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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 5

Regulation of SRLI by miR-223.

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Regulation of SRLI by miR-223.
(A) Expression of miR-223 3p and Nlrp3 tr...
(A) Expression of miR-223 3p and Nlrp3 transcripts in isolated macrophages from livers of the experiment in Figure 1A assessed by real-time RT-PCR and normalized to U6 or B2m housekeeping genes, respectively. **P < 0.01, ****P < 0.0001, 2-way ANOVA, n = 3–5 per group. (B) Experimental design of the miR-223 posttranscriptional replacement model during spontaneous recovery from liver inflammation after CCL4 treatment. (C) Levels of ALT in serum as measured by colorimetry. **P < 0.01, 1-way ANOVA, n = 3–4 per group. (D) Liver sections representing images of liver cells and total macrophages after staining with H&E and anti-F4/80 antibody, respectively. Scale bars: 250 or 100 μm for H & E or F4/80 images, respectively. (E) Necroinflammatory grade examined according to the Ishak system. **P < 0.01, 1-way ANOVA, n = 3–4 per group. (F) Percentage of area positive for F4/80 in 10 randomly chosen images quantified by ImageJ. ***P < 0.001, ****P < 0.0001, 1-way ANOVA, n = 3–6 per group. (G) Serum levels of IL-12 measured by colorimetric ELISA. **P < 0.01, 2-tailed unpaired t test, n = 3–4 per group. Data are shown as means ± SD.
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