Kir2.1 modulation in macrophages sensitises dorsal root ganglion neurons through TNF secretion after nerve injury

Abstract

AbstractMacrophages and satellite glial cells are found between injured and uninjured neurons in the lumbar dorsal root ganglia (DRG). We explored the mechanism of neuro-immune and neuron–glia crosstalk leading to hyperexcitability of DRG neurons. After spared nerve injury (SNI), CX3CR1+resident macrophages became activated, proliferated and increased inward-rectifying potassium channel Kir2.1 currents. Conditioned medium (CM) by macrophages, obtained from DRG of SNI mice, sensitised small DRG neurons from naïve mice. However, treatment with CM from GFAP+glial cells did not affect neuronal excitability. When subjected to this macrophage-derived CM, DRG neurons had increased spontaneous activity, current-evoked responses and voltage-gated NaV1.7 and NaV1.8 currents. Silencing Kir2.1 in macrophages after SNI prevented the induction of neuronal hyperexcitability from their CM. Blocking vesicular exocytosis or soluble tumour necrosis factor (TNF) in CM or interfering with the downstream intracellular p38 pathway in neurons, also prevented neuronal hyperexcitability. Blocking protein trafficking in neurons reduced the effect of CM, suggesting that the hyperexcitable state resulted from changes in NaVchannel trafficking. These results suggest that DRG macrophages, primed by peripheral nerve injury, contribute to neuron–glia crosstalk, NaVchannel dysregulation and neuronal hyperexcitability implicated in the development of neuropathic pain.Graphical abstract