Comparison and immunobiological characterization of retinoic acid inducible gene-I-like receptor expression in mesenchymal stromal cells

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.

Preconditioning of Rat Bone Marrow-Derived Mesenchymal Stromal Cells with Toll-Like Receptor Agonists

“…These results validated the use of this protocol (brief stimulation of rBM-MSCs with Poly(I:C) for 1 h) and are in agreement with previous studies reporting the expression of TLR3 mRNA by mouse and human BM-MSCs (mBM-MSCs and hBM-MSCs, respectively) [15, 55–58]. These findings are also in line with the work by Raicevic et al, who reported that hBM-MSCs express functional MDA5 [59]. In their study, Poly(I:C) internalization was facilitated by the transfection reagent LyoVec, an approach that has been shown to stimulate retinoic acid-inducible gene- (RIG-) I-like receptors (RLR), such as MDA5, rather than TLR3 [60, 61].…”

“…In their study, Poly(I:C) internalization was facilitated by the transfection reagent LyoVec, an approach that has been shown to stimulate retinoic acid-inducible gene- (RIG-) I-like receptors (RLR), such as MDA5, rather than TLR3 [60, 61]. Although the activation of RLR can trigger cell death, Raicevic et al showed that only prolonged stimulation (48 h) with high doses of Poly(I:C) in conjunction with LyoVec (but not with Poly(I:C) alone) can induce cell death in hBM-MSCs [59]. Our results agree with these findings, indicating that a brief exposure to Poly(I:C) for 1 h does not affect the viability of rBM-MSCs.…”

Investigating the effects of IDO1, PTGS2, and TGF-β1 overexpression on immunomodulatory properties of hTERT-MSCs and their extracellular vesicles

“…For the first time, a report by Krampera attributed IFN-γ priming of bone marrow-derived MSCs to the enhancement of immunomodulatory proteins, mainly IDO1 79 . Similar observations were also described for poly(I:C), a well-known analog of dsRNA 80 – 82 , and BiP/Glucose-Regulated Protein 78 (GRP78) 83 – 90 , albeit IFN-γ has been investigated most intensively. The ability of type II interferon for inducing the expression of immunoregulatory encountered genes, including IDO1 , in MSCs from different sources was previously reviewed 91 , 92 .…”

Immune Reconstitution Disorders: Spotlight on Interferons

“…Thus, NLR-inflammasome represents an alternative (to interferon type II) and very damaging route of responses to PAMPs [ 27 ]. The RLR activation by RNA viruses in numerous non-immune cells also leads to type I and III interferon production [ 28 , 29 ]. The upregulation of interferon and interferon response pathways helps limit viral replication, but since these defense pathways are accompanied by apoptosis it may contribute to slow immune reconstitution and immune complication, such as IRIS [ 30 ].…”