Guillot, Adrien

Tacke, Frank

English

Institutional Repository of the Freie Universität Berlin

749HEPATOLOGY ELSEWHERE | Hepatology, Vol. 71, No. 2, 2020  EDITORSKathleen E. Corey, Boston, MAHarmeet Malhi, Rochester, MNThe Unexpected Role of Neutrophils for Resolving Liver Inflammation by Transmitting MicroRNA-223 to MacrophagesNeutrophils are commonly recognized as prototypic inflammatory cells: They invade the liver upon injury, have a short half-life in inflamed tissue, and aggra-vate injury as well as inflammatory reactions. This has been conclusively demonstrated for acute acetamin-ophen injury in mice, where myeloid-cell–specific receptor for advanced glycation end products defi-ciency dramatically altered neutrophil recruitment to necrotic areas, and high-mobility group box 1 epithelial cell deficiency in the liver prevented all acetaminophen- induced mortality.(1) Similar findings in alcoholic hepatitis in humans support the detrimental roles of neutrophils in aggravating tissue injury and inflam-mation.(2) On the other hand, neutrophil recruitment impairment does not seem to influence bile duct ligation or acute or long-term carbon- tetrachloride–induced liver injury and fibrosis.(2)The current study by Jimenez Calvente et al. chal-lenged the “traditional view” on detrimental effects of neutrophils in liver disease by demonstrating that neutrophils mediate the resolution of liver inflamma-tion and fibrosis through microRNA-223 (miR-223) delivery to liver macrophages.(3) The investigators used an in vivo model of neutrophil depletion by injecting Ly6G monoclonal antibodies during recov-ery phases of two different chronic liver disease mod-els in mice, namely carbon tetrachloride repeated gavages or methionine and choline–deficient diet. In this setup, isotype-injected mice recovered from tissue injury, whereas neutrophil-depleted animals exhibited prolonged tissue damage, inflammation, and fibrosis. This work further described that neutrophil depletion led to a down-regulation of miR-223 levels in hepatic macrophages. Consequently, macrophages exhibited an increased NACHT, LRR and PYD domains- containing protein 3 (NLRP3) inflammasome acti-vation and a proinflammatory phenotype, as revealed by increased Ly6C staining, decreased CD14 and CD163 staining, and increased proinflammatory gene expression in neutrophil-depleted mice. The study elaborated on the cell-to-cell communication between neutrophils and macrophages, and based on a gran-ulocyte membrane marker (CD177) staining and adoptive cell transfer experiments, the investigators suggested that neutrophil-derived extracellular ves-icles (EVs) deliver miR-223 to liver macrophages, thus controlling their activation state and promoting inflammation  resolution (Fig. 1).(3)The work by Ariel Feldstein’s group explores the exciting idea that neutrophils are not only to be considered as the harmful tissue-attacking immune cells, but also as crucial actors of tissue physiology restoration.(3) Interestingly enough, this is mediated by shaping the phenotype of hepatic macrophages. This work fits perfectly to another recent study by Yang et al. that identified the beneficial effects of neutrophil-derived reactive oxygen species (ROS) in polarizing macrophages toward an alternative or proregenerative and anti-inflammatory phenotype.(4) Thereby, neutrophil biology is much more elaborate than previously established, given that they are seem-ingly able to adopt a plethora of phenotypes tightly regulated by the integration of numerous signals derived from the microenvironment. Novel technolo-gies like single-cell RNA sequencing or multispectral imaging currently allow a much more detailed insight into the different cell subpopulations present in the liver, for instance highlighting the functional diversity of macrophages during chronic liver injury.