IL-10 is required for polarization of macrophages to M2-like phenotype by mycobacterial DnaK (heat shock protein 70) |
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| Affiliation: | 1. Department of Surgery, Institute of Molecular Medicine, Trinity Health Sciences Centre, St. James''s Hospital, Dublin 8, Ireland;2. Department of Clinical Medicine and Oncology, Institute of Molecular Medicine, Trinity Health Sciences Centre, St. James''s Hospital, Dublin 8, Ireland;3. Department of Pathology, Beaumont Hospital, Dublin 9, Ireland;4. Cancer and Aging Research Program, Queensland University of Technology, Brisbane, Queensland, Australia;1. Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran;2. Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91778-99191, Iran;3. Nuclear Medicine Research Center, Mashhad University of Medical Sciences, Mashhad 98451-3546, Iran;4. Department of Immunology, School of Medicine, Mashhad University of Medical Sciences, Mashhad 919677-3117, Iran;5. Biotechnology Research Center, Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91775-1365, Iran;1. Anesthesiology Department, Hospital Clínic, University of Barcelona, and Institute d’Investigacions Biomèdica Agustí Pi i Sunyer (IDIBAPS), Barcelona, Spain;2. Institute of Liver Studies & Transplantation, King’s College Hospital Foundation NHS Trust, London, United Kingdom;3. Liver Sciences, School of Immunology & Microbial Sciences, King’s College London, United Kingdom;4. Institute of Hepatology, Foundation for Liver Research, London, United Kingdom;5. Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands;6. Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, and University of Barcelona, Barcelona, Spain;7. Section of Hepatobiliairy Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands |
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| Abstract: | Macrophages are key cells in the innate immune system. They phagocytose pathogens and cellular debris, promote inflammation, and have important roles in tumor immunity. Depending on the microenvironment, macrophages can polarize to M1 (inflammatory) or M2 (anti-inflammatory) phenotypes. Extracellular DnaK (the bacterial ortholog of the mammalian Hsp70) from Mycobacterium tuberculosis (Mtb) was described to exert immune modulatory roles in an IL-10 dependent manner. We have previously observed that endotoxin-free DnaK can polarize macrophages to an M2-like phenotype. However, the mechanisms that underlie this polarization need to be further investigated. IL-10 has been described to promote macrophage polarization, so we investigated the involvement of this cytokine in macrophages stimulated with extracellular DnaK. IL-10 was required to induce the expression of M2 markers - Ym1 and Fizz, when macrophages were treated with DnaK. Blockade of IL-10R also impaired DnaK induced polarization, demonstrating the requirement of the IL-10/IL-10R signaling pathway in this polarization. DnaK was able to induce TGF-β mRNA in treated macrophages in an IL-10 dependent manner. However, protein TGF-β could not be detected in culture supernatants. Finally, using an in vivo allogeneic melanoma model, we observed that DnaK-treated macrophages can promote tumor growth in an IL-10-dependent manner. Our results indicate that the IL-10/IL-10R axis is required for DnaK-induced M2-like polarization in murine macrophages. |
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| Keywords: | Macrophage Anti-inflammatory DnaK M2-phenotype |
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