A Novel Mechanism of Mesenchymal Stromal Cell‐Mediated Protection against Sepsis: Restricting Inflammasome Activation in Macrophages by Increasing Mitophagy and Decreasing Mitochondrial ROS

Abstract

Sepsis, a systemic inflammatory response to infection, is the leading cause of death in the intensive care unit (ICU). Previous studies indicated that mesenchymal stromal cells (MSCs) might have therapeutic potential against sepsis. The current study was designed to investigate the effects of MSCs on sepsis and the underlying mechanisms focusing on inflammasome activation in macrophages. The results demonstrated that the bone marrow-derived mesenchymal stem cells (BMSCs) significantly increased the survival rate and organ function in cecal ligation and puncture (CLP) mice compared with the control-grouped mice. BMSCs significantly restricted NLRP3 inflammasome activation, suppressed the generation of mitochondrial ROS, and decreased caspase-1 and IL-1β activation when cocultured with bone marrow-derived macrophages (BMDMs), the effects of which could be abolished by Mito-TEMPO. Furthermore, the expression levels of caspase-1, IL-1β, and IL-18 in BMDMs were elevated after treatment with mitophagy inhibitor 3-MA. Thus, BMSCs exert beneficial effects on inhibiting NLRP3 inflammasome activation in macrophages primarily via both enhancing mitophagy and decreasing mitochondrial ROS. These findings suggest that restricting inflammasome activation in macrophages by increasing mitophagy and decreasing mitochondrial ROS might be a crucial mechanism for MSCs to combat sepsis.

Presepsin Levels in Experimental Sepsis and Massive Bowel Resection Models in Rats

“…In our study, we observed increased presepsin levels both in CLP and MBR models, which were significantly higher than those in sham-operated control rats. It is known that CLP-induced sepsis is associated with a remarkable inflammatory response and the production of ROS (32). We also observed significantly higher ROS and RNS levels in the liver and intestinal tissues of CLP and MBR experimental groups than those in shamoperated control tissues.…”

NLRP3 Inflammasome and Inflammatory Diseases

“…In atherosclerosis, the NLRP3 inflammasome drives IL-1β release, thus contributing to the progression of atherosclerosis [58]. Similarly, the inhibition of caspase-1 and IL-1β activation induced by bone marrowderived mesenchymal stem cells can suppress the generation of mitochondrial ROS and then inhibit the NLRP3 inflammasome activation [59]. Systemic inflammation has been reported to be related to an overproduction of IL-1β and IL-18 [60].…”

The Role of Mitophagy in Innate Immunity

“…Therefore, mitophagy regulation is indispensable for the proper determination of M1/M2 macrophage phenotypes (Figure 4 ). Recently, the essential role of fine-tuned mitochondrial metabolism and mitophagy was underlined in a mouse model of sepsis ( 139 ). Bone marrow-derived mesenchymal stem cells (BMSCs) promote survival and performance of various organs during septic shock.…”

“…Bone marrow-derived mesenchymal stem cells (BMSCs) promote survival and performance of various organs during septic shock. It is shown that the beneficial effects of BMSCs were mediated by mitophagy induction in cocultured BMDMs resulting in decreased mtROS levels and inflammasome restriction during cecal ligation and puncture-induced sepsis ( 139 ). Although the beneficial effect of mitophagy induction during pronounced inflammatory conditions, mitophagy hyperstimulation could also be detrimental for cellular physiology.…”