Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans.

Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the brain, retina, liver, and kidney. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3'-5' DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of radiation injury, we reasoned that nuclear TREX1 would cause DNA damage. Here, we show that RVCL-associated TREX1 variants trigger DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.

STING-associated lung disease in mice relies on T cells but not type I interferon.

BACKGROUND: Monogenic interferonopathies are thought to be mediated by type I interferon. For example, a gain-of-function mutation in stimulator of interferon genes (STING; N153S) upregulates type I interferon-stimulated genes and causes perivascular inflammatory lung disease in mice. The equivalent mutation in human subjects also causes lung disease, which is thought to require signaling through the cyclic GMP-AMP synthase (cGAS)-STING pathway and subsequent activation of interferon regulatory factors (IRFs) 3 and 7, type I interferon, and interferon-stimulated genes. OBJECTIVE: We set out to define the roles of cGAS, IRF3, IRF7, the type I interferon receptor (IFN-α and IFN-ß receptor subunit 1 [IFNAR1]), T cells, and B cells in spontaneous lung disease in STING N153S mice. METHODS: STING N153S mice were crossed to animals lacking cGAS, IRF3/IRF7, IFNAR1, adaptive immunity, αß T cells, and mature B cells. Mice were evaluated for spontaneous lung disease. Additionally, bone marrow chimeric mice were assessed for lung disease severity and survival. RESULTS: Lung disease in STING N153S mice developed independently of cGAS, IRF3/IRF7, and IFNAR1. Bone marrow transplantation revealed that certain features of STING N153S-associated disease are intrinsic to the hematopoietic compartment. Recombination-activating gene 1 (Rag1)-/- STING N153S mice that lack adaptive immunity had no lung disease, and T-cell receptor ß chain (Tcrb)-/- STING N153S animals only had mild disease. STING N153S led to a reduction in percentages and numbers of naive and regulatory T cells, as well as an increased frequency of cytokine-producing effector T cells. CONCLUSION: Spontaneous lung disease in STING N153S mice develops independently of type I interferon signaling and cGAS. STING N153S relies primarily on T cells to promote lung disease in mice.

A Truncated IL-17RC Peptide Ameliorates Synovitis and Bone Destruction of Arthritic Mice.

Peptide-based therapy, such as modified peptides, has attracted increased attention. IL-17 is a promising therapeutic target for autoimmune diseases, and levels of circulating bioactive IL-17 are associated with rheumatoid arthritis severity. In this study, a modified truncated IL-17RC is generated to ameliorate inflammation and bone destruction in arthritis. The truncated IL-17RC binds to both IL-17A and IL-17F with higher binding capacity compared to nonmodified IL-17RC. In addition, the truncated IL-17RC reduces the secretion of inflammatory and osteoclastogenic factors induced by IL-17A/F in vitro. Moreover, the administration of truncated IL-17RC dramatically improves symptoms of inflammation and inhibited bone destruction in collagen-induced arthritis mice. Collectively, these data demonstrate that modified truncated IL-17RC peptide may be a more effective treatment strategy in the simultaneous inhibition of both IL-17A and IL-17F signaling, whereas the existing agents neutralize IL-17A or IL-17F alone. These suggest that the truncated IL-17RC may be a potential candidate in the treatment of inflammatory associated bone diseases.