Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury.
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.
Department of Animal Biology, School of Veterinary Medicine University of Pennsylvania, Philadelphia, PA, USA.
Sabyasachi
S
Bhattacharya
Kanstantsin V
KV
Katlinski
Maximilian
M
Reichert
Shigetsugu
S
Takano
Angela
A
Brice
Bin
B
Zhao
Qiujing
Q
Yu
Hui
H
Zheng
Christopher J
CJ
Carbone
Yuliya V
YV
Katlinskaya
N Adrian
NA
Leu
Kelly A
KA
McCorkell
Satish
S
Srinivasan
Melanie
M
Girondo
Hallgeir
H
Rui
Michael J
MJ
May
Narayan G
NG
Avadhani
Anil K
AK
Rustgi
Serge Y
SY
Fuchs
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000601:surgery / Q000662:veterinary; D002908:Chronic Disease; D005260:Female; D055879:Gene Knock-In Techniques; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000502:physiology; D010195:Pancreatitis / Q000139:chemically induced / Q000473:pathology / Q000601:surgery; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054875:Ubiquitination
C508032:Ifnar1 protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D053633:Receptor, Interferon alpha-beta