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Tribbles pseudokinase 1 ( Trib1 ) is a negative regulator of CCAAT/enhancer binding protein α (C/EBPα) and is known to induce granulopoiesis while suppressing monocyte differentiation. Loss of  Trib1  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  Trib1 ‐deficient mice. Interestingly, loss of  Trib1  suppressed fibrosis in the CCl 4 ‐induced chronic liver injury model.  Trib1  knockout increased neutrophils but had a minimal effect on the macrophage population in the liver. Hepatic expressions of neutrophil matrix metalloproteinases ( Mmp ) 8  and  Mmp9  were increased, but the production of fibrogenic factors, including transforming growth factor β1, was not affected by loss of  Trib1 . These results suggest that neutrophils are responsible for the suppression of fibrosis in  Trib1 ‐deficient liver. Consistently, transplantation of  Trib1 ‐deficient bone marrow cells into wild‐type mice alleviated CCl 4 ‐induced fibrosis. Furthermore, expression of chemokine (C‐X‐C motif) ligand 1 ( Cxcl1 ) by adeno‐associated viral vector in the normal liver recruited neutrophils and suppressed CCl 4 ‐induced fibrosis; infusion of wild‐type neutrophils in CCl 4 ‐treated mice also ameliorated fibrosis. Using recombinant adeno‐associated virus‐mediated expression of  Mmp8  and  Mmp9  alleviated liver fibrosis. Finally, neutrophil depletion by infusion of Ly6G antibody significantly enhanced CCl 4 ‐induced fibrosis.  Conclusion : 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. ( Hepatology Communications  2018;2:703‐717)

Neutrophils alleviate fibrosis in the CCl 4 ‐induced mouse chronic liver injury model