An Autocrine Neuronal Interleukin-6 Loop Mediates Chloride Accumulation and NKCC1 Phosphorylation in Axotomized Sensory Neurons

Abstract

The cation-chloride cotransporter NKCC1 plays a fundamental role in the central and peripheral nervous systems by setting the value of intracellular chloride concentration. Following peripheral nerve injury, NKCC1 phosphorylation-induced chloride accumulation contributes to neurite regrowth of sensory neurons. However, the molecules and signaling pathways that regulate NKCC1 activity remain to be identified. Functional analysis of cotransporter activity revealed that inhibition of endogenously produced cytokine interleukin-6 (IL-6), with anti-mouse IL-6 antibody or in IL-6 Ϫ/Ϫ mice, prevented chloride accumulation in a subset of axotomized neurons. Nerve injury upregulated the transcript and protein levels of IL-6 receptor in myelinated, TrkB-positive sensory neurons of murine lumbar dorsal root ganglia. Expression of phospho-NKCC1 was observed mainly in sensory neurons expressing IL-6 receptor and was absent from IL-6 Ϫ/Ϫ dorsal root ganglia. The use of IL-6 receptor blocking-function antibody or soluble IL-6 receptor, together with pharmacological inhibition of Janus kinase, confirmed the role of neuronal IL-6 signaling in chloride accumulation and neurite growth of a subset of axotomized sensory neurons. Cell-specific expression of interleukin-6 receptor under pathophysiological conditions is therefore a cellular response by which IL-6 contributes to nerve regeneration through neuronal NKCC1 phosphorylation and chloride accumulation.

Morphology and Nanomechanics of Sensory Neurons Growth Cones following Peripheral Nerve Injury

“…This could be related to an increased volume necessary for fast elongation. Interestingly, we reported that nerve injury induced activation of the volume regulatory co-transporter Na + -K + -2Cl − that could account for volume increase in neurites thereby contributing to growth velocity [12], [13]. This size increase is compatible with our observation that growth cones become much softer than those from control neurones.…”

“…In vitro , the neurons conditioned by the first traumatism display a faster, elongated mode of neurite growth called regenerative growth [10], [11]. This provides a convenient model to decipher post-transcriptional molecular adaptation involved in regenerative growth [12], [13].…”

Presynaptic GABAergic inhibition regulated by BDNF contributes to neuropathic pain induction

“…An increased activity of NKCC1 and a depolarizing shift of E GABA in DRG neurons have been observed after nerve injury in several studies13142931. However, the net effect of the depolarizing shift of E GABA remains unclear.…”

IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection

“…IL-6R, soluble IL-6R, and gp130 are expressed in the cornea, 57 and the gp130 receptor is thought to be ubiquitously expressed in sensory neurons. 60 Thus, we speculate that the mechanism of corneal nerve regression after infection might involve direct action of local IL-6 on cells present in the cornea (resident and/or infiltrating immune cells), and/or IL-6 triggered signaling within sensory neurons innervating the tissue. Whether HSV-1 infection of sensory neurons in the trigeminal ganglia plays a role in the degeneration of corneal nerves remains unknown and should be further explored.…”