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.
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
Guidelines: The Editorial Board will only consider letters that we deem relevant and of interest to our readers. We will not post data that have not been subjected to peer review, nor will we post letters that are essentially a reiteration of another letter. All accepted letters will be posted on our website within one week of acceptance. We reserve the right to edit any letter for length, content, and clarity. Authors of all accepted letters will be asked to preview any changes. Authors will be notified by e-mail if their letters were not accepted. As this is a final decision, no appeals will be considered.
Specific requirements: All letters must be 400 words or fewer. You may enter the letter as plain text or HTML. The author's name and e-mail address are required, and will be posted with the letter. All possible conflicts of interest must be noted, even if they are not posted. If you wish to include a figure (keep in mind that non-peer-reviewed data will not be posted), please contact the editors directly at email@example.com.