Mycobacterium tuberculosis ESAT6 Drives the Activation and Maturation of Bone Marrow-Derived Dendritic Cells via TLR4-Mediated Signaling
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6-kDa early secretory antigenic target (ESAT6), a virulent factor of Mycobacterium tuberculosis, is involved in immune regulation. However, the underlying mechanism behind the activation and maturation of dendritic cells (DCs) by ESAT6 remains unclear. In this study, we investigated the effect on TLRs signaling on the regulation of ESAT6-induced activation and maturation of DCs. ESAT6 induced production of IL-6, TNF-α, and IL-12p40 in bone marrow-derived dendritic cells (BMDCs) from wild-type and TLR2-deficient mice, with this induction abolished in TLR4-deficient cells. NF-κB is essential for the ESAT6-induced production of the cytokines in BMDCs. TLR4 was also required for ESAT6-induced activation of NF-κB and MAPKs in BMDCs. ESAT6 additionally upregulated the expression of surface molecules CD80, CD86, and MHC-II, and also promoted the ability of CD4+ T cells to secrete IFN-γ via the TLR4-dependent pathway. Our findings suggest that TLR4 is critical in the activation and maturation of DCs in response to ESAT6.
Abstract
6-kDa early secretory antigenic target (ESAT6), a virulent factor of Mycobacterium tuberculosis, is involved in immune regulation. However, the underlying mechanism behind the activation and maturation of dendritic cells (DCs) by ESAT6 remains unclear. In this study, we investigated the effect on TLRs signaling on the regulation of ESAT6-induced activation and maturation of DCs. ESAT6 induced production of IL-6, TNF-α, and IL-12p40 in bone marrow-derived dendritic cells (BMDCs) from wild-type and TLR2-deficient mice, with this induction abolished in TLR4-deficient cells. NF-κB is essential for the ESAT6-induced production of the cytokines in BMDCs. TLR4 was also required for ESAT6-induced activation of NF-κB and MAPKs in BMDCs. ESAT6 additionally upregulated the expression of surface molecules CD80, CD86, and MHC-II, and also promoted the ability of CD4+ T cells to secrete IFN-γ via the TLR4-dependent pathway. Our findings suggest that TLR4 is critical in the activation and maturation of DCs in response to ESAT6.
참고문헌 (29)
- Pai M, "Tuberculosis", Nat Rev Dis Primers, 2, pp.16076~ (2016)
- Global Tuberculosis Report 2017, "World Health Organization", World Health Organization, ~ (2017)
- Wong KW, "The role of ESX-1 in Mycobacterium tuberculosis pathogenesis", Microbiol Spectr, 5 (2017)
- Gröschel MI, "ESX secretion systems: mycobacterial evolution to counter host immunity", Nat Rev Microbiol, 14, pp.677~691 (2016)
- Janssens S, "Role of Toll-like receptors in pathogen recognition", Clin Microbiol Rev, 16, pp.637~646 (2003)
- Takeda K, "Toll-like receptors in innate immunity", Int Immunol, 17, pp.1~14 (2005)
- Jayalakshmi Krishnan, "Toll-like receptor signal transduction", Experimental and Molecular Medicine, 39(4), pp.421~438 (2007), 생화학분자생물학회
- Erridge C, "Endogenous ligands of TLR2 and TLR4: agonists or assistants", J Leukoc Biol, 87, pp.989~999 (2010)
- Gekara NO, "Signals triggered by a bacterial pore-forming toxin contribute to Toll-like receptor redundancy in gram-positive bacterial recognition", J Infect Dis, 199, pp.124~133 (2009)
- Kim WS, "Mycobacterium tuberculosis GrpE, a heat-shock stress responsive chaperone, promotes Th1-biased T cell immune response via TLR4-mediated activation of dendritic cells", Front Cell Infect Microbiol, 8, pp.95~ (2018)
