Τίτλος:
REDD1/autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A)
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Objectives The release of neutrophil extracellular traps (NETs) represents a novel neutrophil effector function in systemic lupus erythematosus (SLE) pathogenesis. However, the molecular mechanism underlying NET release and how NETs mediate end-organ injury in SLE remain elusive. Methods NET formation and NET-related proteins were assessed in the peripheral blood and biopsies from discoid lupus and proliferative nephritis, using immunofluorescence, immunoblotting, quantitative PCR and ELISA. Autophagy was assessed by immunofluorescence and immunoblotting. The functional effects of NETs in vitro were assessed in a primary fibroblast culture. Results Neutrophils from patients with active SLE exhibited increased basal autophagy levels leading to enhanced NET release, which was inhibited in vitro by hydroxychloroquine. NETosis in SLE neutrophils correlated with increased expression of the stress-response protein REDD1. Endothelin-1 (ET-1) and hypoxia-inducible factor-1α (HIF-1α) were key mediators of REDD1-driven NETs as demonstrated by their inhibition with bosentan and L-ascorbic acid, respectively. SLE NETs were decorated with tissue factor (TF) and interleukin-17A (IL-17A), which promoted thrombin generation and the fibrotic potential of cultured skin fibroblasts. Notably, TF-bearing and IL-17A-bearing NETs were abundant in discoid skin lesions and in the glomerular and tubulointerstitial compartment of proliferative nephritis biopsy specimens. Conclusions Our data suggest the involvement of REDD1/autophagy/NET axis in end-organ injury and fibrosis in SLE, a likely candidate for repositioning of existing drugs for SLE therapy. Autophagy-mediated release of TF-bearing and IL-17A-bearing NETs provides a link between thromboinflammation and fibrosis in SLE and may account for the salutary effects of hydroxychloroquine. © © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Συγγραφείς:
Frangou, E.
Chrysanthopoulou, A.
Mitsios, A.
Kambas, K.
Arelaki, S.
Angelidou, I.
Arampatzioglou, A.
Gakiopoulou, H.
Bertsias, G.K.
Verginis, P.
Ritis, K.
Boumpas, D.T.
Περιοδικό:
Annals of the Rheumatic Diseases
Εκδότης:
BMJ Publishing Group
Λέξεις-κλειδιά:
ascorbic acid; bosentan; endothelin 1; heat shock protein; hydroxychloroquine; hypoxia inducible factor 1alpha; interleukin 17; protein REDD1; thrombin; thromboplastin; unclassified drug; DDIT4 protein, human; IL17A protein, human; interleukin 17; thromboplastin; transcription factor, Article; autophagy; blood; clinical article; controlled study; discoid lupus erythematosus; enzyme linked immunosorbent assay; extracellular trap; fibroblast culture; fibrosis; human; human cell; human tissue; immunoblotting; immunofluorescence; in vitro study; inflammation; molecular mechanics; nephritis; pathogenesis; polymerase chain reaction; priority journal; protein expression; skin biopsy; skin fibroblast; systemic lupus erythematosus; autophagy; cell culture technique; extracellular trap; fibroblast; fibrosis; inflammation; metabolism; physiology; signal transduction; systemic lupus erythematosus; thrombosis, Autophagy; Cell Culture Techniques; Extracellular Traps; Fibroblasts; Fibrosis; Humans; Inflammation; Interleukin-17; Lupus Erythematosus, Systemic; Signal Transduction; Thromboplastin; Thrombosis; Transcription Factors
DOI:
10.1136/annrheumdis-2018-213181
