Abstract
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.
Highlights
Macrophages are myeloid cells which have an important role during inflammation, infection resolution, tissue repair and cancer [1]
To verify the effect of DnaK treatment on macrophages polarization, we treated macrophages differentiated from bone-marrow cells (BMMs) of B6 mice with different DnaK concentrations and compared iNOS and arginase activities between cells stimulated with LPS (M1), IL-4 (M2) or untreated cells. iNOS activity was induced in M1 macrophages but not in cells treated with DnaK (30 or 60 mg/mL) or in M2 (Fig. 1A)
In this study we provide functional evidence that DnaK from Mycobacterium tuberculosis skews macrophages towards the M2 phenotype
Summary
Macrophages are myeloid cells which have an important role during inflammation, infection resolution, tissue repair and cancer [1]. Activated macrophages (M1) are induced by Th1 cytokines (IFN-c), or by bacterial products (e.g LPS). They are able to control infections, have a tumoricidal activity and secrete high levels of pro-inflammatory cytokines. Activated macrophages (M2) are induced by Th2 cytokines (IL-4 and/or IL-13) and have important roles in allergy, parasitic infections and tissue repair [2]. Both phenotypes can be differentiated by surface receptors, gene expression and cytokines profile produced. M2 macrophage polarization can be defined based on a specific genetic signature characterized by the upregulation of Ym1 ( known as Chil3l3) and FIZZ1 ( known as Retnla) genes [4, 5]
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