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Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223
Carolina Jimenez Calvente, … , Josh Boyer, Ariel E. Feldstein
Carolina Jimenez Calvente, … , Josh Boyer, Ariel E. Feldstein
Published July 11, 2019
Citation Information: J Clin Invest. 2019;129(10):4091-4109. https://doi.org/10.1172/JCI122258.
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Research Article Hepatology

Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223

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Abstract

Persistent, unresolved inflammation in the liver represents a key trigger for hepatic injury and fibrosis in various liver diseases and is controlled by classically activated proinflammatory macrophages, while restorative macrophages of the liver are capable of reversing inflammation once the injury trigger ceases. Here we exhibit neutrophils as key contributors to resolving the inflammatory response in the liver using two models of liver inflammation resolution. Using two models of liver inflammatory resolution, we found that mice undergoing neutrophil depletion during the resolution phase exhibited unresolved hepatic inflammation, activation of the fibrogenic machinery, and early fibrosis. These findings were associated with an impairment of the phenotypic switch of proinflammatory macrophages into a restorative stage after removal of the cause of injury and an increased NLRP3/miR-223 ratio. Mice with a deletion of the granulocyte-specific miR-223 gene showed a similarly impaired resolution profile that could be reversed by replacing miR-223 levels using a miR-223 3p mimic or by infusion of neutrophils from wild-type animals. Collectively, our findings reveal hepatic neutrophils as resolving effector cells that induce proinflammatory macrophages into a restorative phenotype, potentially via miR-223.

Authors

Carolina Jimenez Calvente, Masahiko Tameda, Casey D. Johnson, Hana del Pilar, Yun Chin Lin, Nektaria Adronikou, Xavier De Mollerat Du Jeu, Cristina Llorente, Josh Boyer, Ariel E. Feldstein

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Figure 4

Neutrophil abrogation impairs the spontaneous resolution of inflammation and advanced fibrosis in NASH.

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Neutrophil abrogation impairs the spontaneous resolution of inflammation...
(A) Experimental design showing neutrophil depletion with anti-Ly6G or control IgG2b mAb during 2 weeks (spontaneous resolution period) after a 6-week course of feeding with control MCS or MCD diet to induce fibrotic NASH. Mice treated with PBS were euthanized immediately after feeding with MCD or MCS diet to serve as the inflamed or WT controls, respectively. (B) Representative IHC images of accumulated collagen, activated HSCs, and antiinflammatory macrophages stained with Sirius red or antibodies against αSMA or CD163, respectively. Scale bars: 100 μm. (C–E) Percentage of area positive for Sirius red, αSMA, or CD163 calculated in 10 aleatory selected images. *P < 0.05, **P < 0.01, 1-way ANOVA, n = 4–5. Data are shown as means ± SD. Representative experiment of 2 independent repeats.
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