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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 9

miR-223 abolition augments NLRP3 expression in hepatic macrophages during SRLI.

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miR-223 abolition augments NLRP3 expression in hepatic macrophages durin...
Macrophages were isolated from mouse livers from the experiment in Figure 5B. (A) Expression of miR-223 3p and Nlrp3 transcripts normalized by B2m mRNA and measured by real-time quantitative RT-PCR. *P < 0.05, ***P < 0.001, ****P < 0.0001, 2-way ANOVA, n = 3. (B) Number of cells positive for anti-NLRP3 mAb normalized by total cell number per field in 10 random pictures, quantified with ImageJ and expressed as percentage. ****P < 0.0001, 1-way ANOVA, n = 3–5 per group. (C) Representative confocal immunofluorescent images of NLRP3-expressing cells (red) and nuclei (blue) stained with anti-NLRP3 mAb or DAPI, respectively. Individual merges are shown where indicated. For clear distinction of area positive for anti-NLRP3 mAb, white arrowheads indicate cells and cellular areas negative for anti-NLRP3 mAb. Scale bars: 100 μm. (D and E) Expression of Nfkb p50 and Il10 mRNA normalized by B2m housekeeping gene and quantified by quantitative RT-PCR. *P < 0.05, ***P < 0.001, ****P < 0.0001, 1-way ANOVA, n = 3–4 per group. Data are shown as means ± SD.
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