bims-inflin Biomed News
on Inflammasome and infection
Issue of 2024‒08‒04
two papers selected by
Juliane Cristina Ribeiro Fernandes, Faculdade de Medicina de Ribeirão Preto
  1. Hypoxia activates macrophage-NLRP3 inflammasome promoting atherosclerosis via PFKFB3-driven glycolysis.
  2. Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.
  1. FASEB J. 2024 Aug 15. 38(15): e23854
    Hypoxia activates macrophage-NLRP3 inflammasome promoting atherosclerosis via PFKFB3-driven glycolysis.
    Xuan Wang, Xiangbin Liu, Wanzhou Wu, Longshen Liao, Ming Zhou, Xiaobo Wang, Zeming Tan, Guogang Zhang, Yongping Bai, Xiang Li, Min Zhao.
      The onset and progression of atherosclerosis are closely linked to the involvement of macrophages. While the contribution of NLRP3 inflammasome activation to the creation of a local highly inflammatory microenvironment is well recognized, the precise triggers remain unclear. In this study, we aimed to investigate the regulatory mechanism of NLRP3 inflammasome activation in response to hypoxia-induced glycolysis involving PFKFB3 in the development of atherosclerosis. To develop an atherosclerosis model, we selected ApoE knockout mice treated with a high-fat western diet. We then quantified the expression of HIF-1α, PFKFB3, and NLRP3. In addition, we administered the PFKFB3 inhibitor PFK158 during atherosclerosis modeling. The glycolytic activity was subsequently determined through 18F-FDG micro-PET/CT, ex vivo glucose uptake, and ECAR analysis. Furthermore, we employed lipopolysaccharide (LPS) and TNF-α to induce the differentiation of bone marrow-derived macrophages (BMDMs) into M1-like phenotypes under both hypoxic and normoxic conditions. Our histological analyses revealed the accumulation of PFKFB3 in human atherosclerotic plaques, demonstrating colocalization with NLRP3 expression and macrophages. Treatment with PFK158 reduced glycolytic activity and NLRP3 inflammasome activation, thereby mitigating the occurrence of atherosclerosis. Mechanistically, hypoxia promoted glycolytic reprogramming and NLRP3 inflammasome activation in BMDMs. Subsequent blocking of either HIF-1α or PFKFB3 downregulated the NLRP3/Caspase-1/IL-1β pathway in hypoxic BMDMs. Our study demonstrated that the HIF-1α/PFKFB3/NLRP3 axis serves as a crucial mechanism for macrophage inflammation activation in the emergence of atherosclerosis. The therapeutic potential of PFKFB3 inhibition may represent a promising strategy for atheroprotection.
    Keywords:  NLRP3; PFKFB3; atherosclerosis; hypoxia; macrophage
    DOI:  https://doi.org/10.1096/fj.202400283R
  2. Nat Commun. 2024 Jul 31. 15(1): 6438
    Phosphorylation of PFKL regulates metabolic reprogramming in macrophages following pattern recognition receptor activation.
    Meiyue Wang, Heinrich Flaswinkel, Abhinav Joshi, Matteo Napoli, Sergi Masgrau-Alsina, Julia M Kamper, Antonia Henne, Alexander Heinz, Marleen Berouti, Niklas A Schmacke, Karsten Hiller, Elisabeth Kremmer, Benedikt Wefers, Wolfgang Wurst, Markus Sperandio, Jürgen Ruland, Thomas Fröhlich, Veit Hornung.
      Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than PfklS775A/S775A after LPS treatment. In an in vivo inflammation model, PfklS775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis.
    DOI:  https://doi.org/10.1038/s41467-024-50104-7
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