Date: Sunday, November 5, 2017
Session Title: Pediatric Rheumatology – Pathogenesis and Genetics
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: Pulmonary fibrosis, is a life-threatening complication of the monogenic autoinflammatory interferonopathy, STING-Associated Vasculopathy with onset in Infancy (SAVI) that is caused by gain-of-function mutations in the viral sensor/adaptor TMEM173/STING. Pathogenic mechanisms causing fibrosis and factors modifying the onset and severity of lung fibrosis in SAVI patients (pts.) are unknown. Here we show that STING-mediated endothelial cell activation induces an endothelial-mesenchymal transition (EndMT)-like differentiation program that causes lung fibrosis in SAVI pts.
Methods: To understand the role of STING signaling in pulmonary fibrosis, we assessed chest computed tomography (CT), pulmonary function tests (PFTs) in 13 SAVI patients (pts.), and lung histopathology was available from 4 pts. We conducted pts. and control fibroblast, human lung and umbilical vein endothelial cell (EC) lines (HMVEC-L and HUVECs, respectively) and pts. and control induced pluripotent stem cell (iPSC)-derived EC stimulations with endogenous and microbial cGAMP plus/minus IFNb. Gene expression (q-RT-PCR, RNA-seq), cytokine production, and EndMT (by cell morphology and gene expression studies), were assessed. Pts. were genotyped for a common STING SNP (R232H, rs1131769) and the modifying effect of the variant was examined in transfection studies in HEK293T cells.
Results: Of 13 SAVI pts., 10 had severe lung disease, 4 succumbed to pulmonary complications. Pulmonary findings included hilar lymphadenopathy, diffuse ground glass opacities and cystic emphysematous changes on chest CT, and reduced diffusing lung capacity for carbon monoxide (DLCO) and abnormal 6-minute walk test on PFTs. In contrast to control lung biopsies (n=5), pts.’ biopsies (n=4) displayed perivascular fibrosis on Masson’s trichrome-stain around medium-sized and small alveolar vessels. In pts., endothelial lining co-expressed mesenchymal (α-SMA) and stromal fibroblast (FSP-1) markers within the subendothelial compartment. cGAMP stimulation in pt. and control fibroblasts showed no expression of myofibroblast and extracellular matrix (ECM) markers by RNA-seq and q-RT-PCR. Endogenous cGAMP stimulation on HMVEC-L induced morphologic transition to fibroblasts with a decreased expression of EC markers CDH5 (V-cadherin), VWF and PECAM1 (CD31), and an increased expression of the mesenchymal markers ACTA2 (α-SMA) and FAP and of the stromal fibroblast marker S100A4 (FSP-1). IFNβ and cGAMP stimulation synergize and addition of a JAK inhibitor attenuated the mesenchymal transformation. IPSC-derived EC (iEC) from 4 SAVI pts. but not HCs spontaneously differentiated into myofibroblasts in culture. Differentiation was attenuated by JAK inhibition and in shRNA STING knock down iEC. Homozygosity for R232/R232, a STING SNP associated with increased IFNβ production, in addition to the SAVI STING mutation led to a more severe clinical lung phenotype in SAVI patients.
Conclusion: We suggest a novel pathway of STING-mediated ECs activation to induce EndMT-like mesenchymal transformation as cause for lung fibrosis in SAVI pts.
To cite this abstract in AMA style:Malle L, Yang D, Almeida de Jesus A, Chen G, Marrero B, Montealegre Sanchez GA, Liu Y, Dueckers G, Ramsey S, Fontana J, VanTries R, Huang Y, Santiago L, Gonzalez B, Brogan P, Brunner J, Omoyinmi E, Ramanan AV, Paller A, Jones OY, Ozen S, Brooks SR, Boehm M, Goldbach-Mansky R. Stimulator of Interferon Genes (STING)-Induced Endothelial-Mesenchymal Transition (EndMT) Contributes to Interstitial Lung Disease in Sting-Associated Vasculopathy with Onset in Infancy (SAVI) Patients [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/stimulator-of-interferon-genes-sting-induced-endothelial-mesenchymal-transition-endmt-contributes-to-interstitial-lung-disease-in-sting-associated-vasculopathy-with-onset-in-infancy-savi-patient/. Accessed January 25, 2021.
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