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

Area of Science:

• Immunology
• Cell Biology
• Genetics

Background:

• The Parkinson's disease (PD)-associated gene, leucine-rich repeat kinase 2 (LRRK2), is primarily studied in the brain.
• Emerging evidence links LRRK2 mutations to susceptibility to mycobacterial infections, suggesting a role in immunity.

Purpose of the Study:

• To investigate the role of LRRK2 in macrophage innate immune responses.
• To elucidate the mechanisms underlying LRRK2's control of immune gene expression and mitochondrial function.

Main Methods:

• Utilized LRRK2 knockout (KO) mouse models and primary macrophages.
• Analyzed type I interferon (IFN) and interferon-stimulated gene (ISG) expression.
• Assessed mitochondrial function, including oxidative stress and fragmentation.
• Investigated mitochondrial DNA (mtDNA) leakage and cGAS pathway activation.
• Evaluated host response to Mycobacterium tuberculosis (Mtb) infection in vivo.

Main Results:

• Loss of LRRK2 in macrophages leads to elevated basal type I IFN and ISG levels.
• LRRK2 deficiency results in blunted IFN responses to mycobacterial pathogens and cytosolic nucleic acid agonists.
• Mitochondrial dysfunction, including oxidative stress and fragmentation, drives altered immune gene expression in LRRK2 KO macrophages.
• Defects promote mtDNA leakage, chronic cGAS engagement, and exacerbated lung inflammation with reduced ISG expression in Mtb-infected LRRK2 KO mice.

Conclusions:

• LRRK2 plays a critical role in regulating innate immune responses in macrophages.
• LRRK2-dependent mitochondrial integrity is essential for proper interferon signaling and response to pathogens.
• Mitochondrial defects associated with LRRK2 loss have significant consequences for innate immunity and host defense.