title: 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⁻/⁻ 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⁻/⁻ 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.
authors.affiliation: Inserm, U-1051, Institute for Neurosciences of Montpellier-Hôpital St Eloi, 34091 Montpellier, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Pieraut
authors.forename: Olivier
authors.initials: O
authors.lastname: Lucas
authors.forename: Sina
authors.initials: S
authors.lastname: Sangari
authors.forename: Chamroeun
authors.initials: C
authors.lastname: Sar
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boudes
authors.forename: Carine
authors.initials: C
authors.lastname: Bouffi
authors.forename: Danièle
authors.initials: D
authors.lastname: Noel
authors.forename: Frédérique
authors.initials: F
authors.lastname: Scamps
mesh_terms: D000818:Animals; D019771:Axotomy / Q000379:methods; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis / Q000502:physiology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism* / Q000502:physiology; D064506:Solute Carrier Family 12, Member 2; D015854:Up-Regulation
chemical_list: D002712:Chlorides; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; C578878:Slc12a2 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D053612:Janus Kinases