Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury

Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury

Abstract Type 1 interferons (IFN) protect the host against viruses by engaging a cognate receptor (consisting of IFNAR1/IFNAR2 chains) and inducing downstream signaling and gene expression. However, inflammatory stimuli can trigger IFNAR1 ubiquitination and downregulation thereby attenuating IFN eff...

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Bibliographic Details
Main Authors: Sabyasachi Bhattacharya, Kanstantsin V Katlinski, Maximilian Reichert, Shigetsugu Takano, Angela Brice, Bin Zhao, Qiujing Yu, Hui Zheng, Christopher J Carbone, Yuliya V Katlinskaya, N Adrian Leu, Kelly A McCorkell, Satish Srinivasan, Melanie Girondo, Hallgeir Rui, Michael J May, Narayan G Avadhani, Anil K Rustgi, Serge Y Fuchs
Format: Article
Language:English
Published: Springer Nature 2014-03-01
Series:EMBO Molecular Medicine
Subjects:
hepatitis
inflammation
interferon
pancreatitis
receptor
Online Access:https://doi.org/10.1002/emmm.201303236
Description
Summary:Abstract Type 1 interferons (IFN) protect the host against viruses by engaging a cognate receptor (consisting of IFNAR1/IFNAR2 chains) and inducing downstream signaling and gene expression. However, inflammatory stimuli can trigger IFNAR1 ubiquitination and downregulation thereby attenuating IFN effects in vitro. The significance of this paradoxical regulation is unknown. Presented here results demonstrate that inability to stimulate IFNAR1 ubiquitination in the Ifnar1SA knock‐in mice renders them highly susceptible to numerous inflammatory syndromes including acute and chronic pancreatitis, and autoimmune and toxic hepatitis. Ifnar1SA mice (or their bone marrow‐receiving wild type animals) display persistent immune infiltration of inflamed tissues, extensive damage and gravely inadequate tissue regeneration. Pharmacologic stimulation of IFNAR1 ubiquitination is protective against from toxic hepatitis and fulminant generalized inflammation in wild type but not Ifnar1SA mice. These results suggest that endogenous mechanisms that trigger IFNAR1 ubiquitination for limiting the inflammation‐induced tissue damage can be purposely mimicked for therapeutic benefits.
ISSN:1757-4676
1757-4684

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