Mesenchymal Stem/Stromal Cells Inhibit the NLRP3 Inflammasome by Decreasing Mitochondrial Reactive Oxygen Species

Abstract

Mesenchymal stem/stromal cells (MSCs) control excessive inflammatory responses by modulating a variety of immune cells including monocytes/macrophages. However, the mechanisms by which MSCs regulate monocytes/macrophages are unclear. Inflammasomes in macrophages are activated upon cellular "danger" signals and initiate inflammatory responses through the maturation and secretion of proinflammatory cytokines such as interleukin 1b (IL-1b). Here we demonstrate that human MSCs (hMSCs) negatively regulate NLRP3 inflammasome activation in human or mouse macrophages stimulated with LPS and ATP. Caspase-1 activation and subsequent IL-1b release were decreased in macrophages by direct or transwell coculture with hMSCs. Addition of hMSCs to macrophages either at a LPS priming or at a subsequent ATP step similarly inhibited the inflammasome activation. The hMSCs had no effect on NLRP3 and IL-1b expression at mRNA levels during LPS priming. However, MSCs markedly suppressed the generation of mitochondrial reactive oxygen species (ROS) in macrophages. Further analysis showed that NLRP3-activated macrophages stimulated hMSCs to increase the expression and secretion of stanniocalcin (STC)-1, an antiapoptotic protein. Addition of recombinant protein STC-1 reproduced the effects of hMSCs in inhibiting NLRP3 inflammasome activation and ROS production in macrophages. Conversely, the effects of hMSCs on macrophages were largely abrogated by an small interfering RNA (siRNA) knockdown of STC-1. Together, our results reveal that hMSCs inhibit NLRP3 inflammasome activation in macrophages primarily by secreting STC-1 in response to activated macrophages and thus by decreasing mitochondrial ROS. STEM CELLS 2014;32:1553-1563

Effects of Mesenchymal Stem/Stromal Cells on Cultures of Corneal Epithelial Progenitor Cells With Ethanol Injury

“…Previous studies reported that STC-1 is secreted by hMSCs in response to signals from apoptotic cells and mediates an antiapoptotic action of hMSCs. 9,10 In fact, STC-1 has been shown to have multiple biological effects in mammals, involving protection of cells against ischemia, 19,20 suppression of inflammatory responses, 21,22 or reduction of reactive oxygen species [21][22][23] and the subsequent apoptosis in alveolar epithelial cancer cells, photoreceptors, or retinal ganglion cells. 10,12,13 Similarly, our data demonstrate that TNF-a-activated hMSCs secreted a large amount of STC-1, and STC-1 was responsible at least in part for the protective effects of hMSCs on corneal epithelial cells.…”

Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials

“…In addition to interacting with adaptive and innate lymphocyte populations, MSCs have also been shown to modulate the differentiation, expansion, and/or function of myeloid cells towards more immunosuppressive and immunomodulatory phenotypes. These interactions include myeloid populations ranging from monocytes [28, 29], dendritic cells (DCs) [30, 31], macrophages [32, 33], and myeloid-derived suppressor cells (MDSCs) [34]. Most recently, there is also data showing modulation of granulocytes by BM and placental MSCs [35, 36].…”

Mesenchymal Stem/Stromal Cells in Liver Fibrosis: Recent Findings, Old/New Caveats and Future Perspectives

“…Thus, therapeutic avenues/strategies able to protect hepatocytes/biliary duct cells from insults and/ or to modulate inflammation could prevent the development of liver fibrosis/cirrhosis. It is worth noting that MSCs are immune-privileged cells able to inhibit or modulate immune responses through different and complex mechanisms, some of them causing a reduction in the amplification of proinflammatory signals [52][53][54][55], which were the subject of recent and detailed reviews [51,[56][57][58] and are briefly summarized in Fig. 2.…”