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 1

Intrathecally administered NPCs ameliorate chronic EAE.

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Intrathecally administered NPCs ameliorate chronic EAE. (A) Top: Clinica...
(A) Top: Clinical scores of EAE mice treated at the peak of the disease (4 days after the clinical onset, arrow) with intrathecal injection (into cisterna magna) of either NPCs (red dots) or PBS (black dots), n = 20 mice per group. Each point represents the mean ± SEM; 70 to 82 dpi, 2-way ANOVA with Bonferroni’s post-test, *P ≤ 0.05. Bottom: Linear regression curves of clinical score from the day of treatment with either NPCs or PBS until 60 or 80 dpi. Dashed lines indicate 95% CI. **P ≤ 0.01; ***P ≤ 0.001. (B–D) Quantification and representative images of spinal cord demyelination (Luxol fast blue staining) (B) and axonal loss quantified on Bielschowsky silver staining (C; at bottom right, high-magnification insets, ×100) and immunohistochemistry for neurofilaments (NF) (D) at 80 dpi in PBS-treated (black bars) versus NPC-treated (white bars) EAE mice (n = 15 sections per mouse, 3–6 mice per group). (E) Quantification and representative images of inflammatory infiltrates (H&E staining) at 30 dpi in PBS-treated (black bars) versus NPC-treated (white bars) EAE mice (n = 12–20 sections per mouse, 3 mice per group). Data are mean ± SEM and represent the percentage area of damage over total section area. *P ≤ 0.05, **P ≤ 0.01, unpaired t test. Scale bars: B–E, 100 μm.