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Mitohormesis reprogrammes macrophage metabolism to enforce tolerance
Greg A Timblin1,2, Kevin M Tharp3, Breanna Ford4,5
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. greg.timblin@ucsf.edu.
Nature Metabolism
|May 25, 2021
Summary
Macrophages utilize mitochondrial stress responses, known as mitohormesis, to limit inflammation. This process impairs pro-inflammatory gene transcription, offering a novel anti-inflammatory strategy.
Area of Science:
- Immunology
- Cellular Biology
- Mitochondrial Biology
Background:
- Macrophages produce mitochondrial reactive oxygen and electrophilic species during Toll-like receptor (TLR)-dependent inflammation.
- The impact of this mitochondrial stress on macrophage function remains unclear.
Purpose of the Study:
- To investigate if mitochondrial stress influences macrophage function.
- To determine the role of mitohormesis in TLR-dependent inflammatory responses and macrophage tolerance.
Main Methods:
- Induction of mitochondrial stress in macrophages using pharmacological agents and lipopolysaccharide (LPS).
- Analysis of macrophage responses, including pro-inflammatory gene transcription and mitochondrial metabolism.
- Investigation of hydroxyoestrogen-induced mitohormesis.
Main Results:
- Both pharmacological and LPS-driven mitochondrial stress trigger mitohormesis in macrophages.
- LPS-induced mitohormesis correlates with the transition to an LPS-tolerant state, characterized by impaired pro-inflammatory gene transcription.
- Hydroxyoestrogen-induced mitohormesis suppresses mitochondrial metabolism and acetyl-CoA production, leading to impaired histone acetylation and pro-inflammatory gene expression, enforcing LPS tolerance.
Conclusions:
- Mitochondrial reactive oxygen and electrophilic species act as TLR-dependent signaling molecules that induce mitohormesis.
- Mitohormesis serves as a negative feedback mechanism to restrain inflammation through macrophage tolerance.
- Pharmacologically inducing mitohormesis offers a potential anti-inflammatory strategy by disrupting the epigenetic support of pro-inflammatory gene transcription.
