Mycobacterium tuberculosis stimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3

Mol Immunol. 2021 Jul;135:285-293. doi: 10.1016/j.molimm.2021.04.022. Epub 2021 May 3.

Abstract

Despite its critical roles in immune responses against tuberculosis infection and immune pathology, the molecular details of interleukin (IL)-1β production in tuberculosis infection remain elusive. To explore IL-1β production in tuberculosis infection, we infected mouse bone marrow-derived macrophages (BMDM) with Mycobacterium tuberculosis (Mtb) H37Rv, its early secreted antigenic target protein of 6 kDa (ESAT-6) gene deletion (H37Rv:Δ3875) or complemented strain (H37Rv:Δ3875C) and evaluated IL-1β production. H37Rv induced significantly increased IL-1β production by BMDMs compared to non-infected BMDMs. In contrast, H37Rv:Δ3875 induced significantly less mature IL-1β production despite eliciting comparable levels of pro-IL-1β and IL-8 from BMDMs compared to H37Rv and H37Rv:Δ3875C. Blocking either NLRP3 or K+ efflux diminished H37Rv-induced IL-1β production by BMDMs. Infection of mice intranasally with H37Rv:Δ3875 induced less IL-1β production in the lungs compared with H37Rv. Intranasal delivery of ESAT-6 but not CFP10 induced production of IL-1β in mouse lungs and RNA-Seq analysis identified serum amyloid A (SAA) 3 as one of the highly expressed genes in mouse lungs. Infection of mice with H37Rv but not H37Rv:Δ3875 induced expression of lung SAA3 mRNA and protein, consistent with the effect of intranasal delivery of ESAT-6. Silencing SAA3 reduced Mtb-induced IL-1β production by BMDMs. We conclude that SAA3 plays critical role in ESAT-6 dependent IL-1β production by macrophages in tuberculosis infection.

Keywords: ESAT-6; IL-1β; Inflammasome; Macrophages; SAA3; Tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Bacterial / genetics*
  • Bacterial Proteins / genetics*
  • Female
  • Interleukin-1beta / biosynthesis*
  • Lung / metabolism
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mycobacterium tuberculosis / immunology*
  • Serum Amyloid A Protein / genetics
  • Serum Amyloid A Protein / immunology*
  • Tuberculosis, Pulmonary / immunology
  • Tuberculosis, Pulmonary / microbiology
  • Tuberculosis, Pulmonary / pathology

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • ESAT-6 protein, Mycobacterium tuberculosis
  • IL1B protein, mouse
  • Interleukin-1beta
  • Serum Amyloid A Protein