A TLR2/S100A9/CXCL-2 signaling network is necessary for neutrophil recruitment in acute and chronic liver injury in the mouse

作者：Moles Anna; Murphy Lindsay; Wilson Caroline L; Chakraborty Jayashree Bagchi; Fox Christopher; Park Eek Joong; Mann Jelena; Oakley Fiona; Howarth Rachel; Brain John; Masson Steven; Karin Michael; Seki Ekihiro; Mann Derek A^*

来源：Journal of Hepatology, 2014, 60(4): 782-791.

DOI：10.1016/j.jhep.2013.12.005

• Liver fibrosis
• Neutrophil
• Toll like receptor
• Inflammation
• S100A9

Background & Aims: Neutrophils are important immune effectors required for sterile and non-sterile inflammatory responses. However, neutrophils are associated with pathology in drug-induced liver injury, acute alcoholic liver disease, and ischemia-reperfusion injury. An understanding of the complex mechanisms that control neutrophil recruitment to the injured liver is desirable for developing strategies aimed at limiting neutrophil-mediated cellular damage.
Methods: Wt, tlr2(-/-), tlr4(-/-), and s100a9(-/-) mice were administered CCl4 either acutely (8, 24, 48, or 72 h) or chronically (8 weeks) and livers investigated by histological (IHC for neutrophils, fibrogenesis, proliferation, and chemotactic proteins) or molecular approaches (qRT-PCR for neutrophil chemoattractant chemokines and cytokines as well as pro-fibrogenic genes).
Results: Mice lacking TLR2 or S100A9 failed to recruit neutrophils to the injured liver and had a defective hepatic induction of the neutrophil chemokine CXCL-2. Hierarchy between TLR2 and S100A9 proved to be complex. While induction of S100A9 was dependent on TLR2 in isolated neutrophils, there was a more complicated two-way signalling cross-talk between TLR2 and S100A9 in whole liver. However, wound-healing and regenerative responses of the liver were unaffected in these genetic backgrounds as well as in wild type mice, in which neutrophils were depleted by infusion of Ly-6G antibody.
Conclusions: We have identified TLR2 and S100A8/S100A9 as key regulators of hepatic CXCL-2 expression and neutrophil recruitment. This novel TLR2-S100A9-CXCL-2 pathway may be of use in development of new strategies for selectively manipulating neutrophils in liver disease without impairing normal wound healing and regenerative responses.

• 出版日期2014-4