Abstract
Due to their immunomodulatory and regenerative properties, Mesenchymal stromal cells (MSC) have generated major interests in several clinical settings including transplantation and inflammatory diseases. MSC functions can be influenced by their tissue origin. Their microenvironment strongly affects their biology notably through TLR sensing. In this study, we show that MSC isolated from four different sources express another type of cytosolic pathogen recognition receptors known as retinoic acid inducible gene-I (RIG-I)-like receptors (RLR). RLR activation in MSC induces the production of Type I IFN (IFN-β) and Type III IFN (IFN-λ1). The highest producers are adipose tissue(AT)-MSC. We further show that Interferon production is induced through TBK1/IKK-ε signaling and IRF7 phosphorylation. Depending on MSC source, the knockdown of TLR3 and/or RIG-I decreases the MSC response to RLR ligand poly(I:C)/Lyovec. Among the different MSC types, AT-MSCs display the highest sensitivity to viral stimuli as shown by the alteration of their viability after prolonged stimulation. Our work indicates that this could be linked to an increase of pro-apoptotic Noxa expression. Finally, the expression of IDO1 and LIF upon RLR activation indicate the increase of MSC immunomodulatory potential, especially in AT-MSCs. Altogether, these data should be considered when designing MSC-based therapy in clinical settings where inflammation or infection are present.
Highlights
Inflammatory responses are caused by various factors including microbial infections or tissue injuries
MDA-5 was highly expressed in FSK-Mesenchymal stromal cells (MSC), lower expression was observed in adipose tissue (AT)- and WJ-MSCs and the lowest one in bone marrow (BM)-MSCs
Up to date, nothing is known about the expression profile and role of RLRs in human MSCs isolated from different tissues
Summary
Inflammatory responses are caused by various factors including microbial infections or tissue injuries. MSC-induced immunomodulation seems to process as a network involving the induction of immune regulatory cells from both the innate and adaptive responses to establish a tolerogenic state (reviewed in refs 3 and 4) According to their origin, MSCs may have distinct immunomodulatory effects depending on the regulatory factors produced during interaction with immune cells[5, 6]. The role of LGP2 in cytosolic RNA sensing is still unclear but some reports suggest that it functions as a positive regulator of RIG-I and MDA5-mediated antiviral responses[17] Both RIG-I and MDA5 induce antiviral response through the activation of IRF3/7 and NF-kB transcription factors leading to upregulation of gene expression and production of type I IFN, type III IFN as well as pro-inflammatory cytokines such as IL-6 and IL-815. These data could help designing new new MSC-based therapeutic strategies in inflammatory and infectious contexts
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