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.
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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

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Figure 4

NPC transplantation dampens the pathogenic signature of the CNS-infiltrating Th cells.

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NPC transplantation dampens the pathogenic signature of the CNS-infiltra...
(A and B) Production of GM-CSF by CNS-infiltrating Th1 (CD45hiCD3+CD4+IFN-γ+) and Th17 cells (CD45hiCD3+CD4+IL-17A+) in EAE mice 7 days after PBS or NPC treatment as analyzed by flow cytometry. Frequency of GM-CSF+ Th1, GM-CSF+ Th17, and total GM-CSF+ Th cells are shown in the plots (A) and quantified in the graph (n = 4 mice per group) (B). (C) Frequency of FoxP3+ CNS-infiltrating CD4+ T cells (CD45hiCD11b–CD4+) in PBS- and NPC-treated EAE mice at the same time point as A is shown in plots and graph (n = 4 mice per group). (D and E) Expression of FoxP3 (D) and Rorc, Il23r, Tbet, Il22, Csf2, and Cxcl3 (E) in CD45hiCD11b–CD4+ Th cells sorted from the CNS of PBS- and NPC-treated EAE mice at the same time point, relative value to PBS-treated mice (n = 4 mice per group). (F) GM-CSF quantification by ELISA in hindbrain and cervical and dorsal spinal cord (SC) tissues of PBS- and NPC-treated EAE mice at 7 days after transplantation (n = 6 mice per group). Black bars, PBS-treated mice; white bars, NPC-treated mice. Data are mean ± SEM and are representative of 2 independent experiments. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, unpaired t test.