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

doi:10.1016/j.expneurol.2021.113915

Cited by 6 publications

(8 citation statements)

References 46 publications

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“…While miR‐21 has been described in pain, research has mainly focused on its role in sensory DRG neuron–macrophage communication via exosomes 9 and on its proinflammatory effect, for example, stimulation of CC‐chemokine ligand (CCL) 5 in nerves 10 . In addition, hypoxia and inflammatory mediators, such as cytokines, are major regulators of miR‐21 transcription 23,24 .…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, miR‐21 has been described as both anti‐ and proinflammatory 28 . Indeed, its proalgesic effect has previously been attributed to proinflammatory properties 9,10 . miR‐21 plays a central role in nerve injury, both in cell–cell and intracellular communication.…”

Section: Discussionmentioning

confidence: 99%

“…miR‐21 regulates the TGF‐β signaling pathway by targeting mothers against decapentaplegic homolog 7 (SMAD7), ultimately leading to an increase in TGF‐β 35,36 . In mice, nerve Tgfb is increased after nerve injury 10 . We explored Tgfb because it inhibits claudin‐1 via MEK signaling 16 .…”

Section: Discussionmentioning

confidence: 99%

“…Studies suggest a destabilizing effect of circulating miR‐21 on the blood brain 11 and intestinal barriers 12 . However, few studies have looked at miR‐21 in the peripheral nerve, 10,13 and none have considered the BNB.…”

Section: Introductionmentioning

confidence: 99%

“…8 In painful polyneuropathy, miR-21 levels rise both locally, in sural nerve biopsies, and systemically, in white blood cells. 7 While proinflammatory miR-21 interactions in the context of pain are well-characterized, 9,10 little is known about the effects independent of inflammation. Studies suggest a destabilizing effect of circulating miR-21 on the blood brain 11 and intestinal barriers.…”

Section: Introductionmentioning

confidence: 99%

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

Reinhold

Krug

Salvador

et al. 2022

Annals of the New York Academy of Sciences

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%