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

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.

Role of the MicroRNAs in the Pathogenic Mechanism of Painful Symptoms in Long COVID: Systematic Review

“…Plus, Leinders et al [ 75 ] evaluated a cohort of patients that suffered from neuropathic pain from different etiologies; in them the authors found that miR-21-5p expression is significantly higher in white blood cells and the sural verve of patients with polyneuropathies. In a more recent study, Reinhold et al [ 76 ] found that patients with complex regional pain syndrome (CRPS), as well as a rodent model of neuropathic pain, presented a significant higher expression of miR-21-5p; the authors concluded that this miRNA is a major switch in neuropathic pain due to its role in affecting pain behavior through different pathways, including inflammation-independent barrier impairment.…”

“…Furthermore, an indirect modulation of claudin-1 in long COVID can also be hypothesized; by means of the modulation of matrix metalloprotease-9 (MMP-9), an important regulator of axon demyelination and extension [ 105 ]; MMPs are predominantly expressed in Schwann cells of peripheral nerves under normal conditions and are upregulated in peripheral nerve injury [ 106 , 107 ]. Several miRNAs of the ones here reviewed exert direct or indirect modulation of MMP-9; miR-21-5p has been shown to impair BNB integrity by inhibiting RECK, giving rise to MMP-9 and further downregulating claudin-1 [ 108 ]; plus, a direct induction of MMP-9 expression by miR-21-5p was also shown [ 76 ]. In the present review, the levels of miR-21-5p were divided between being down- and upregulated; the former could be associated with a mechanism of protection and the latter with pathogenic one.…”

Schwann cell‐derived exosomes promote lung cancer progression via miRNA‐21‐5p

“…Furthermore, using WT and RECK mutant NSCLC cells treated with SC exosomes, we also revealed that mutated non‐functional RECK with a blocked ability to interact with exosomal miR‐21‐5p completely counteracted activation of tumor cell motility and invasiveness induced by SC exosomes. Interestingly, RECK targeting by miR‐21 was implicated in neuropathic pain independent of prior inflammation (Reinhold et al, 2022). Hypoxia may also increase miR‐21‐5p delivery by bone‐marrow‐derived mesenchymal stem cell‐secreted exosomes and promote lung cancer development by reducing apoptosis and promoting macrophage M2 polarization (Ren et al, 2019).…”

Pathophysiology of Post-Traumatic Trigeminal Neuropathic Pain

“…For example, expression of microRNA-21-5p (miR-21) was elevated in plasma of patients with complex regional pain syndrome and in nerves of mice exposed to nerve injury. Mice presented with BNB leakage and loss of claudin-1 in injured and spared nerves [ 145 ]. Additionally, RECK gene, a putative target of miR-21, was decreased, as was downstream Mmp9 and Tgfb was upregulated in the nerves.…”

“…Additionally, RECK gene, a putative target of miR-21, was decreased, as was downstream Mmp9 and Tgfb was upregulated in the nerves. These findings suggest that the effect of miR-21 on pain-like behavior are exerted via the inhibition of REC, the rise in MMP9 and, ultimately, claudin-1 downregulation [ 145 ]. Therefore, miR-21 was proposed to play a major role in neuropathic pain and affects pain-like behavior through different pathways, including inflammation-independent barrier impairment.…”