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

The A(3) adenosine receptor (A(3)AR) has emerged as a therapeutic target with A(3)AR agonists to tackle the global challenge of neuropathic pain, and investigation into its mode of action is essential for ongoing clinical development. Immune cell A(3)ARs, and their activation during pathology, modulate cytokine release. Thus, the use of immune cells as a cellular substrate for the pharmacological action of A(3)AR 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 A(3)AR 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 A(3)AR 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 A(3)AR activation. Notably, A(3)AR agonism reduced DRG neuron excitability when cocultured with CD4+ T cells in an IL-10-dependent manner. A(3)AR 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 A(3)AR on CD4+ T cells to release IL-10 is required and sufficient evidence for the use of A(3)AR agonists as therapeutics.

Automated summary

The A(3) adenosine receptor has been identified as a therapeutic target for neuropathic pain, with agonists showing promising results in modulating cytokine release through immune cells. Studies have highlighted the crucial role of CD4+ T cells in mediating the anti-allodynic effects of A(3)AR agonists, particularly through IL-10 release. Targeting A(3)AR on CD4+ T cells may provide a novel approach for developing therapeutics for neuropathic pain.