Advertisement

Concise CommunicationIn-Press PreviewNeuroscienceTherapeutics Free access | 10.1172/JCI139299

Adenosine A3 agonists reverse neuropathic pain via T cell-mediated production of IL-10

Mariaconcetta Durante,1 Silvia Squillace,2 Filomena Lauro,2 Luigino Antonio Giancotti,2 Elisabetta Coppi,1 Federica Cherchi,1 Lorenzo Di Cesare Mannelli,1 Carla Ghelardini,1 Grant Kolar,3 Carrie Wahlman,2 Adeleye Opejin,4 Cuiying Xiao,5 Marc L. Reitman,6 Dilip K. Tosh,7 Daniel Hawiger,8 Kenneth A. Jacobson,7 and Daniela Salvemini2

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

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

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

Find articles by Squillace, S. in: JCI | PubMed | Google Scholar

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

Find articles by Lauro, F. in: JCI | PubMed | Google Scholar |

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

Find articles by Giancotti, L. in: JCI | PubMed | Google Scholar |

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

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

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

Find articles by Cherchi, F. in: JCI | PubMed | Google Scholar |

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

Find articles by Di Cesare Mannelli, L. in: JCI | PubMed | Google Scholar |

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

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

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

Find articles by Kolar, G. in: JCI | PubMed | Google Scholar

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

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

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

Find articles by Opejin, A. in: JCI | PubMed | Google Scholar

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

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

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

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

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

Find articles by Tosh, D. in: JCI | PubMed | Google Scholar |

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

Find articles by Hawiger, D. in: JCI | PubMed | Google Scholar

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

Find articles by Jacobson, K. in: JCI | PubMed | Google Scholar |

1Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy

2Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, United States of America

3Department of Pathology, Saint Louis University School of Medicine, St. Louis, United States of America

4Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, United States of America

5Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

6Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

7Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

8Saint Louis University School of Medicine, St. Louis, United States of America

Find articles by Salvemini, D. in: JCI | PubMed | Google Scholar

Published February 23, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI139299.
Copyright © 2021, American Society for Clinical Investigation
Published February 23, 2021 - Version history
View PDF
Abstract

The A3 adenosine receptor (A3AR) has emerged as a therapeutic target with A3AR agonists to tackle the global challenge of neuropathic pain; investigation into their mode of action is essential for ongoing clinical development. A3ARs on immune cells, and their activation during pathology, modulates cytokine release. Thus, immune cells as a cellular substrate for the pharmacological action of A3AR agonists is enticing but unknown. Studies herein discovered that RagKO mice lacking T- and B-cells are insensitive to the anti-allodynic effects of A3AR agonists versus wild-type (WT) mice. Similar findings were observed in interleukin-10 and interleukin-10 receptor knockout mice. Adoptive transfer of CD4+ T-cells (CD4+-T) from WT mice infiltrated the dorsal root ganglion (DRG) and restored A3AR agonist-mediated anti-allodynia in RagKO mice; CD4+-T from Adora3KO or Il10KO mice did not. Transfer of CD4+-T from WT, but not Il10KO, into Il10KO mice fully reinstated anti-allodynic effects of A3AR activation. Transfer of CD4+-T from WT, but not Il10KO, into Adora3KO mice fully reinstated anti-allodynic effects of A3AR activation. Notably, A3AR agonism reduced DRG neuron excitability when co-cultured with CD4+-T in an IL-10-dependent manner. A3AR actions on CD4+-T infiltrate in the DRG decreased phosphorylation of GluN2B-containing N‐methyl‐D‐aspartate receptors at Tyr1472, a modification associated with regulating neuronal hypersensitivity. Our findings establish that activation of A3AR on CD4+-T cells to release of IL-10 is required and sufficient for A3AR agonists as therapeutics.

Supplemental material

View

Version history
  • Version 1 (February 23, 2021): In-Press Preview
Advertisement
Advertisement