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.Subject Categories Immunology; Digestive System
Highlights
Inflammation has evolved as an adaptive process that combines the counteractive elements of tissue destruction versus healing to limit and eventually eliminate the harmful effects of irritants and infectious agents
Wild type (Ifnar1+/+) and Ifnar1À/À mice displayed a similar severity of these alterations (Fig 1, Supplementary Figs 3– 5) suggesting that either IFN signaling plays no role in pathogenesis of acute pancreatitis or IFNAR1 is inactivated under these conditions in wild type tissues
Given that trypsin can cleave the extracellular domain of IFNAR1 in vitro (Supplementary Fig 6) and diverse inflammatory stimuli can induce ubiquitination of the intracellular domain of IFNAR1 leading to its endocytosis and degradation in cultured mammalian cells (Qian et al, 2011; Zheng et al, 2011b; Huangfu et al, 2012), it is plausible that a similar proteolytic inactivation of IFNAR1 could occur in vivo
Summary
Inflammation has evolved as an adaptive process that combines the counteractive elements of tissue destruction versus healing to limit and eventually eliminate the harmful effects of irritants and infectious agents. IFN act on cells through engaging a cell surface-located cognate receptor (formed by IFNAR1 and IFNAR2 chains) and subsequent stimulation of the signal transduction cascade including activation of the Janus kinases (JAK) and signal transduction and activators of transcription (STAT1/2) proteins (Uze et al, 2007) The latter interact with IRF9 to form a specific transcriptionally active complex capable of inducing a plethora of IFN-stimulated proteins that act in concert to mediate the anti-viral, anti-tumorigenic and immunomodulatory effects of IFNs. The latter interact with IRF9 to form a specific transcriptionally active complex capable of inducing a plethora of IFN-stimulated proteins that act in concert to mediate the anti-viral, anti-tumorigenic and immunomodulatory effects of IFNs These effects underlie the use of pharmacologically formulated IFN for treatment of viral infections, cancers and multiple sclerosis (Stark et al, 1998; Platanias, 2005; Stark & Darnell, 2012)
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