TY - JOUR
T1 - Disruption of type-I IFN pathway ameliorates preservation damage in mouse orthotopic liver transplantation via HO-1 dependent mechanism
AU - Shen, X. D.
AU - Ke, B.
AU - Ji, H.
AU - Gao, F.
AU - Freitas, M. C.S.
AU - Chang, W. W.
AU - Lee, C.
AU - Zhai, Y.
AU - Busuttil, R. W.
AU - Kupiec-Weglinski, Jerzy W.
PY - 2012/7
Y1 - 2012/7
N2 - Ischemia/reperfusion injury (IRI) remains unresolved problem in clinical organ transplantation. We analyzed the role of Type-I interferon (IFN) pathway in a clinically relevant murine model of extended hepatic cold preservation followed by orthotopic liver transplantation (OLT). Livers from Type-I IFN receptor (IFNAR) knockout (KO) or wild-type (WT) mice (C57/BL6) were harvested, preserved at 4°C in UW solution for 20 h and transplanted to groups of syngeneic IFNAR KO or WT recipients. Liver graft but not recipient IFNAR deficiency was required to consistently ameliorate IRI in OLTs. Indeed, disruption of Type-I IFN signaling decreased serum alanine aminotransferase (sALT) levels (p < 0.001), diminished Suzuki's score of histological OLT damage (p < 0.01) and improved 14-day survival (from 42% [5/12] in WT to 92% [11/12] in IFNAR KO; p < 0.05). Unlike in WT group, IFNAR deficiency attenuated OLT expression of TNF-α, IL-1β, IL-6, MCP-1, CXCL-10, ICAM-1; diminished infiltration by macrophages/PMNs; and enhanced expression of antioxidant HO-1/Nrf2. The frequency of TUNEL+ apoptotic cells and caspase-3 activity/expression selectively decreased in IFNAR KO group. Small interfering (si)RNA-directed targeting of HO-1 restored cardinal features of liver IRI in otherwise resistant IFNAR-deficient OLTs. Thus, intact Type-I IFN signaling is required for hepatic IRI, whereas HO-1 is needed for cytoprotection against innate immunity-dominated organ preservation damage in IFNAR-deficient liver transplants.
AB - Ischemia/reperfusion injury (IRI) remains unresolved problem in clinical organ transplantation. We analyzed the role of Type-I interferon (IFN) pathway in a clinically relevant murine model of extended hepatic cold preservation followed by orthotopic liver transplantation (OLT). Livers from Type-I IFN receptor (IFNAR) knockout (KO) or wild-type (WT) mice (C57/BL6) were harvested, preserved at 4°C in UW solution for 20 h and transplanted to groups of syngeneic IFNAR KO or WT recipients. Liver graft but not recipient IFNAR deficiency was required to consistently ameliorate IRI in OLTs. Indeed, disruption of Type-I IFN signaling decreased serum alanine aminotransferase (sALT) levels (p < 0.001), diminished Suzuki's score of histological OLT damage (p < 0.01) and improved 14-day survival (from 42% [5/12] in WT to 92% [11/12] in IFNAR KO; p < 0.05). Unlike in WT group, IFNAR deficiency attenuated OLT expression of TNF-α, IL-1β, IL-6, MCP-1, CXCL-10, ICAM-1; diminished infiltration by macrophages/PMNs; and enhanced expression of antioxidant HO-1/Nrf2. The frequency of TUNEL+ apoptotic cells and caspase-3 activity/expression selectively decreased in IFNAR KO group. Small interfering (si)RNA-directed targeting of HO-1 restored cardinal features of liver IRI in otherwise resistant IFNAR-deficient OLTs. Thus, intact Type-I IFN signaling is required for hepatic IRI, whereas HO-1 is needed for cytoprotection against innate immunity-dominated organ preservation damage in IFNAR-deficient liver transplants.
KW - HO-1
KW - Ischemia/reperfusion injury
KW - Liver transplantation
KW - Type-I IFN
UR - http://www.scopus.com/inward/record.url?scp=84863187438&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863187438&partnerID=8YFLogxK
U2 - 10.1111/j.1600-6143.2012.04021.x
DO - 10.1111/j.1600-6143.2012.04021.x
M3 - Article
C2 - 22429450
AN - SCOPUS:84863187438
SN - 1600-6135
VL - 12
SP - 1730
EP - 1739
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 7
ER -