ALBERT

Description: Neutrophils are the first immune cells recruited to a site of injury or infection, where they perform many functions. Having completed their role, neutrophils must be removed from the inflammatory site—either by apoptosis and efferocytosis or by reverse migration away from the wound—for restoration of normal tissue homeostasis. Disruption of these tightly controlled physiological processes of neutrophil removal can lead to a range of inflammatory diseases. We used an in vivo zebrafish model to understand the role of lipid mediator production in neutrophil removal. Following tailfin amputation in the absence of macrophages, neutrophillic inflammation does not resolve, due to loss of macrophage-dependent handling of eicosanoid prostaglandin E2 (PGE 2 ) that drives neutrophil removal via promotion of reverse migration. Knockdown of endogenous PGE synthase gene reveals PGE 2 as essential for neutrophil inflammation resolution. Furthermore, PGE 2 is able to signal through EP4 receptors during injury, causing an increase in Alox12 production and switching toward anti-inflammatory eicosanoid signaling. Our data confirm regulation of neutrophil migration by PGE 2 and LXA 4 (lipoxin A 4 ) in an in vivo model of inflammation resolution. This pathway may contain therapeutic targets for driving inflammation resolution in chronic inflammatory disease.

Description: Many key components of innate immunity to infection are shared between Drosophila and humans. However, the fly Toll ligand Spaetzle is not thought to have a vertebrate equivalent. We have found that the structurally related cystine-knot protein, nerve growth factor beta (NGFbeta), plays an unexpected Spaetzle-like role in immunity to Staphylococcus aureus infection in chordates. Deleterious mutations of either human NGFbeta or its high-affinity receptor tropomyosin-related kinase receptor A (TRKA) were associated with severe S. aureus infections. NGFbeta was released by macrophages in response to S. aureus exoproteins through activation of the NOD-like receptors NLRP3 and NLRP4 and enhanced phagocytosis and superoxide-dependent killing, stimulated proinflammatory cytokine production, and promoted calcium-dependent neutrophil recruitment. TrkA knockdown in zebrafish increased susceptibility to S. aureus infection, confirming an evolutionarily conserved role for NGFbeta-TRKA signaling in pathogen-specific host immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255479/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255479/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hepburn, Lucy -- Prajsnar, Tomasz K -- Klapholz, Catherine -- Moreno, Pablo -- Loynes, Catherine A -- Ogryzko, Nikolay V -- Brown, Karen -- Schiebler, Mark -- Hegyi, Krisztina -- Antrobus, Robin -- Hammond, Katherine L -- Connolly, John -- Ochoa, Bernardo -- Bryant, Clare -- Otto, Michael -- Surewaard, Bas -- Seneviratne, Suranjith L -- Grogono, Dorothy M -- Cachat, Julien -- Ny, Tor -- Kaser, Arthur -- Torok, M Estee -- Peacock, Sharon J -- Holden, Matthew -- Blundell, Tom -- Wang, Lihui -- Ligoxygakis, Petros -- Minichiello, Liliana -- Woods, C Geoff -- Foster, Simon J -- Renshaw, Stephen A -- Floto, R Andres -- 084953/Wellcome Trust/United Kingdom -- 089981/Wellcome Trust/United Kingdom -- 100140/Wellcome Trust/United Kingdom -- G0700091/Medical Research Council/United Kingdom -- G0701932/Medical Research Council/United Kingdom -- NC/K500392/1/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom -- Department of Health/United Kingdom -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2014 Oct 31;346(6209):641-6. doi: 10.1126/science.1258705.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cambridge Institute for Medical Research, University of Cambridge, UK. Department of Medicine, University of Cambridge, UK. ; Krebs Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK. Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK. Bateson Centre, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK. ; Cambridge Institute for Medical Research, University of Cambridge, UK. ; Bateson Centre, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK. Department of Infection and Immunity, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK. ; Bateson Centre, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK. ; Cambridge Institute for Medical Research, University of Cambridge, UK. Department of Medicine, University of Cambridge, UK. Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK. ; Krebs Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK. Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK. ; Department of Biochemistry, University of Cambridge, UK. ; Department of Veterinary Medicine, University of Cambridge, UK. ; Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, USA. ; Department of Medical Microbiology, University Medical Centre, Utrecht, Netherlands. ; Department of Clinical Immunology, Royal Free Hospital London, UK. ; Department of Medicine, University of Cambridge, UK. Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK. ; Department of Pathology and Immunology, Geneva University, Switzerland. ; Department of Medical Biochemistry and Biophysics, Umea University, Sweden. ; Department of Medicine, University of Cambridge, UK. ; Department of Medicine, University of Cambridge, UK. Wellcome Trust Sanger Institute, Hinxton, UK. ; Wellcome Trust Sanger Institute, Hinxton, UK. School of Medicine, University of St. Andrews, UK. ; Biochemistry Department, Oxford University, UK. ; Pharmacology Department, Oxford University, UK. ; Cambridge Institute for Medical Research, University of Cambridge, UK. Department of Medical Genetics, University of Cambridge, UK. ; Krebs Institute, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK. Bateson Centre, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK. Department of Infection and Immunity, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK. arf27@cam.ac.uk s.a.renshaw@sheffield.ac.uk. ; Cambridge Institute for Medical Research, University of Cambridge, UK. Department of Medicine, University of Cambridge, UK. Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, UK. arf27@cam.ac.uk s.a.renshaw@sheffield.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25359976" target="_blank"〉PubMed〈/a〉