(5) Not so much is known about the heterogeneity of neutro-phils, and in light of the recent aforementioned find-ings, advances are awaited in the near future to answer these questions. It must be kept in mind, however, that the model herein used to deplete neutrophils may not be optimal. The use of anti-Ly6G antibodies induces neutrophil death in situ; thus, the accumulation of cell debris in the injured tissue may exacerbate immune Hepatology, February 2020HEPATOLOGY ELSEWHERE750cell (i.e., macrophage) activation and phenotype, thus promoting liver fibrosis. Thorough characterization of immune cell phenotypes must take into account such potential drawbacks.The data presented by Jimenez Calvente et al. indi-cate that neutrophils could be a source of miR-223 that is transmitted by microvesicles to shape macro-phage phenotypes. However, this may possibly repre-sent only a part of the full picture, because previous studies have claimed that monocytes and macrophages represent a potent source of miR-223, and even epi-thelial cells from the liver (e.g., hepatocytes) might express miR-223, or be the targets of immune-cell– derived miR-223 as well.(6) Moreover, miR-223 could also be transferred in a non-membrane-bound form associated with lipoproteins or Argonaut 2 (Ago2; Fig.  1). Thorough characterization of the source and delivery mechanisms of miR-223, together with in-depth analyses of intercellular communication, may unravel more complex roles of miR-223 in inflam-matory diseases and highlight potential therapeutic applications.Interestingly, miR-223 was recently implicated in the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. miR-223 was found to be increased in mice with experimental steatohepatitis as well as in human NASH samples, whereas miR-223-deficient mice developed more severe steatohepatitis and liver cancer upon high- fat-diet feeding, suggesting that miR-223 represents a key counter-regulatory pathway for limiting disease progression.(6) In fact, miR-223 targeted inflammatory and tumorigenic genes in hepatocytes.(6) Similarly, miR-223 down-regulation led to increased intestinal inflammation, attributed to more potent macrophage activation.(7)Collectively, these experimental studies demon-strate that the endogenous microvesicular delivery of miR-223 seems to have beneficial effects on mac-rophages during injury resolution,(3) on hepatocytes during NASH progression,(6) as well as on limiting intestinal inflammation.(7) The fundamental rel-evance of this pathway makes it tempting to spec-ulate that exogenous delivery of miR-223 and/or augmenting the beneficial roles of neutrophils during tissue regeneration might be interesting therapeu-tic approaches in chronic liver diseases, particularly NASH and fibrosis.The current work also broadens our view on neutro-phils—instead of viewing them as passive responders to tissue damage, neutrophils are active orchestrators of inflammation and repair mechanisms in the liver (Fig. 1). Nonetheless, shaping macrophages toward “repair macrophages” is only one aspect of neutrophil biology in the liver. Additional mechanisms include phagocytosis, release of ROS, bactericidal activity, and formation of neutrophil extracellular traps; all of which have been related to exacerbation of inflam-mation, autoimmunity, and tumor progression.(8) Our increasing insight into immune cell heterogeneity and molecular mechanisms of immune cell functionality FIg. 1. Neutrophils participate in liver inflammation resolution by miR-223 delivery to macrophages. Jimenez Calvente et al. showed that neutrophils are crucial for tissue inflammation resolution in liver disease models, through transferring miR-223 to macrophages by EVs, or possibly also in the non-membrane-bound form associated with high-density lipoprotein (HDL) or Ago2. This study further proposed that miR-223 represses Nlrp3 at the transcriptional level, thus inhibiting proinflammatory gene expression and favoring macrophage polarization toward a regenerative phenotype. This is opposed to the classical view that neutrophils would essentially participate in liver injury and inflammation aggravation.Hepatology, Vol. 71, No. 2, 2020 HEPATOLOGY ELSEWHERE751underline once more the need for immune-modu-latory, rather than immunosuppressive, therapeutic approaches to counteract inflammatory, fibrogenic, or carcinogenic pathways driving chronic liver diseases.Adrien Guillot, Ph.D. Frank Tacke, M.D., Ph.D. Department of Hepatology & Gastroenterology Charité Universitätsmedizin Berlin Berlin, GermanyReFeReNCeS 1) Huebener p, pradere Jp, Hernandez C, Gwak GY, Caviglia JM, Mu X, et al. The HMGB1/RAGE axis triggers neutrophil-mediated in-jury amplification following necrosis. J Clin Invest 2015;125:539-550. 