Journal
HEPATOLOGY
Volume 47, Issue 1, Pages 207-214Publisher
WILEY
DOI: 10.1002/hep.21986
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Funding
- NIAID NIH HHS [R01 AI023847, AI23847, AI42223, R01 AI042223] Funding Source: Medline
- NIDDK NIH HHS [R01 DK062357] Funding Source: Medline
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R21AI023847, R01AI042223, R01AI023847, R56AI023847] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK062357] Funding Source: NIH RePORTER
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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 moo ligand 10 (CXCL10). The induction of CXCL10 by liver IR was rapid (I 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 1 beta (IL-1 beta), IL-6, and IL-12 beta 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. Conclusion: 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.
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