- Kim JS, "Mycobacterium tuberculosis RpfB drives Th1-type T cell immunity via a TLR4-dependent activation of dendritic cells", J Leukoc Biol, 94, pp.733~749 (2013)
- Byun EH, "Mycobacterium tuberculosis Rv0577, a novel TLR2 agonist, induces maturation of dendritic cells and drives Th1 immune response", FASEB J, 26, pp.2695~2711 (2012)
- Chatterjee S, "Early secreted antigen ESAT-6 of Mycobacterium tuberculosis promotes protective T helper 17 cell responses in a Toll-like receptor-2-dependent manner", PLoS Pathog, 7, pp.e1002378~ (2011)
- Mihret A, "The role of dendritic cells in Mycobacterium tuberculosis infection", Virulence, 3, pp.654~659 (2012)
- Amaral EP, "Innate immunity in tuberculosis: how the sensing of mycobacteria and tissue damage modulates macrophage death", Microbes Infect, 18, pp.11~20 (2016)
- Guirado E, "Macrophages in tuberculosis: friend or foe", Semin Immunopathol, 35, pp.563~583 (2013)
- Ganguly N, "Mycobacterium tuberculosis secretory proteins CFP-10, ESAT-6 and the CFP10:ESAT6 complex inhibit lipopolysaccharide-induced NF-kappaB transactivation by downregulation of reactive oxidative species (ROS) production", Immunol Cell Biol, 86, pp.98~106 (2008)
- Pathak SK, "Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages", Nat Immunol, 8, pp.610~618 (2007)
- Jung BG, "Early secreted antigenic target of 6-kDa of Mycobacterium tuberculosis stimulates IL-6 production by macrophages through activation of STAT3", Sci Rep, 7, pp.40984~ (2017)
- Wang X, "Early secreted antigenic target of 6-kDa protein of Mycobacterium tuberculosis primes dendritic cells to stimulate Th17 and inhibit Th1 immune responses", J Immunol, 189, pp.3092~3103 (2012)
- Choi HG, "Rv2299c, a novel dendritic cell-activating antigen of Mycobacterium tuberculosis, fused-ESAT-6 subunit vaccine confers improved and durable protection against the hypervirulent strain HN878 in mice", Oncotarget, 8, pp.19947~19967 (2017)
- Jang AR, "Mycobacterium tuberculosis ESAT6 induces IFN-β gene expression in Macrophages via TLRs-mediated signaling", Cytokine, 104, pp.104~109 (2018)
- Shin AR, "Improved sensitivity of diagnosis of tuberculosis in patients in Korea via a cocktail enzyme-linked immunosorbent assay containing the abundantly expressed antigens of the K strain of Mycobacterium tuberculosis", Clin Vaccine Immunol, 15, pp.1788~1795 (2008)
- Lutz MB, "An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow", J Immunol Methods, 223, pp.77~92 (1999)
- Zhou ZQ, "Role of ESAT-6 in renal injury by regulating microRNA-155 expression via TLR4", MyD88 signaling pathway in mice with Mycobacterium tuberculosis infection, 2017, pp.37, BS20170021~
- Newton K, "Signaling in innate immunity and inflammation", Cold Spring Harb Perspect Biol, 4, pp.a006049~ (2012)
- Boggaram V, "Early secreted antigenic target of 6 kDa (ESAT-6) protein of Mycobacterium tuberculosis induces interleukin-8 (IL-8) expression in lung epithelial cells via protein kinase signaling and reactive oxygen species", J Biol Chem, 288, pp.25500~25511 (2013)
- Peng H, "The Mycobacterium tuberculosis early secreted antigenic target of 6 kDa inhibits T cell interferon-γ production through the p38 mitogen-activated protein kinase pathway", J Biol Chem, 286, pp.24508~24518 (2011)
- Ma J, "Early secreted antigenic target of 6 kDa of Mycobacterium tuberculosis stimulates macrophage chemoattractant protein-1 production by macrophages and its regulation by p38 mitogen-activated protein kinases and interleukin-4", Scand J Immunol, 84, pp.39~48 (2016)