Research ArticleImmunology

The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps

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Science Signaling  09 Mar 2021:
Vol. 14, Issue 673, eaax7942
DOI: 10.1126/scisignal.aax7942

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Taking in the NETs

Neutrophils can respond to various microbes by undergoing a form of cell death called NETosis, during which they extrude chromatin, granular proteins, neutrophil elastase, and various antimicrobial peptides. As well as physically trapping and killing microbes, NETs activate macrophages to produce type I interferon (IFN). Apel et al. found that macrophages phagocytosed NETs, components of which translocated from phagolysosomes to the cytosol, where the DNA backbone of the NETs stimulated the innate immune sensor cGAS, leading to type I IFN secretion in vitro. In mice, NETs stimulated IFN production in a cGAS-dependent manner, thus suggesting that cGAS acts as a sensor of NETs to stimulate immune responses during infection.

Abstract

Neutrophil extracellular traps (NETs) are structures consisting of chromatin and antimicrobial molecules that are released by neutrophils during a form of regulated cell death called NETosis. NETs trap invading pathogens, promote coagulation, and activate myeloid cells to produce type I interferons (IFNs), proinflammatory cytokines that regulate the immune system. Here, we showed that macrophages and other myeloid cells phagocytosed NETs. Once in phagosomes, NETs translocated to the cytosol, where the DNA backbones of these structures activated the innate immune sensor cyclic GMP-AMP synthase (cGAS) and induced type I IFN production. The NET-associated serine protease neutrophil elastase (NE) mediated the activation of this pathway. We showed that NET induction in mice treated with the lectin concanavalin A, a model of autoimmune hepatitis, resulted in cGAS-dependent stimulation of an IFN response, suggesting that NETs activated cGAS in vivo. Thus, our findings suggest that cGAS is a sensor of NETs, mediating immune cell activation during infection.

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