These authors equally contributed to this work.
Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury
Version of Record online: 31 JAN 2014
© 2014 The Authors.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 6, Issue 3, pages 384–397, March 2014
How to Cite
EMBO Mol Med (2014) 6, 384–397
- Issue online: 7 MAR 2014
- Version of Record online: 31 JAN 2014
- Manuscript Accepted: 13 DEC 2013
- Manuscript Revised: 21 NOV 2013
- Manuscript Received: 26 JUN 2013
- NIH. Grant Numbers: CA092900, CA142425, CA022762, RO1HL080612, DK060694, P30-DK050306
- National Pancreas Foundation
- Honjo International Scholarship Foundation
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.
Inflammatory process in response to injury starts by inducing tissue damage followed by resolution of inflammation. Here, endogenous or induced IFNAR1 ubiquitination and degradation are shown to limit the extent of tissue damage and accelerate healing.
- The IFNAR1 chain of type 1 interferon receptor is rapidly ubiquitinated and degraded under conditions of pancreatic, hepatic and generalized inflammation.
- Downregulation of IFNAR1 in inflamed tissues represents a fundamental mechanism that limits the tissue injury phase and promotes transition to regeneration and restoration of tissue function.
- Preemptive pharmacologic targeting of IFNAR1 for ubiquitination is a novel therapeutic strategy for tissue protection within the context of acute inflammatory syndromes.