2) Moles A, Murphy L, Wilson CL, Chakraborty JB, Fox C, Park EJ, et al. A TLR2/S100A9/CXCL-2 signaling network is necessary for neutrophil recruitment in acute and chronic liver injury in the mouse. J Hepatol 2014;60:782-791. 3) Jimenez Calvente C, tameda M, Johnson CD, Del Pilar H, Chin Lin Y, Andronikou N, et al. Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223.  J Clin Invest 2019;130:122258. 4) yang W, tao y, Wu Y, Zhao X, Ye W, Zhao D, et al. Neutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver repair. Nat Commun 2019;10:1076. 5) Krenkel O, Hundertmark J, Abdallah AT, Kohlhepp M, Puengel T, Roth T, et al. Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis. Gut 2019 May 10. pii: gutjnl-2019-318382. https ://doi.org/10.1136/gutjnl-2019-318382. [Epub ahead of print] 6) He Y, Hwang S, Cai Y, Kim SJ, Xu M, Yang D, et al. MicroRNA-223 ameliorates nonalcoholic steatohepatitis and cancer by target-ing multiple inflammatory and oncogenic genes in hepatocytes. Hepatology 2019 Apr 9. https ://doi.org/10.1002/hep.30645 . [Epub ahead of print] 7) Neudecker V, Haneklaus M, Jensen O, Khailova L, Masterson JC, Tye H, et al. Myeloid-derived miR-223 regulates intestinal inflam-mation via repression of the NLRP3 inflammasome. J Exp Med 2017;214:1737-1752. 8) Honda M, Kubes P. Neutrophils and neutrophil extracellular traps in the liver and gastrointestinal system. Nat Rev Gastroenterol Hepatol 2018;15:206-221.Author names in bold designate shared co-first authorship.A.G. is a recipient of a Humboldt Research Fellowship for Postdoctoral Researchers. This work has been supported by the German Research Foundation (DFG CRC1382).© 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.View this article online at wileyonlinelibrary.com.DOI 10.1002/hep.30925Potential conflict of interest: Dr. Tacke consults for, advises for, is on the Biliary Atresia: Biliary-Enteric Drainage or Primary Liver Transplant?The article from LeeVan et al.,(1) entitled “Biliary-enteric drainage vs primary liver transplant as ini-tial treatment for children with biliary atresia,” is a retrospective cohort study that examines long-term outcomes for children with biliary atresia (BA) through analysis of information obtained from the California Office of Statewide Health Planning and Development (OSHPD), an administrative data-base. Specifically, the researchers compare outcomes between a cohort of BA patients who underwent a biliary enteric drainage (BED) procedure (presumably a Kasai hepatoportoenterostomy) as the primary ther-apy to those who underwent a primary liver transplant (pLT) without a previous BED. This study is partic-ularly interesting, because despite our best efforts, adjuvant therapy to BED has not proven successful in improving transplant-free outcomes. Two recent stud-ies have shown adjuvant corticosteroids or intravenous immunoglobulin to be ineffective in improving short-term outcomes.(2,3)The results of the current study show that overall survival in the BED group was inferior to the pLT group at 5-, 10-, 15-, and 20-year time points. They also demonstrate that a significant contributor to the inferior outcomes is the relatively poor outcomes of salvage liver transplant following BED compared to pLT. Finally, they show that while the difference in outcomes between BED and pLT were not signifi-cantly different before 2002, they are significant after 2002 largely attributable to a significant improve-ment in pLT outcomes. Ultimately, the researchers are attempting to answer the question of whether or not BA patients should ever undergo a BED or whether they would be better off going straight to liver trans-plantation. While this is an appropriate question to ask given the significant improvement in overall pedi-atric liver transplantation outcomes, this study does speakers’ bureau for, and received grants from Inventiva, Allergan, and Bristol-Myers Squibb. He consults for, advises for, and is on the speakers’ bureau for Bayer, GalMed, Gilead, AbbVie, and MSD. He received grants from Galapagos.

The Unexpected Role of Neutrophils for Resolving Liver Inflammation by Transmitting MicroRNA‐223 to Macrophages

Jimenez Calvente C

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The Unexpected Role of Neutrophils for Resolving Liver Inflammation by Transmitting MicroRNA‐223 to Macrophages

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