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Papers of the Week

Papers: 20 Feb 2021 - 26 Feb 2021

Animal Studies, Pharmacology/Drug Development

2021 Feb 23

J Clin Invest

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


Durante M, Squillace S, Lauro F, Giancotti L A, Coppi E, Cherchi F, Di Cesare Mannelli L, Ghelardini C, Kolar G, Wahlman C, Opejin A, Xiao C, Reitman ML, Tosh DK, Hawiger D, Jacobson KA, Salvemini D
J Clin Invest. 2021 Feb 23.
PMID: 33621215.


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.