cGAS/STING/TBK1/IRF3 Signaling Pathway Activates BMDCs Maturation Following Mycobacterium bovis Infection

Int J Mol Sci. 2019 Feb 19;20(4):895. doi: 10.3390/ijms20040895.

Abstract

Cyclic GMP-AMP synthase (cGAS) is an important cytosolic DNA sensor that plays a crucial role in triggering STING-dependent signal and inducing type I interferons (IFNs). cGAS is important for intracellular bacterial recognition and innate immune responses. However, the regulating effect of the cGAS pathway for bone marrow-derived dendritic cells (BMDCs) during Mycobacterium bovis (M. bovis) infection is still unknown. We hypothesized that the maturation and activation of BMDCs were modulated by the cGAS/STING/TBK1/IRF3 signaling pathway. In this study, we found that M. bovis promoted phenotypic maturation and functional activation of BMDCs via the cGAS signaling pathway, with the type I IFN and its receptor (IFNAR) contributing. Additionally, we showed that the type I IFN pathway promoted CD4⁺ T cells' proliferation with BMDC during M. bovis infection. Meanwhile, the related cytokines increased the expression involved in this signaling pathway. These data highlight the mechanism of the cGAS and type I IFN pathway in regulating the maturation and activation of BMDCs, emphasizing the important role of this signaling pathway and BMDCs against M. bovis. This study provides new insight into the interaction between cGAS and dendritic cells (DCs), which could be considered in the development of new drugs and vaccines against tuberculosis.

Keywords: CD4+ T cells; Mycobacterium bovis; cGAS pathway; dendritic cells; type I interferons.

MeSH terms

  • Animals
  • Cattle
  • Cell Differentiation
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Female
  • Host-Pathogen Interactions
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferon Type I / metabolism
  • Membrane Proteins / metabolism*
  • Mice
  • Mycobacterium bovis*
  • Nucleotidyltransferases / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Tuberculosis, Bovine / immunology*
  • Tuberculosis, Bovine / metabolism*
  • Tuberculosis, Bovine / microbiology

Substances

  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Membrane Proteins
  • Sting1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Nucleotidyltransferases
  • cGAS protein, mouse