期刊
MOLECULAR IMMUNOLOGY
卷 135, 期 -, 页码 285-293出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2021.04.022
关键词
Tuberculosis; ESAT-6; Macrophages; SAA3; IL-1 beta; Inflammasome
资金
- University of Texas Health Science Center at Tyler, Texas, USA
The study reveals the critical role of SAA3 in ESAT-6 dependent IL-1β production by macrophages during tuberculosis infection, suggesting its involvement in regulating immune responses by influencing macrophage function.
Despite its critical roles in immune responses against tuberculosis infection and immune pathology, the molecular details of interleukin (IL)-1 beta production in tuberculosis infection remain elusive. To explore IL-1 beta 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:Delta 3875) or complemented strain (H37Rv:Delta 3875C) and evaluated IL-1 beta production. H37Rv induced significantly increased IL-1 beta production by BMDMs compared to non-infected BMDMs. In contrast, H37Rv:Delta 3875 induced significantly less mature IL-1 beta production despite eliciting comparable levels of pro-IL-1 beta and IL-8 from BMDMs compared to H37Rv and H37Rv:Delta 3875C. Blocking either NLRP3 or K+ efflux diminished H37Rv-induced IL-1 beta production by BMDMs. Infection of mice intranasally with H37Rv:Delta 3875 induced less IL1 beta production in the lungs compared with H37Rv. Intranasal delivery of ESAT-6 but not CFP10 induced production of IL-1 beta 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:Delta 3875 induced expression of lung SAA3 mRNA and protein, consistent with the effect of intranasal delivery of ESAT-6. Silencing SAA3 reduced Mtb-induced IL-1 beta production by BMDMs. We conclude that SAA3 plays critical role in ESAT-6 dependent IL-1 beta production by macrophages in tuberculosis infection.
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