Konopko Adrian, Kazek Michalina, Waraksa-Zasada Emilia, Łukomska Agnieszka, Ratajczak Janina, Kucia Magdalena, Ratajczak Mariusz Z
Center for Preclinical Studies and Technology, Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland.
Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.
Stem Cell Rev Rep. 2025 Jul 28. doi: 10.1007/s12015-025-10948-y.
The Nlrp3 inflammasome is a pattern recognition receptor (PRR) and an important component of innate immunity, located in the cytoplasm of various cell types, including those derived from hematopoietic lineages. It is highly expressed in hematopoietic stem/progenitor cells (HSPCs) and in the cells that constitute the bone marrow (BM) hematopoietic microenvironment. The Nlrp3 inflammasome plays a role in several biological processes depending on the level of activation. At low activation levels, within the so-called "hormetic beneficial zone," it positively regulates the trafficking of HSPCs, as seen during mobilization, homing, and engraftment following transplantation. It is also essential for maintaining a pool of HSPCs in the bone marrow (BM), and we have reported that Nlrp3 knockout (KO) mice demonstrate a decrease in the number of these cells. The primary mediators activated and released from the Nlrp3 inflammasome are interleukin-1 beta (IL-1β) and interleukin-18 (IL-18). Additionally, we have suggested that by promoting gasdermin channels in the cell membrane, multiple factors are released, including danger-associated molecular pattern molecules (DAMPs) or alarmins, which activate the corresponding receptors expressed on cell membranes. This process of creating "alarmin fog" in the hematopoietic microenvironment is responsible for the biological effects of this PRR through positive feedback that activates cell surface receptors, elevating intracellular ROS signaling. Here, we report for the first time that Nlrp3 inflammasome knockout mice exhibit defects in oxidative consumption rates. This was paralleled by a decreased level of expression of the mitochondria-encoded cytochrome b gene (CYTB), which encodes a crucial component of complex III in the electron transport chain (ETC). This data highlights the role of the Nlrp3 inflammasome in regulating cell metabolism by ensuring the proper "tonic activation" of the electron transport chain in mitochondria.
Nlrp3炎性小体是一种模式识别受体（PRR），是固有免疫的重要组成部分，位于包括造血谱系来源的各种细胞类型的细胞质中。它在造血干细胞/祖细胞（HSPCs）以及构成骨髓（BM）造血微环境的细胞中高度表达。Nlrp3炎性小体根据激活水平在多个生物学过程中发挥作用。在低激活水平下，即在所谓的“应激性有益区”内，它正向调节HSPCs的运输，如在移植后的动员、归巢和植入过程中所见。它对于维持骨髓（BM）中HSPCs的库也至关重要，并且我们已经报道Nlrp3基因敲除（KO）小鼠中这些细胞的数量减少。从Nlrp3炎性小体激活并释放的主要介质是白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）。此外，我们已经提出，通过促进细胞膜中的gasdermin通道，会释放多种因子，包括危险相关分子模式分子（DAMPs）或警报素，它们激活细胞膜上表达的相应受体。在造血微环境中产生“警报素雾”的这个过程通过激活细胞表面受体的正反馈负责该PRR的生物学效应，提高细胞内ROS信号传导。在此，我们首次报道Nlrp3炎性小体基因敲除小鼠在氧化消耗率方面存在缺陷。这与线粒体编码的细胞色素b基因（CYTB）表达水平的降低平行，该基因编码电子传递链（ETC）中复合物III的关键成分。这些数据突出了Nlrp3炎性小体在通过确保线粒体中电子传递链的适当“张力激活”来调节细胞代谢中的作用。
