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Therapeutic mitochondria treatment amplifies macrophage-mediated phagocytosis and recycling exocytosis
Masayoshi Tanaka1, Shin Ishikane1,2, Dong Bin Back1
1Neuroprotection Research Laboratories, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Abstract:
Therapeutic administration of mitochondria has been increasingly explored. However, how these administered mitochondria impact immune response remains to be fully addressed. In this proof-of-concept study, we show that extracellularly added mitochondria to cultured peritoneal macrophages increase phagocytosis and recycling exocytosis that amplifies neuroplasticity mediated by recycled mitochondria transfer. Macrophage activation markers such as Nos2, Arg1, and Cd163 were unchanged at 3 h post-treatment with mitochondria, but whole mitochondria or delivery of mRNAs extracted from whole mitochondria appeared to increase SQSTM1 protein and activate Nrf2-mediated phagocytosis in macrophages, whereas mitochondria treatment did not change the ability of phagocytosis in cultured microglia or astrocytes. Notably, the once engulfed mitochondria in macrophages appear to be released via Rab27a-mediated recycling pathway that were favorably incorporated in mechanically damaged neurons compared with healthy neurons, resulting in accelerating neurite extension in damaged neurons in a direct co-culture model. Altogether, these findings uncover unappreciated mechanisms that mitochondria-treated macrophages upregulate phagocytosis and recycling exocytosis, implicating that engineering mitochondria delivery to macrophages is a new therapeutic intervention to promote neurorecovery in CNS disorders.
Insights
Therapeutic mitochondria administration enhances macrophage phagocytosis and recycling. Engulfed mitochondria are transferred to damaged neurons, promoting neurite extension and neurorecovery in central nervous system disorders.
Area of Science:
- Immunology and Neuroscience
- Cellular Biology and Therapeutics
Background:
- Therapeutic potential of mitochondria administration is gaining interest.
- The impact of exogenous mitochondria on immune responses requires further investigation.
Purpose of the Study:
- To investigate how extracellular mitochondria influence immune cells, specifically peritoneal macrophages.
- To explore the mechanisms by which mitochondria-treated macrophages promote neuroplasticity and neurorecovery.
Main Methods:
- Treatment of cultured peritoneal macrophages, microglia, and astrocytes with extracellular mitochondria.
- Analysis of macrophage activation markers (Nos2, Arg1, Cd163), SQSTM1 protein, and Nrf2 pathway activation.
- Co-culture model of macrophages and mechanically damaged neurons to assess mitochondria transfer and neurite extension.
Main Results:
- Extracellular mitochondria enhanced phagocytosis and recycling exocytosis in macrophages, but not in microglia or astrocytes.
- Mitochondria treatment increased SQSTM1 protein and activated Nrf2-mediated phagocytosis in macrophages.
- Macrophages released engulfed mitochondria via a Rab27a-mediated pathway, which were preferentially incorporated by damaged neurons, accelerating neurite extension.
Conclusions:
- Mitochondria-treated macrophages exhibit upregulated phagocytosis and recycling exocytosis.
- Engineered mitochondria delivery to macrophages represents a novel therapeutic strategy for promoting neurorecovery in central nervous system disorders.
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