Extracellular mycobacterial DnaK polarizes macrophages to the M2-like phenotype

• Published in: PloS one Vol. 9; no. 11; p. e113441
• Main Authors: Lopes, Rafael L, Borges, Thiago J, Araújo, Jessica F, Pinho, Nathana G, Bergamin, Letícia S, Battastini, Ana Maria O, Muraro, Stéfanie P, Souza, Ana Paula D, Zanin, Rafael F, Bonorino, Cristina
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24-11-2014; Public Library of Science (PLoS)
• Subjects: Animals; Antigens; Arginase; Arginase - immunology; Arginase - metabolism; Bacteria; Bacterial Proteins - immunology; Bacterial Proteins - metabolism; beta-N-Acetylhexosaminidases - genetics; beta-N-Acetylhexosaminidases - immunology; beta-N-Acetylhexosaminidases - metabolism; Biology and Life Sciences; Biomedical research; Bone marrow; Cancer; Cells, Cultured; Cytokines; Cytokines - immunology; Cytokines - metabolism; Dendritic cells; DnaK protein; Female; Flow Cytometry; Gene expression; Gene Expression - immunology; Genetic aspects; Heat shock proteins; Homeostasis; HSP70 Heat-Shock Proteins - immunology; HSP70 Heat-Shock Proteins - metabolism; Immune response; Immunology; Immunosuppression; Infections; Inflammation; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - immunology; Intercellular Signaling Peptides and Proteins - metabolism; Interferon; Interleukin 10; Interleukin 4; Interleukin-10 - immunology; Interleukin-10 - metabolism; Laboratories; Lectins - genetics; Lectins - immunology; Lectins - metabolism; Lipopolysaccharides - immunology; Macrophage Activation - immunology; Macrophages; Macrophages - immunology; Macrophages - metabolism; Medicine and Health Sciences; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular biology; Molecular Chaperones - immunology; Molecular Chaperones - metabolism; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; Mycobacterium tuberculosis - metabolism; Myeloid cells; Pathogens; Peritoneum; Pharmacy; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Tuberculosis; Tumors; Virulence; Virulence factors; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0113441

Macrophages are myeloid cells that play an essential role in inflammation and host defense, regulating immune responses and maintaining tissue homeostasis. Depending on the microenvironment, macrophages can polarize to two distinct phenotypes. The M1 phenotype is activated by IFN-γ and bacterial products, and displays an inflammatory profile, while M2 macrophages are activated by IL-4 and tend to be anti-inflammatory or immunosupressive. It was observed that DnaK from Mycobacterium tuberculosis has immunosuppressive properties, inducing a tolerogenic phenotype in dendritic cells and MDSCs, contributing to graft acceptance and tumor growth. However, its role in macrophage polarization remains to be elucidated. We asked whether DnaK was able to modulate macrophage phenotype. Murine macrophages, derived from bone marrow, or from the peritoneum, were incubated with DnaK and their phenotype compared to M1 or M2 polarized macrophages. Treatment with DnaK leads macrophages to present higher arginase I activity, IL-10 production and FIZZ1 and Ym1 expression. Furthermore, DnaK increased surface levels of CD206. Importantly, DnaK-treated macrophages were able to promote tumor growth in an allogeneic melanoma model. Our results suggest that DnaK polarizes macrophages to the M2-like phenotype and could constitute a virulence factor and is an important immunomodulator of macrophage responses.