MicroRNA-21-5p functions via RECK/MMP9 as a proalgesic regulator of the blood nerve barrier in nerve injury

Ann Kristin Reinhold, Susanne M. Krug, Ellaine Salvador, Reine S. Sauer, Franziska Karl-Schöller, Marzia Malcangio, Claudia Sommer, Heike L. Rittner

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired-partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA-21-5p (miR-21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR-21 in neuropathic pain and its impact on the BNB in a human-murine back translational approach. MiR-21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin-1 in both injured and spared nerves. Moreover, the putative miR-21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR-21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR-21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR-21 after nerve injury reversed it. In summary, the data support a novel role for miR-21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9.

Original languageEnglish
Pages (from-to)184-195
Number of pages12
JournalAnnals of the New York Academy of Sciences
Volume1515
Issue number1
DOIs
Publication statusPublished - 1 Sept 2022

Keywords

  • blood nerve barrier
  • claudin-1
  • CRPS
  • microRNA
  • MMP9
  • neuropathic pain
  • RECK

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