The miR-26a/SIRT6/HIF-1α axis regulates glycolysis and inflammatory responses in host macrophages during Mycobacterium tuberculosis infection

FEBS Lett. 2024 Oct;598(20):2592-2614. doi: 10.1002/1873-3468.15001. Epub 2024 Aug 18.

Abstract

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis. Here, a macrophage infection model was used to unravel the role of the histone deacetylase sirtuin 6 (SIRT6) in Mtb-triggered regulation of the innate immune response. Mtb infection downregulated microRNA-26a and upregulated its target SIRT6. SIRT6 suppressed glycolysis and expression of HIF-1α-dependent glycolytic genes during infection. In addition, SIRT6 regulated the levels of intracellular succinate which controls stabilization of HIF-1α, as well as the release of interleukin (IL)-1β. Furthermore, SIRT6 inhibited inducible nitric oxide synthase (iNOS) and proinflammatory IL-6 but augmented anti-inflammatory arginase expression. The miR-26a/SIRT6/HIF-1α axis therefore regulates glycolysis and macrophage immune responses during Mtb infection. Our findings link SIRT6 to rewiring of macrophage signaling pathways facilitating dampening of the antibacterial immune response.

Keywords: Mycobacterium tuberculosis; glycolysis; immunometabolism; innate immunity; macrophage response; sirtuin 6.

MeSH terms

  • Animals
  • Arginase / genetics
  • Arginase / metabolism
  • Glycolysis*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit* / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism
  • Immunity, Innate
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / microbiology
  • Interleukin-1beta* / genetics
  • Interleukin-1beta* / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Macrophages* / microbiology
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Mycobacterium tuberculosis* / immunology
  • Nitric Oxide Synthase Type II* / genetics
  • Nitric Oxide Synthase Type II* / metabolism
  • Signal Transduction
  • Sirtuins* / genetics
  • Sirtuins* / metabolism
  • Succinic Acid / metabolism
  • Tuberculosis* / genetics
  • Tuberculosis* / immunology
  • Tuberculosis* / metabolism
  • Tuberculosis* / microbiology

Substances

  • Sirtuins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MicroRNAs
  • Sirt6 protein, mouse
  • Nitric Oxide Synthase Type II
  • Hif1a protein, mouse
  • Interleukin-1beta
  • Mirn26 microRNA, mouse
  • Interleukin-6
  • Nos2 protein, mouse
  • Arginase
  • Succinic Acid
  • IL1B protein, mouse