IL-10 is required for polarization of macrophages to M2-like phenotype by mycobacterial DnaK (heat shock protein 70)

• Published in: Cytokine (Philadelphia, Pa.) Vol. 85; pp. 123 - 129
• Main Authors: Lopes, Rafael L., Borges, Thiago J., Zanin, Rafael F., Bonorino, Cristina
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-09-2016
• Subjects: Animals; Anti-inflammatory; Bacterial Proteins - metabolism; DnaK; Female; HSP70 Heat-Shock Proteins - metabolism; Inflammation - metabolism; Interleukin-10 - metabolism; M2-phenotype; Macrophage; Macrophage Activation - physiology; Macrophages - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Molecular Chaperones - metabolism; Mycobacterium tuberculosis; Mycobacterium tuberculosis - metabolism; Phagocytosis - physiology; Phenotype; Signal Transduction - physiology; Transforming Growth Factor beta - metabolism; M2-phenotype; DnaK; Anti-inflammatory; Macrophage
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2016.06.018

•DnaK-induced polarization of macrophages depends not only on IL-10 production, but also on IL-10 receptor signaling.•DnaK induces TGF-β mRNA transcription, but not translation, in macrophages in vitro.•Tgfb1 mRNA transcription induced by DnaK in macrophages is dependent on IL-10.•DnaK-polarized macrophages effect on allograft tumor growth in vivo depends on IL-10.
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.