Mesenchymal Stem Cells Shape Microglia Effector Functions Through the Release of CX3CL1

Abstract

Mesenchymal stem cells (MSC) display a remarkable ability to modulate the immune response and protect the central nervous system mainly through the release of soluble factors in a paracrine fashion, affecting the functional behavior of cells in the tissues. Here we investigated the effect of the interaction between MSC and microglia in vitro, and we dissected the molecular and cellular mechanisms of this crosstalk. We demonstrated that MSC impair microglia activation by inflammatory cues through the inhibition of the expression and release of inflammatory molecules and stress-associated proteins. We showed that MSC significantly increase microglial expression and release of molecules associated with a neuroprotective phenotype such as CX3CR1, nuclear receptor 4 family, CD200 receptor, and insulin growth factor 1. Interestingly, MSC can enhance functional changes on microglia as depicted by the increase of intracellular calcium concentration and phagocytic activity. This last event is associated with an increased expression of triggering receptor expressed on myeloid cells-2, an innate immune receptor involved in phagocytosis in the absence of inflammation. The observed effects on CX3CR1-expressing microglia are due to the release of CX3CL1 by MSC, driven by inflammatory signals, as demonstrated by the reversal of the observed results when CX3CL1 expression was silenced in MSC or its release was blocked. Finally, we showed that exogenous CX3CL1 induce phenotypic and functional changes of microglia similar to those induced by MSC. These findings demonstrate that MSC instruct, through the release of CX3CL1, microglia responsiveness to proinflammatory signals by modulating constitutive ''calming'' receptors, typically expressed by ''steady-state microglia'' thus switching microglia from a detrimental phenotype to a neuroprotective one.

Regulation of Mouse Microglia Activation and Effector Functions by Bone Marrow-Derived Mesenchymal Stem Cells

“…We can only speculate that due to the fact that mononuclear phagocytes with various phenotypic polarization are crucial for tissue repair and regeneration [47,48], the MCP-1/CCL2-induced microglia accumulation at the site of tissue injury or inflammation could have a beneficial effect on the repair process. On the other hand, the IL-1b secretion by MGs in the presence of stem cells is consistent with an earlier report [35] and could be explained by two facts. First, IL-1b, as a powerful proinflammatory cytokine, is involved in the ''licensing'' of MSCs necessary to exert their immunosuppressive properties [7].…”

“…inflammatory (M1-like) into an anti-inflammatory (M2-like) phenotype [26,31,36] mainly through COX-2 mediated production of PGE2 and possibly some other soluble factors [35,37]. Similar PGE2-mediated interaction was also described between other tissue macrophages and MSCs in vitro [12], as well as in vivo [43].…”

“…Since previous data [35] demonstrated an elevated IL-1b production by LPS-stimulated MGs in the presence of …”

“…However, the precise polarization states of microglia in the presence of MSCs under physiological or inflammatory conditions remain largely unknown. In most studies, xenogenic experimental systems were used; that is, cocultures of human MSCs with mouse or rat MGs [26,[31][32][33] and primary microglia were frequently replaced with neoplastic cell lines (BV2 or N9) [34][35][36] or with hippocampal slices [37]. Only two laboratories used autologous mouse [35] or rat [38] primary MGs and MSCs.…”

Monocytes and CD4 + T cells contribution to the under-expression of NR4A2 and TNFAIP3 genes in patients with multiple sclerosis

“…A recent study showed that NR4A2 and other neuroprotective molecules can "calm" microglia after the intervention of mesenchymal stem cells and the release of CX3CL1 (Giunti et al, 2012).…”