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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 3

Neutrophil deletion aggravates spontaneous resolution of early liver fibrosis.

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Neutrophil deletion aggravates spontaneous resolution of early liver fib...
(A) Sections from livers from the experiment in Figure 1A displaying representative staining for collagen and for a subset of activated HSCs with Sirius red or anti-αSMA mAb, respectively. Scale bars: 250 μm. (B and C) Area of Sirius red and αSMA expressed as percentages of 10 aleatory selected microscopic fields, quantified by ImageJ. ***P < 0.001, ****P < 0.0001, 1-way ANOVA, n = 3–6 per group. (D–G) Relative mRNA expression of Mmp3, Mmp8, Mmp9, and Timp1 genes from liver homogenates of the experiment in Figure 1A, assessed by real-time RT-PCR and normalized to B2m mRNA housekeeping gene. *P < 0.05, ***P < 0.001, ****P < 0.0001, 1-way ANOVA, n = 3–6 per group. Data are shown as means ± SD. Representative experiment of 2 independent repeats.
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