Wolfgang Junger, PhD
Professor of Surgery, Harvard Medical School
Mona Arbab, MD
Yi Bao, PhD
Mahtab Fakhari, MD
Carola Ledderose, PhD
Yutaka Kondo, MD, PhD
Xiaoou Li, MD
Christian Slubowski, PhD
Koichiro Sueyoshi, MD, PhD
Immune cells release cellular ATP that fuels inside-out signaling mechanisms that regulate the activation and functions of neutrophils and T lymphocytes. Under normal circumstances, the released ATP regulates chemotaxis and proliferation of immune cells through autocrine feedback mechanisms that involve ATP and adenosine receptors. These purinergic signaling mechanisms regulate calcium influx and other downstream signaling pathways that are required for proper function of neutrophils and T lymphocytes. However, severe injuries, burns, and infections can cause the release of ATP from inflamed and damaged tissues. This systemic ATP interferes with the autocrine purinergic signaling mechanisms that regulate immune cell responses. This results in immune dysfunction that causes clinical complications such as multiple organ failure, immunosuppression, and sepsis. The focus of this laboratory has been to define the cellular and molecular mechanisms that lead to these complications.
Our work has revealed a complex network of metabolic pathways that regulate ATP release and the purinergic signaling mechanisms that control immune cell functions. This network involves mitochondria that produce the ATP that fuels purinergic signaling. Thus, mitochondria are the link between the metabolic and calcium signaling events and the purinergic signaling mechanisms that regulate immune cell functions. We found that mitochondrial function in T cells is reduced in critical care patients and that impaired mitochondrial ATP production is directly correlated with the severity of sepsis. Our studies suggest that pharmacological targeting of purinergic signaling is a promising new approach to restore immune competence in critical care and trauma patients.
Ad hoc reviewer for scientific journals including Nature, Science, Nature Reviews, Nature Medicine, Nature Biotechnology, Nature Communications, Nature Medicine, Science Signaling, PLoS ONE, EMBO Journal, Shock, Critical Care Medicine, Purinergic Signalling, Journal of Clinical Investigations, Journal of Leukocyte Biology, FASEB Journal, and many more
- Reviewer of grant proposals submitted to National Institutes of Health, the Swiss National Research Foundation, the French National Research Agency, Israeli National Research Foundation, Austrian National Research Foundation, and Belgium National Research Foundation, Wellcome Trust, and others
- Faculty mentor for underrepresented minority medical students; Harvard Medical School, Boston
- Invited plenary session speaker at the Conference on Shock Wave Therapy in Vienna, Austria; invited plenary speaker at the CD38 & CD157 Brainstorming Meeting in Mantua, Italy.
- Visiting Professor Brown University, Providence, Rhode Island
- Editorial Board member of the journal Shock: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches; Associated Editor of Purinergic Signalling
Teaching, Training, and Education
Advisor and career counseling of Yi Bao, PhD, and Carola Ledderose, PhD
- Thesis advisor of medical students from the Paracelsus Medical University, Salzburg, Austria
- Program Director of Harvard Trauma Inflammation Training Program
- Thesis advisor of master students from the Fachhochschule Technikum, Vienna, Austria
- Faculty mentor of T32 fellows enrolled in the Harvard Trauma Inflammation Training Program
Selected Research Support
Neutrophil activation and trauma; NIH, 1999-2017; PI: Wolfgang Junger, PhD
Autocrine regulation of neutrophil chemotaxis; NIH, 2009-2019; PI: Wolfgang Junger, PhD
Administrative supplement for neutrophil activation and trauma grant; NIH, 2013-2016; PI: Wolfgang Junger, PhD
Regulation of T cell signaling in trauma; NIH, 2013-2018; PI: Wolfgang Junger, PhD
Harvard Trauma Inflammation Training Program; NIH, 2013-2018; PD: Wolfgang Junger, PhD
Chronic subdural hematoma and inflammation; Eleanor and Miles Shore Fellowship Program; 2014-2016; Co-Investigator: Wolfgang Junger, PhD (PI: Martina Stippler, MD)
Li X, Kondo Y, Bao Y, Staudenmaier L, Lee A, Zhang J, Ledderose C, Junger WG. Systemic adenosine triphosphate impairs neutrophil chemotaxis and host defense in sepsis. Crit Care Med 2017;45(1):e97-e104.
Ledderose C, Bao Y, Kondo Y, Fakhari M, Slubowski C, Zhang J, Junger WG. Purinergic signaling and the immune response in sepsis: A review. Clin Ther 2016;38(5):1054-65.
Ledderose C, Woehrle T, Ledderose S, Strasser K, Seist R, Bao Y, Zhang J, Junger WG. Cutting off the power: Inhibition of leukemia cell growth by pausing basal ATP release and P2X receptor signaling? Purinergic Signal 2016;12(3):439-51.
Gupta PK, Godec J, Wolski D, Adland E, Yates K, Pauken KE, Cosgrove C, Ledderose C, Junger WG, Robson SC, Wherry EJ, Alter G, Goulder PJ, Klenerman P, Sharpe AH, Lauer GM, Haining WN. CD39 expression identifies terminally exhausted CD8+ T cells. PLoS Pathog 2015;11(10):e1005177.
Bao Y, Ledderose C, Graf AF, Brix B, Birsak T, Lee A, Zhang J, Junger WG. mTOR and differential activation of mitochondria orchestrate neutrophil chemotaxis. J Cell Biol 2015;210(7):1153-64.
Ledderose C, Bao Y, Ledderose S, Woehrle T, Heinisch M, Yip L, Zhang J, Robson SC, Shapiro NI, Junger WG. Mitochondrial dysfunction, depleted purinergic signaling, and defective T cell vigilance and immune defense. J Infect Dis 2016;213(3):456-64.