SEARCH

SEARCH BY CITATION

Keywords:

  • hepatitis;
  • inflammation;
  • interferon;
  • pancreatitis;
  • receptor

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.

Synopsis

Thumbnail image of graphical abstract

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.