Scientists in the laboratory of Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care, have discovered how mitochondria influence the body’s immune response through modulating specific cell signaling pathways, according to a recent study published in Science Advances.
The findings highlight the potential of targeting mitochondrial function specifically in immune cells to treat a range of inflammation-related diseases.
“Therapies aimed at improving mitochondrial activity could benefit inflammatory diseases such as inflammatory bowel disease, sepsis, and chronic infections by enhancing the immune system’s ability to regulate inflammation,” said Chandel, also a professor of Biochemistry and Molecular Genetics and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Mitochondria contain the mitochondrial electron transport chain (ETC), or a series of protein complexes in which electrons pass through and produce ATP, or energy, for the cell. Mitochondrial ETC function also controls macrophages, or specialized immune cells that are essential for fighting infections and regulating inflammation in the body.
Macrophages also release an anti-inflammatory protein called IL-10, which reduces inflammation and prevents excess immune responses that can harm the body. The underlying mechanisms that allow mitochondrial ETC to control macrophage immune responses, however, have remained poorly understood.
Using bulk-RNA sequencing to study mice with macrophages deficient in mitochondria ETC complex III, the scientists discovered that a type of reactive oxygen species (ROS), or unstable molecules that contain oxygen and easily react with other molecules in a cell, that is produced by mitochondrial complex III, called superoxide, is critical for macrophages to release IL-10.
The scientists also discovered those mice with the defective mitochondrial complex also struggled to recover from infection and inflammation because their cells released less IL-10. However, activating a specific ROS dependent signaling pathway in the cells restored IL-10 release, according to the study.
“This finding highlights a previously unknown connection between mitochondrial activity, inflammation control and the signaling pathways that regulate it,” Chandel said.
Overall, the findings underscore mitochondria’s essential role beyond energy production and suggest that mitochondria may be a promising therapeutic target for treating a range of inflammatory diseases and enhancing current therapies, according to Chandel.
“Boosting IL-10 levels through mitochondrial pathways offers promise for managing autoimmune disorders like rheumatoid arthritis and lupus, where the immune system mistakenly attacks the body. Enhancing the function of mitochondrial complex III, or mimicking its effects, may also improve recovery from severe infections. Additionally, inhibiting mitochondrial complex III would decrease IL-10 suppression of inflammation, and could cooperate with existing immunotherapies,” Chandel said.
Joshua Stoolman, PhD, a research associate in the Chandel laboratory, was lead author of the study.
Co-authors include Rogan Grant, PhD, a Schmidt Science Fellow at Northwestern, Samuel Weinberg, ‘19 MD, ‘19 PhD, assistant professor of Pathology in the Division of Experimental Pathology, Jason Miska, PhD, assistant professor of Neurological Surgery, and Scott Budinger, MD, the Ernest S. Bazley Professor of Airway Diseases and chief of Pulmonary and Critical Care in the Department of Medicine.
This work was supported by the National Institutes of Health grants 2P01AG049665-06, 5P01HL154998, NI2T32AI083216-11, 1S10OD011996-01, 5P01HL154998 and 5T32HL076139-18; National Cancer Institute grants CCSG P30 CA060553, CCSG P30 CA060553 and 1S10OD011996-01; and Schmidt Science Fellows, in partnership with the Rhodes Trust.
