CXCL10 regulates liver innate immune response against ischemia and reperfusion injury.
We have shown that activation of toll-like receptor 4 (TLR4) and its interferon regulatory factor 3 (IRF3)-dependent downstream signaling pathway are required for the development of liver ischemia/reperfusion injury (IRI). This study focused on the role of TLR4-IRF3 activation pathway products, in particular, chemokine (C-X-C motif) ligand 10 (CXCL10). The induction of CXCL10 by liver IR was rapid (1 hour postreperfusion), restricted (ischemic lobes), and specific (no CXCL9 and CXCL11 induction). Functionally, CXCL10 was critical for IR-induced liver inflammation and hepatocellular injury. CXCL10 knockout (KO) mice were protected from IRI, as evidenced by reduced serum alanine aminotransferase (sALT) levels and preserved liver histological detail. The induction of pro-inflammatory genes, such as tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), IL-6, and IL-12beta was diminished, whereas the induction of the IL-10 gene remained intact in CXCL10 KO mice, indicating an altered liver response against IR. This was accompanied by selective down-regulation of extracellular signal-regulated kinase (ERK), but intact Jun N-terminal kinase (JNK), activation in the KO IR livers. This altered liver inflammation response was (1) specific to IR, because lipopolysaccharide (LPS) induced a comparable pro-inflammatory response in CXCL10 KO and wild-type (WT) mice; and (2) responsible for liver cytoprotection from IR, because neutralization of IL-10 restored local inflammation and hepatocellular damage.


CONCLUSIONS
CXCL10 regulates liver inflammation response against IRI, and its deficiency protected livers from IRI by local IL-10-mediated cytoprotection. Targeting CXCL10 may provide a novel therapeutic means to ameliorate liver IRI in clinics.
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Yuan
Y
Zhai
Xiu-Da
XD
Shen
Feng
F
Gao
Alice
A
Zhao
Maria Cecilia
MC
Freitas
Charles
C
Lassman
Andrew D
AD
Luster
Ronald W
RW
Busuttil
Jerzy W
JW
Kupiec-Weglinski
D000818:Animals; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D007113:Immunity, Innate / Q000502:physiology; D007249:Inflammation / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides; D008107:Liver Diseases / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism*
D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D008070:Lipopolysaccharides; D016753:Interleukin-10; D048049:Extracellular Signal-Regulated MAP Kinases