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ResearchIn-Press PreviewTherapeutics Open Access | 10.1172/jci.insight.142376

A STAT3 inhibitor ameliorates CNS autoimmunity by restoring Teff:Treg Balance

Saba I. Aqel,1 Xiaozhi Yang,2 Emma E. Kraus,1 Jinhua Song,2 Marissa F. Farinas,3 Erin Y. Zhao,1 Wei Pei,1 Amy E. Lovett-Racke,4 Michael K. Racke,1 Chenglong Li,2 and Yuhong Yang1

1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America

2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America

3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America

4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America

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1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America

2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America

3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America

4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America

Find articles by Yang, X. in: JCI | PubMed | Google Scholar

1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America

2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America

3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America

4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America

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1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America

2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America

3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America

4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America

Find articles by Song, J. in: JCI | PubMed | Google Scholar |

1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America

2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America

3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America

4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America

Find articles by Farinas, M. in: JCI | PubMed | Google Scholar

1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America

2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America

3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America

4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America

Find articles by Zhao, E. in: JCI | PubMed | Google Scholar

1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America

2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America

3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America

4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America

Find articles by Pei, W. in: JCI | PubMed | Google Scholar

1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America

2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America

3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America

4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America

Find articles by Lovett-Racke, A. in: JCI | PubMed | Google Scholar

1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America

2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America

3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America

4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America

Find articles by Racke, M. in: JCI | PubMed | Google Scholar

1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America

2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America

3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America

4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America

Find articles by Li, C. in: JCI | PubMed | Google Scholar

1Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, United States of America

2Department of Medicinal Chemistry, University of Florida, Gainesville, United States of America

3Neuroscience Program, The Ohio State University College of Arts and Sciences, Columbus, United States of America

4Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, United States of America

Find articles by Yang, Y. in: JCI | PubMed | Google Scholar

Published January 7, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.142376.
Copyright © 2021, Aqel et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 7, 2021 - Version history
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Abstract

Reestablishing an appropriate balance between T effector cells (Teff) and T regulatory cells (Treg) is essential for correcting autoimmunity. Multiple Sclerosis (MS) is an immune-mediated chronic central nervous system (CNS) disease characterized by neuroinflammation, demyelination, and neuronal degeneration, in which the Teff:Treg balance is skewed toward pathogenic Teff cells, Th1 and Th17 cells. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of Teff:Treg balance. Using the structure-based design, we have developed a novel small-molecule prodrug LLL12b that specifically inhibits STAT3 and suppresses Th17 differentiation and expansion. Moreover, LLL12b regulates the fate decision between Th17 and Tregs in an inflammatory environment, shifting Th17:Treg balance toward Tregs and favoring the resolution of inflammation. Therapeutic administration of LLL12b after disease onset significantly suppresses disease progression in adoptively transferred, chronic, and relapsing-remitting experimental autoimmune encephalomyelitis. Disease relapses were also significantly suppressed by LLL12b given during the remission phase. Additionally, LLL12b shifts Th17:Treg balance of CD4 T cells from MS patients toward Tregs and increases Teff sensitivity to Treg-mediated suppression. These data suggest selective inhibition of STAT3 by the novel small molecule LLL12b recalibrates the effector and regulatory arms of CD4 T responses, representing a potentially clinically translatable therapeutic strategy for MS.

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