Abstract
IntroductionMesenchymal stem cells, also called mesenchymal stromal cells, MSCs, have great potential in stem cell therapy partly due to their immunosuppressive properties. How these cells respond to chronic inflammatory stimuli is therefore of importance. Toll‐like receptors (TLR)s are innate immune receptors that mediate inflammatory signals in response to infection, stress, and damage. Caspase‐8 is involved in activation of NF‐kB downstream of TLRs in immune cells. Here we investigated the role of caspase‐8 in regulating TLR‐induced cytokine production from human bone marrow‐derived mesenchymal stromal cells (hBMSCs).MethodsCytokine expression in hBMCs in response to poly(I:C) and LPS was evaluated by PCR, multiplex cytokine assay, and ELISA. TLR3, TRIF, and caspase‐8 were silenced using siRNA. Caspase‐8 was also inhibited using a caspase‐8 inhibitor, z‐IEDT.ResultsWe found that TLR3 agonist poly(I:C) and TLR4 agonist LPS induced secretion of several pro‐inflammatory cytokines in a TLR‐dependent manner which required the TLR signaling adaptor molecule TRIF. Further, poly(I:C) reduced the expression of anti‐inflammatory cytokines HGF and TGFβ whereas LPS reduced HGF expression only. Notably, caspase‐8 was involved in the induction of IL‐ IL‐1β, IL‐6, CXCL10, and in the inhibition of HGF and TGFβ.ConclusionCaspase‐8 appears to modulate hBMSCs into gaining a pro‐inflammatory phenotype. Therefore, inhibiting caspase‐8 in hBMSCs might promote an immunosuppressive phenotype which could be useful in clinical applications to treat inflammatory disorders.
Highlights
Mesenchymal stem cells, called mesenchymal stromal cells, MSCs, have great potential in stem cell therapy partly due to their immunosuppressive properties
To test whether the cytokine production was mediated by TLR3 signaling we knocked down TLR3 in human bone marrow-derived mesenchymal stromal cells (hBMSCs) by siRNA
IL-6 was reduced at both protein and mRNA level when TLR3 was silenced (Fig. 1E and F), as were CXCL10 protein and mRNA upon TLR3 knock-down (Fig. 1G and H). These results indicate that the induction of inflammatory cytokines induced by poly(I:C) in the hBMSCs is mediated by TLR3, as supported by previous studies [29, 30]
Summary
Mesenchymal stem cells, called mesenchymal stromal cells, MSCs, have great potential in stem cell therapy partly due to their immunosuppressive properties. Tissue damage or infections can, change the phenotype of the MSCs from immune suppressive to immune stimulatory, and Caspase-8 modulates cytokine expression toll-like receptors (TLRs) might play an important role in this [11, 12]. Human bone marrow-derived MSCs (hBMSCs) express TLR1-6 and TLR9 [11, 15, 16], and TLR activation induce pro-inflammatory cytokines such as IL-6, CXCL8, and CXCL10 [9, 11, 15]. Another study showed increased T-cell suppression caused by increased IDO expression by the BMSCs in response to the same ligands [17] Such differences can be explained by different experimental setups in terms of responder cells, timing and concentrations of the TLR agonists
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