期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 16, 页码 7941-7950出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1818281116
关键词
STING; SAVI; type I interferonopathies; T cells; cell death
资金
- Target Identification in Lupus Grant from the Lupus Research Alliance
- NIH [R01AI128358]
Studies over the past decade have revealed a central role for innate immune sensors in autoimmune and autoinflammatory diseases. cGAS, a cytosolic DNA sensor, detects both foreign and host DNA and generates a second-messenger cGAMP, which in turn binds and activates stimulator of IFN genes (STING), leading to induction of type I interferons and inflammatory cytokines. Recently, gain-of-function mutations in STING have been identified in patients with STING-associated vasculopathy with onset in infancy (SAVI). SAVI patients present with early-onset systemic inflammation and interstitial lung disease, resulting in pulmonary fibrosis and respiratory failure. Here, we describe two independent SAVI mouse models, harboring the two most common mutations found in patients. A direct comparison of these strains reveals a hierarchy of immune abnormalities, lung inflammation and fibrosis, which do not depend on either IFN-alpha/beta receptor signaling or mixed lineage kinase domainlike pseudokinase (MLKL)-dependent necroptotic cell death path-ways. Furthermore, radiation chimera experiments reveal how bone marrow from the V154M mutant mice transfer disease to the WT host, whereas the N1535 does not, indicating mutation-specific disease outcomes. Moreover, using radiation chimeras we find that T cell lymphopenia depends on T cell-intrinsic expression of the SAVI mutation. Collectively, these mutant mice recapitulate many of the disease features seen in SAVI patients and highlight mutation-specific functions of STING that shed light on the heterogeneity observed in SAVI patients.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据