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

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

doi:10.1172/JCI92387

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

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 (Lead / Corresponding author)

Population Health and Genomics

Research output: Contribution to journal › Article › peer-review

48 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3937-3953
Number of pages	17
Journal	Journal of Clinical Investigation
Volume	127
Issue number	11
DOIs	https://doi.org/10.1172/JCI92387
Publication status	Published - 25 Sept 2017

ASJC Scopus subject areas

General Medicine

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10.1172/JCI92387

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Feo, D. D., Merlini, A., Brambilla, E., Ottoboni, L., Laterza, C., Menon, R., Srinivasan, S., Farina, C., Manteiga, J. M. G., Butti, E., Bacigaluppi, M., Comi, G., Greter, M., & Martino, G. (2017). Neural precursor cell-secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity. Journal of Clinical Investigation, 127(11), 3937-3953. https://doi.org/10.1172/JCI92387

@article{3e563769279240839f9cc59029f19d41,

title = "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.",

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

note = "Funding Information: We thank the Center for Translational Genomics and BioInfor-matics, San Raffaele Scientific Institute, for RNA sequencing and bioinformatics analysis; Advanced Light and Electron Microscopy BioImaging Center, San Raffaele Scientific Institute, for the use of equipment; the Center for Microscopy and Image Analysis, University of Z{\"u}rich, for the use of equipment; the Mouse HistoPathology Unit, San Raffaele Scientific Institute, for support and equipment usage for immunohistochemistry; F. Ruffini and A. Finardi, San Raffaele Scientific Institute, for technical assistance; Thomas Doetschman, University of Arizona, for providing the Tgfb2-knockout strain; V. Tosevski, University of Z{\"u}rich, for technical help and FACS sorting; and A. Cantore, TIGET San Raffaele Scientific Institute, for Tgfb2-expressing lentiviral vector production. This work has been in part supported by TargetBrain (EU Frame-work 7 project HEALTH-F2-2012–279017), by NEUROKINE network (EU Framework 7 ITN project), by BMW Italy Group, by Fondazione Italiana Sclerosi Multipla (FISM) n the project entitled Progetto Speciale Cellule Staminali, and by CARIPLO Foundation grant no. 2010 1835 to GM and by Ministero della Salute Italiana (Progetto Giovani Ricercatori 58/GR-2011-02348160) to MB.",

year = "2017",

month = sep,

day = "25",

doi = "10.1172/JCI92387",

language = "English",

volume = "127",

pages = "3937--3953",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "11",

}

Feo, DD, Merlini, A, Brambilla, E, Ottoboni, L, Laterza, C, Menon, R, Srinivasan, S, Farina, C, Manteiga, JMG, Butti, E, Bacigaluppi, M, Comi, G, Greter, M & Martino, G 2017, 'Neural precursor cell-secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity.', Journal of Clinical Investigation, vol. 127, no. 11, pp. 3937-3953. https://doi.org/10.1172/JCI92387

TY - JOUR

T1 - Neural precursor cell-secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity.

AU - Feo, Donatella De

AU - Merlini, Arianna

AU - Brambilla, Elena

AU - Ottoboni, Linda

AU - Laterza, Cecilia

AU - Menon, Ramesh

AU - Srinivasan, Sundararajan

AU - Farina, Cinthia

AU - Manteiga, Jose Manuel Garcia

AU - Butti, Erica

AU - Bacigaluppi, Marco

AU - Comi, Giancarlo

AU - Greter, Melanie

AU - Martino, Gianvito

N1 - Funding Information: We thank the Center for Translational Genomics and BioInfor-matics, San Raffaele Scientific Institute, for RNA sequencing and bioinformatics analysis; Advanced Light and Electron Microscopy BioImaging Center, San Raffaele Scientific Institute, for the use of equipment; the Center for Microscopy and Image Analysis, University of Zürich, for the use of equipment; the Mouse HistoPathology Unit, San Raffaele Scientific Institute, for support and equipment usage for immunohistochemistry; F. Ruffini and A. Finardi, San Raffaele Scientific Institute, for technical assistance; Thomas Doetschman, University of Arizona, for providing the Tgfb2-knockout strain; V. Tosevski, University of Zürich, for technical help and FACS sorting; and A. Cantore, TIGET San Raffaele Scientific Institute, for Tgfb2-expressing lentiviral vector production. This work has been in part supported by TargetBrain (EU Frame-work 7 project HEALTH-F2-2012–279017), by NEUROKINE network (EU Framework 7 ITN project), by BMW Italy Group, by Fondazione Italiana Sclerosi Multipla (FISM) n the project entitled Progetto Speciale Cellule Staminali, and by CARIPLO Foundation grant no. 2010 1835 to GM and by Ministero della Salute Italiana (Progetto Giovani Ricercatori 58/GR-2011-02348160) to MB.

PY - 2017/9/25

Y1 - 2017/9/25

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85032988069

U2 - 10.1172/JCI92387

DO - 10.1172/JCI92387

M3 - Article

C2 - 28945200

AN - SCOPUS:85032988069

SN - 0021-9738

VL - 127

SP - 3937

EP - 3953

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 11

ER -

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

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