Institute of Medical Microbiology and Hygiene, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.
BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
EMBO Rep. 2022 Aug 3;23(8):e54226. doi: 10.15252/embr.202154226. Epub 2022 Jun 13.
GM-CSF is a potent inflammatory cytokine regulating myeloid cell differentiation, hematopoiesis, and various other functions. It is functionally associated with a number of inflammatory pathologies including rheumatoid arthritis and inflammatory bowel disease. GM-CSF has been found to promote NLRP3-dependent IL-1β secretion, which may have a significant role in driving inflammatory pathologies. However, the molecular mechanisms remain unknown. Here, we show that GM-CSF induces IL-1β secretion through a ROS-dependent pathway. TNF is required for reactive oxygen species (ROS) generation that strikingly does not promote NLRP3 activation, but instead drives ubiquitylation of IL-1β, promoting its cleavage through basal NRLP3 activity. GM-CSF regulates this pathway through suppression of antioxidant responses via preventing upregulation of NRF2. Thus, the pro-inflammatory effect of GM-CSF on IL-1β is through suppression of antioxidant responses, which leads to ubiquitylation of IL-1β and enhanced processing. This study highlights the role of metabolic regulation of inflammatory signaling and reveals a novel mechanism for GM-CSF to promote inflammation.
粒细胞-巨噬细胞集落刺激因子（GM-CSF）是一种有效的炎症细胞因子，可调节髓样细胞分化、造血和多种其他功能。它与包括类风湿性关节炎和炎症性肠病在内的许多炎症性病理有关。已经发现 GM-CSF 可促进 NLRP3 依赖性 IL-1β 的分泌，这可能在驱动炎症性病理中起重要作用。然而，分子机制尚不清楚。在这里，我们表明 GM-CSF 通过 ROS 依赖途径诱导 IL-1β 的分泌。TNF 是活性氧（ROS）产生所必需的，ROS 不会促进 NLRP3 的激活，而是驱动 IL-1β 的泛素化，通过基础 NLRP3 活性促进其切割。GM-CSF 通过抑制抗氧化反应来调节此途径，防止 NRF2 的上调。因此，GM-CSF 对 IL-1β 的促炎作用是通过抑制抗氧化反应，导致 IL-1β 的泛素化和增强的处理。这项研究强调了炎症信号转导的代谢调节作用，并揭示了 GM-CSF 促进炎症的新机制。
