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

Abstract

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 CCl4‐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 CCl4‐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 CCl4‐induced fibrosis; infusion of wild‐type neutrophils in CCl4‐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 CCl4‐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)

FPR-1 is an important regulator of neutrophil recruitment and a tissue-specific driver of pulmonary fibrosis

“…Recently, it has been reported that infusion of neutrophils into mice with established CCl 4 -induced liver fibrosis significantly reduced collagen accumulation, suggesting that neutrophils can effectively reduce fibrosis. The same study also demonstrated that depletion of neutrophils significantly delayed resolution of liver fibrosis, indicating that neutrophils are involved in natural fibrosis resolution in the liver (39). Overall, these data and our own support the idea that neutrophils play a pathological role in the development and progression of pulmonary fibrosis but add little to the uncertainty regarding the role of neutrophils in the development of hepatic and renal fibrosis.…”

Clinical Characteristics of 162 Patients with Drug-Induced Liver and/or Kidney Injury

“…In patients with drug-induced organ injury, patients with a higher percentage of neutrophils had a lower risk of liver injury. Saijou et al [19] and Wang and Ding [20] found that some sRNAs in neutrophils has a protective effect against acute liver injury. e innate immune system in the human liver mainly consists of Kupffer cells (KCs), neutrophils, monocytes, and natural killer cells/natural killer T cells (NK/ NKT cells) [21][22][23].…”

More friend than foe: the emerging role of neutrophils in tissue repair

“…Neutrophil infusion diminished fibrosis, while neutrophil depletion increased fibrosis (112). As a result, the authors concluded that neutrophils suppressed fibrosis in chronic liver injury potentially by promoting fibrolysis through the production of metalloproteases (112). Along the same lines, in chronic cholestatic liver injury, neutrophil depletion decreased MMP-8 levels and decreased collagen degradation (113).…”

“…Using a mouse deficient in tribbles pseudokinase (Trib1), which increases neutrophil counts, the authors found reduced liver fibrosis, increased intrahepatic neutrophils, and increased MMP-8 and MMP-9 levels. Neutrophil infusion diminished fibrosis, while neutrophil depletion increased fibrosis (112). As a result, the authors concluded that neutrophils suppressed fibrosis in chronic liver injury potentially by promoting fibrolysis through the production of metalloproteases (112).…”