Adenosine A3 Agonists Reverse Neuropathic Pain Via T Cell-mediated Production Of IL-10
Abstract
The A3 adenosine receptor (A3AR) has emerged as a therapeutic target with A3AR agonists to tackle the global challenge of neuropathic pain, and investigation into its mode of action is essential for ongoing clinical development. Immune cell A3ARs, and their activation during pathology, modulate cytokine release. Thus, the use of immune cells as a cellular substrate for the pharmacological action of A3AR agonists is enticing, but unknown. The present study discovered that Rag-KO mice lacking T and B cells, as compared with WT mice, are insensitive to the anti-allodynic effects of A3AR agonists. Similar findings were observed in interleukin-10 and interleukin-10 receptor knockout mice. Adoptive transfer of CD4+ T cells from WT mice infiltrated the dorsal root ganglion (DRG) and restored A3AR agonist-mediated anti-allodynia in Rag-KO mice. CD4+ T cells from Adora3-KO or Il10-KO mice did not. Transfer of CD4+ T cells from WT mice, but not Il10-KO mice, into Il10-KO mice or Adora3-KO mice fully reinstated the anti-allodynic effects of A3AR activation. Notably, A3AR agonism reduced DRG neuron excitability when cocultured with CD4+ T cells in an IL-10-dependent manner. A3AR action on CD4+ T cells infiltrated 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 IL-10 is required and sufficient evidence for the use of A3AR agonists as therapeutics.
Recommended Citation
M. Durante and S. Squillace and F. Lauro and L. A. Giancotti and E. Coppi and F. Cherchi and L. Di Cesare Mannelli and C. Ghelardini and G. Kolar and C. Wahlman and A. Opejin and C. Xiao and M. L. Reitman and D. K. Tosh, "Adenosine A3 Agonists Reverse Neuropathic Pain Via T Cell-mediated Production Of IL-10," Journal of Clinical Investigation, vol. 131, no. 7, article no. e139299, American Society for Clinical Investigation, Apr 2021.
The definitive version is available at https://doi.org/10.1172/JCI139299
Department(s)
Biological Sciences
International Standard Serial Number (ISSN)
1558-8238; 0021-9738
Document Type
Article - Journal
Document Version
Final Version
File Type
text
Language(s)
English
Rights
© 2025 The Authors, All rights reserved.
Creative Commons Licensing
This work is licensed under a Creative Commons Attribution 4.0 License.
Publication Date
01 Apr 2021
PubMed ID
33621215
Comments
National Institute of Diabetes and Digestive and Kidney Diseases, Grant FUV2020-3299