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A translational study: Involvement of miR-21-5p in development and maintenance of neuropathic pain via immune-related targets CCL5 and YWHAE

Karl-Schöller, Franziska ; Kunz, Meik ; Kreß, Luisa ; Held, Melissa ; Egenolf, Nadine ; Wiesner, Anna ; Dandekar, Thomas ; Sommer, Claudia ; Üçeyler, Nurcan

Experimental neurology, 2022-01, Vol.347, p.113915-113915, Article 113915 [Peer Reviewed Journal]

United States: Elsevier Inc

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  • Title:
    A translational study: Involvement of miR-21-5p in development and maintenance of neuropathic pain via immune-related targets CCL5 and YWHAE
  • Author: Karl-Schöller, Franziska ; Kunz, Meik ; Kreß, Luisa ; Held, Melissa ; Egenolf, Nadine ; Wiesner, Anna ; Dandekar, Thomas ; Sommer, Claudia ; Üçeyler, Nurcan
  • Subjects: 14-3-3 Proteins - biosynthesis ; 14-3-3 Proteins - genetics ; 14-3-3 Proteins - immunology ; Animals ; CCL5 ; Chemokine CCL5 - biosynthesis ; Chemokine CCL5 - genetics ; Chemokine CCL5 - immunology ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; MicroRNAs - biosynthesis ; MicroRNAs - genetics ; MicroRNAs - immunology ; miR-21 ; Nerve lesion ; Neuralgia - genetics ; Neuralgia - immunology ; Neuralgia - metabolism ; Neuropathic pain ; Pain Measurement - methods ; Small fiber neuropathy ; Translational Research, Biomedical - methods ; YWHAE
  • Is Part Of: Experimental neurology, 2022-01, Vol.347, p.113915-113915, Article 113915
  • Notes: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Description: Neuropathic pain occurs in more than half of the patients suffering from peripheral neuropathies. We investigated the role of microRNA (miR)-21 in neuropathic pain using a murine-human translational approach. We applied the spared nerve injury (SNI) model at the sciatic nerve of mice and assessed the potential analgesic effect of perineurial miR-21-5p inhibitor application. Immune-related targets of miR-21-5p were determined by a qRT-PCR based cytokine and chemokine array. Bioinformatical analysis identified potential miR-21-5p targets interacting with CC-chemokine ligand (CCL)5. We validated CCL5 and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHAE), an interaction partner of miR-21-5p and CCL5, by qRT-PCR in murine common peroneal and tibial nerves. Validated candidates were then investigated in white blood cell and sural nerve biopsy samples of patients with focal to generalized pain syndromes, i.e. small fiber neuropathy (SFN), polyneuropathy (PNP), and nerve lesion (NL). We showed that perineurial miR-21-5p inhibition reverses SNI-induced mechanical and heat hypersensitivity in mice and found a reduction of the SNI-induced increase of the pro-inflammatory mediators CCL5 (p < 0.01), CCL17 (p < 0.05), and IL-12ß (p < 0.05) in miR-21-5p inhibitor-treated mice. In silico analysis revealed several predicted and validated targets for miR-21-5p with CCL5 interaction. Among these, we found lower YWHAE gene expression in mice after SNI and perineurial injections of a scrambled oligonucleotide compared to naïve mice (p < 0.05), but this was not changed by miR-21-5p inhibition. Furthermore, miR-21-5p inhibition led to a further increase of the SNI-induced increase in TGFß (p < 0.01). Patient biomaterial revealed different systemic expression patterns of miR-21-5p, with higher expression in SFN and lower expression in NL. Further, we showed higher systemic expression of pro-inflammatory mediators in white blood cells of SFN patients compared to healthy controls. We have conducted a translational study comparing results from animal models to human patients with three different neuropathic pain syndromes. We identified CCL5 as a miR-21 dependent common player in the mouse SNI model and the human painful disease SFN. •Perineurial application of a miR-21-5p inhibitor reduces pain behavior in mice after spared nerve injury.•Immune-related mediators in the peripheral nerve are regulated after perineurial application of a miR-21-5p inhibitor.•CCL5 is a miR-21-dependent common player in a mouse model and the human painful disease small fiber neuropathy.•Systemic pro-inflammatory changes are more prevalent in small fiber neuropathy than in polyneuropathy and nerve lesion.
  • Publisher: United States: Elsevier Inc
  • Language: English
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