DRANquilizing neutrophil function in chronic liver disease.

Neutrophils are the most abundant leukocytes in human peripheral blood; as part of the innate immune system, they are traditionally attributed a key role in acute inflammation as well as in host defense. For a long time, neutrophils were solely looked upon as a uniform mass of first responders in the clearance of invading pathogens. However, in contrast to these preconceptions, there is growing evidence of the importance of neutrophils in chronic inflammation, including in atherosclerosis, neurodegeneration and inflammatory bowel disease [1] Soehnlein O. Steffens S. Hidalgo A. Weber C. Neutrophils as protagonists and targets in chronic inflammation. Nat Rev Immunol. 2017; 17: 248-261https://doi.org/10.1038/nri.2017.10 Crossref PubMed Scopus (320) Google Scholar , as well as of their heterogeneity [2] Silvestre-Roig C. Hidalgo A. Soehnlein O. Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood. 2016; 127: 2173-2181https://doi.org/10.1182/blood-2016-01-688887 Crossref PubMed Scopus (280) Google Scholar . While various subsets in physiological as well as pathological settings have been characterized in recent years [2] Silvestre-Roig C. Hidalgo A. Soehnlein O. Neutrophil heterogeneity: implications for homeostasis and pathogenesis. Blood. 2016; 127: 2173-2181https://doi.org/10.1182/blood-2016-01-688887 Crossref PubMed Scopus (280) Google Scholar ,[3] Xie X. Shi Q. Wu P. Zhang X. Kambara H. Su J. et al. Single-cell transcriptome profiling reveals neutrophil heterogeneity in homeostasis and infection. Nat Immunol. 2020; 21: 1119-1133https://doi.org/10.1038/s41590-020-0736-z Crossref PubMed Scopus (214) Google Scholar , it is a striking feature of neutrophils that this cell – originally thought to be terminally differentiated when exiting the bone marrow – can adopt a tissue-specific phenotype similar to what has previously been shown for macrophages [4] Ballesteros I. Rubio-Ponce A. Genua M. Lusito E. Kwok I. Fernández-Calvo G. et al. Co-option of Neutrophil Fates by Tissue Environments. Cell. 2020; 183: 1282-1297.e18https://doi.org/10.1016/j.cell.2020.10.003 Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar ,[5] Lavin Y. Winter D. Blecher-Gonen R. David E. Keren-Shaul H. Merad M. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell. 2014; 159: 1312-1326https://doi.org/10.1016/j.cell.2014.11.018 Abstract Full Text Full Text PDF PubMed Scopus (1392) Google Scholar . Although neutrophil infiltration is a common feature in almost all settings of liver injury, their role, especially in chronic liver disease, has only lately come into focus. In this issue of the Journal of Hepatology, a study by Ariño and colleagues proofs the importance of neutrophil activity in chronic liver injury and reveals possible means of therapeutic interference in a disease setting where up to now treatment options were still relatively scarce. Specifically, the authors show that neutrophils are attracted to the periportal area in a chronic liver injury model; there, they adopt a distinguishable phenotype and perpetuate hepatic injury, while inhibition of neutrophil effector functions ameliorates tissue damage [6] Ariño S. Aguilar-Bravo B. Coll M. Lee W.-Y. Peiseler M. Paula Cantallops-Vilà nullDuctular reaction-associated neutrophils promote biliary epithelium proliferation in chronic liver disease. J Hepatol. 2023; (00423-3): S0168-8278https://doi.org/10.1016/j.jhep.2023.05.045 Abstract Full Text Full Text PDF Google Scholar . Ductular reaction-associated neutrophils promote biliary epithelium proliferation in chronic liver diseaseJournal of HepatologyPreviewDuctular reaction expansion is associated with poor prognosis in patients with advanced liver disease. However, the mechanisms promoting biliary cell proliferation are largely unknown. Here, we identify neutrophils as drivers of biliary cell proliferation and the defective wound-healing response. Full-Text PDF