Faculty Collaboration Database

Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury. EMBO Mol Med 2014 Mar;6(3):384-97

Date

02/01/2014

Pubmed ID

24480543

Pubmed Central ID

PMC3958312

DOI

10.1002/emmm.201303236

Scopus ID

2-s2.0-84896722537 (requires institutional sign-in at Scopus site)   54 Citations

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 Ifnar1(SA) knock-in mice renders them highly susceptible to numerous inflammatory syndromes including acute and chronic pancreatitis, and autoimmune and toxic hepatitis. Ifnar1(SA) 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 Ifnar1(SA) 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.

Author List

Bhattacharya S, Katlinski KV, Reichert M, Takano S, Brice A, Zhao B, Yu Q, Zheng H, Carbone CJ, Katlinskaya YV, Leu NA, McCorkell KA, Srinivasan S, Girondo M, Rui H, May MJ, Avadhani NG, Rustgi AK, Fuchs SY

MESH terms used to index this publication - Major topics in bold

Acute Disease
Animals
Bone Marrow Transplantation
Chemical and Drug Induced Liver Injury
Chronic Disease
Female
Gene Knock-In Techniques
Interleukin-1beta
Interleukin-6
Liver
Mice
Mice, Inbred C57BL
Pancreas
Pancreatitis
Receptor, Interferon alpha-beta
Regeneration
Tumor Necrosis Factor-alpha
Ubiquitination