Neutrophils alleviate fibrosis in the CCl4‐induced mouse chronic liver injury model

Abstract

Tribbles pseudokinase 1 (<i>Trib1</i>) is a negative regulator of CCAAT/enhancer binding protein α (C/EBPα) and is known to induce granulopoiesis while suppressing monocyte differentiation. Loss of <i>Trib1</i> was previously shown to increase the neutrophil population in the spleen but lead to M2-like macrophage reduction. Because M2 macrophages are anti-inflammatory and promote tissue repair by producing fibrogenic factors, we investigated liver fibrosis in <i>Trib1</i>-deficient mice. Interestingly, loss of <i>Trib1</i> suppressed fibrosis in the CCl₄-induced chronic liver injury model. <i>Trib1</i> knockout increased neutrophils but had a minimal effect on the macrophage population in the liver. Hepatic expressions of neutrophil matrix metalloproteinases (<i>Mmp</i>)<i>8</i> and <i>Mmp9</i> were increased, but the production of fibrogenic factors, including transforming growth factor β1, was not affected by loss of <i>Trib1</i>. These results suggest that neutrophils are responsible for the suppression of fibrosis in <i>Trib1</i>-deficient liver. Consistently, transplantation of <i>Trib1</i>-deficient bone marrow cells into wild-type mice alleviated CCl₄-induced fibrosis. Furthermore, expression of chemokine (C-X-C motif) ligand 1 (<i>Cxcl1</i>) by adeno-associated viral vector in the normal liver recruited neutrophils and suppressed CCl₄-induced fibrosis; infusion of wild-type neutrophils in CCl₄-treated mice also ameliorated fibrosis. Using recombinant adeno-associated virus-mediated expression of <i>Mmp8</i> and <i>Mmp9</i> alleviated liver fibrosis. Finally, neutrophil depletion by infusion of Ly6G antibody significantly enhanced CCl₄-induced fibrosis. <i>Conclusion</i>: While neutrophils are well known to exacerbate acute liver injury, our results demonstrate a beneficial role of neutrophils in chronic liver injury by promoting fibrolysis. (<i>Hepatology Communications</i> 2018;2:703-717).