The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3

Expert opinion

The innate immune system is the host’s first-line of defense for confining infection in the first hours following exposure to a microbial or viral infection. Innate immunity is oldest component of the human immune system and is highly complex. It ensures the initial host defense response and plays an essential role in preventing infection, then directing subsequent development of adaptive immune responses.
Sensing cytosolic DNA from microbial, viral, or host-derived (tumor cells) sources is critical for the immune system to protect the host from infection, leading to activation of the inflammasome. Upon binding DNA, the cyclic GMP-AMP Synthase (cGAS) protein forms cyclic GMP-AMP (cGAMP), a ligand for “Stimulator of Interferon Genes” (STING). Binding cGAMP on STING triggers a complex and sequential cascade of phosphorylation events (TBK1, IRF3), ultimately leading to the transcriptional control of inflammatory genes such as IFN-β. But that is only part of a more complex puzzle…
In this article, Mortiz M. Gaidt investigates the possible link of cGAS-STING with the NLRP3 protein. The NLRP3 inflammasome is regarded as the best-characterized among various inflammasome complexes and has been linked with various human autoinflammatory and autoimmune diseases.
Using human myeloid cells, THP1, or LPS-primed BlaER1 monocytes, he showed how the cGAS-STING-NLRP3 axis was formed and triggered, promoting cytokine production and ultimately leading to lysosomal cell death.
The increasing number of publications on the inflammasome demonstrates its importance in the immune response. The inflammasome is becoming an attractive target for therapeutic intervention in a wide range of inflammatory diseases, including autoimmune diseases and even cancer. There is no longer any doubt that the cGAS-STING pathway, now linked to NLRP3, plays a key role. Furthermore, given the importance of human myeloid cells in so many conditions related to sensing cytosolic DNA, the novel findings presented here contribute valuable information for therapeutic targeting of the cGAS-STING pathway.

Abstract

Detection of cytosolic DNA constitutes a central event in the context of numerous infectious and sterile inflammatory conditions. Recent studies have uncovered a bipartite mode of cytosolic DNA recognition, in which the cGAS-STING axis triggers antiviral immunity, whereas AIM2 triggers inflammasome activation. Here, we show that AIM2 is dispensable for DNA-mediated inflammasome activation in human myeloid cells. Instead, detection of cytosolic DNA by the cGAS-STING axis induces a cell death program initiating potassium efflux upstream of NLRP3. Forward genetics identified regulators of lysosomal trafficking to modulate this cell death program, and subsequent studies revealed that activated STING traffics to the lysosome, where it triggers membrane permeabilization and thus lysosomal cell death (LCD). Importantly, the cGAS-STING-NLRP3 pathway constitutes the default inflammasome response during viral and bacterial infections in human myeloid cells. We conclude that targeting the cGAS-STING-LCD-NLRP3 pathway will ameliorate pathology in inflammatory conditions that are associated with cytosolic DNA sensing.