The NLRP3 Inflammasome Transmits Sterile Inflammation Signals to Sustain Proper Mitochondrial Electron Transport Chain Function and Influences Cellular Metabolism.

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.