MDM exhibited glycolysis-dependent upregulation of HLA-DR and CD40, whereas IFN-γ upregulated HLA-DR and CD40 on AM independently of glycolysis. These data indicate that human AM are functionally plastic and respond to IFN-γ in a manner distinct from MDM. These data provide evidence that human AM are a tractable target for inhalable immunomodulatory therapies for respiratory diseases.