Which immune cells trigger inflammation when mice cannot properly clear their own DNA?

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The cyclic GMP-AMP (cGAMP) synthase (cGAS)–stimulator of interferon genes (STING) pathway detects DNA in the cytosol, providing immune defense against pathogens and cancer. When overactivated, however, this pathway can also cause autoimmunity.

The DNA-degrading enzyme three prime repair exonuclease 1 (TREX1) breaks down DNA in the cytosol and prevents the body's own DNA from activating cGAS. Loss-of-function mutations in the TREX1 gene are linked to autoimmune diseases such as Aicardi–Goutières syndrome. Mice lacking TREX1 develop lethal inflammation that depends on cGAS.

To identify the cell type in which cGAS activation drives autoinflammation, the researchers generated conditional cGAS knockout mice on a Trex1−/− background, allowing them to delete cGAS in specific cell types in mice lacking TREX1.

Deleting the cGAS gene in classical dendritic cells (cDCs), but not in macrophages, was sufficient to rescue Trex1−/− mice from all observed disease features. These included lethality, T cell activation, tissue inflammation, antinuclear antibody production, and expression of interferon-stimulated genes.

The findings show that cGAS activation in classical dendritic cells causes autoinflammation in response to the body's own DNA accumulating in the absence of TREX1.