At least 1 million cells die every second in the human body. While the vast majority of those cells die in the context of the normal maintenance of tissue homeostasis, cell death can also be the consequence of an uncontrolled stress such as infection. Therefore, the immune system needs to distinguish the different types of cell death in order to ignore cells dying physiologically, or to mount an adequate immune response in the case of pathological cell death.

Apoptosis is a well described mechanism of cell death, in which mitochondria play a central role. It has long been known that apoptosis is an immunologically silent form of cell death, but the molecular basis of this remains largely unknown. Using mice with genetic deficiencies in the apoptotic machinery, we are uncovering a variety of mechanisms by which cells dying by apoptosis escape immune recognition.

For example, we identified a mechanism by which mitochondria and downstream pro-apoptotic caspases regulate the activation of a cell-intrinsic immune response. Upon permeabilization of mitochondrial membranes in dying cells, mitochondrial DNA (mtDNA) leaks into the cytosol, where it activates the cGAS/STING pathway. This activation triggers an inflammatory response mediated by type I interferons, demonstrating the potent pro-inflammatory potential of mtDNA. However, in apoptotic cells the concomitant caspase activation results in the inhibition of type I interferon expression and the immunologically silent nature of apoptosis.

We are currently investigating a diversity of additional mechanisms by which dying cells affect immune responses. Since cell death is so widespread in the human body, and dysregulated cell death is associated with numerous diseases, our work has the potential to identify new targets for therapeutic interventions.

Selected Publications

Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. A. Rongvaux, R. Jackson, C.C. Harman, T. Li, A.P. West, M.R. de Zoete, Y. Wu, B. Yordy, S.A. Lakhani, C.Y. Kuan, T. Taniguchi, G.S. Shadel, Z.J. Chen, A. Iwasaki, R.A. Flavell. Cell 2014 Dec 18; 159(7):1563-77.

Innate immunity and tolerance toward mitochondria. A. Rongvaux. Mitochondrion. 2018 Jul;41:14-20.