Journal
STEM CELLS
Volume 32, Issue 6, Pages 1553-1563Publisher
WILEY
DOI: 10.1002/stem.1608
Keywords
Macrophage; Mesenchymal stem/stromal cell; NLRP3 inflammasome; Reactive oxygen species
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Funding
- Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [A111609]
- Korea Health Promotion Institute [A111609, HI11C1963000013, HI11C1562000013] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 1 beta (IL-1 beta). 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-1 beta 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-1 beta 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.
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