Neural precursor cell–secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity
Donatella De Feo, … , Melanie Greter, Gianvito Martino
Donatella De Feo, … , Melanie Greter, Gianvito Martino
Published September 25, 2017
Citation Information: J Clin Invest. 2017;127(11):3937-3953. https://doi.org/10.1172/JCI92387.
View: Text | PDF
Research Article Autoimmunity Stem cells

Neural precursor cell–secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity

Abstract

In multiple sclerosis, the pathological interaction between autoreactive Th cells and mononuclear phagocytes in the CNS drives initiation and maintenance of chronic neuroinflammation. Here, we found that intrathecal transplantation of neural stem/precursor cells (NPCs) in mice with experimental autoimmune encephalomyelitis (EAE) impairs the accumulation of inflammatory monocyte-derived cells (MCs) in the CNS, leading to improved clinical outcome. Secretion of IL-23, IL-1, and TNF-α, the cytokines required for terminal differentiation of Th cells, decreased in the CNS of NPC-treated mice, consequently inhibiting the induction of GM-CSF–producing pathogenic Th cells. In vivo and in vitro transcriptome analyses showed that NPC-secreted factors inhibit MC differentiation and activation, favoring the switch toward an antiinflammatory phenotype. Tgfb2–/– NPCs transplanted into EAE mice were ineffective in impairing MC accumulation within the CNS and failed to drive clinical improvement. Moreover, intrathecal delivery of TGF-β2 during the effector phase of EAE ameliorated disease severity. Taken together, these observations identify TGF-β2 as the crucial mediator of NPC immunomodulation. This study provides evidence that intrathecally transplanted NPCs interfere with the CNS-restricted inflammation of EAE by reprogramming infiltrating MCs into antiinflammatory myeloid cells via secretion of TGF-β2.

Authors

Donatella De Feo, Arianna Merlini, Elena Brambilla, Linda Ottoboni, Cecilia Laterza, Ramesh Menon, Sundararajan Srinivasan, Cinthia Farina, Jose Manuel Garcia Manteiga, Erica Butti, Marco Bacigaluppi, Giancarlo Comi, Melanie Greter, Gianvito Martino

×

Figure 9

NPC treatment alters the gene expression signature of CNS-infiltrating inflammatory MCs in EAE.

Options: View larger image (or click on image) Download as PowerPoint
NPC treatment alters the gene expression signature of CNS-infiltrating i...
(A) Cohorts of 4–7 MOG35–55-immunized C57BL/6 mice intrathecally treated with either PBS or NPCs at the peak of the disease (2–4 days after clinical onset). At 7 days after transplantation, CNS tissues were pooled and CNS-infiltrating MCs were FACS-sorted according to the phenotype CD45hiLy6G–CD11b+Ly6ChiMHC-II+. Sorting strategy used for 3 independent FACS sorting experiments is shown. (B) Next-generation sequencing was performed on RNA extracted from sorted cells of 3 independent experiments and respective CNS harvests. Six hundred ten genes that are significantly altered in 3 different statistical tests to a minimum significance threshold of P ≤ 0.01 are shown in the heatmap. (C) Volcano plot showing the fold change and significance of genes in MCs from PBS- versus NPC-treated EAE mice. (D) Bipartite graph of functional enrichment analysis using hallmark data set for NPC treatment obtained by Cytoscape software (http://www.cytoscape.org/). Black and gray nodes represent enriched pathways with sizes corresponding to FDR-adjusted enrichment P value (P ≤ 0.05). Red dots represent upregulated genes and blue dots downregulated genes, whereas the dot size indicates significance (P ≤ 0.01).