Microvascular Barrier Protection by microRNA-183 via FoxO1 Repression: A Pathway Disturbed in Neuropathy and Complex Regional Pain Syndrome

Reinhold, Ann-Kristin; Salvador, Ellaine; Förster, Carola; Birklein, Frank; Rittner, Heike L.

doi:10.1016/j.jpain.2021.12.007

Cited by 12 publications

(14 citation statements)

References 80 publications

(91 reference statements)

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“…In the CCI model, downregulated miR-183 in the sciatic nerve targeting transcription factor FoxO1 and tight junction protein claudin-5 promoted mechanical hypersensitivity. Exosomal miR-183 was found decreased from sera of complex regional pain syndrome patients and can regulate neuropathic pain state via regulating microvascular barrier (Reinhold et al, 2022). In conclusion, our study assesses exosomal noncoding RNAs as one modifier of neuropathic pain (Table 1).…”

Section: Extracellular Vesicles Regulates Neuropathic Pain Via Mirnamentioning

confidence: 67%

Concise review: Current understanding of extracellular vesicles to treat neuropathic pain

Zhang

Jia

et al. 2023

Front. Aging Neurosci.

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Extracellular vesicles (EVs) including exosomes are vesicular vesicles with phospholipid bilayer implicated in many cellular interactions and have the ability to transfer multiple types of cargo to cells. It has been found that EVs can package various molecules including proteins and nucleic acids (DNA, mRNA, and noncoding RNA). The discovery of EVs as carriers of proteins and various forms of RNA, such as microRNAs (miRNA) and long noncoding RNAs (lncRNA), has raised great interest in the field of drug delivery. Despite the underlying mechanisms of neuropathic pain being unclear, it has been shown that uncontrolled glial cell activation and the neuroinflammation response to noxious stimulation are important in the emergence and maintenance of neuropathic pain. Many studies have demonstrated a role for noncoding RNAs in the pathogenesis of neuropathic pain and EVs may offer possibilities as carriers of noncoding RNAs for potential in neuropathic pain treatment. In this article, the origins and clinical application of EVs and the mechanism of neuropathic pain development are briefly introduced. Furthermore, we demonstrate the therapeutic roles of EVs in neuropathic pain and that this involve vesicular regulation of glial cell activation and neuroinflammation.

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Section: Extracellular Vesicles Regulates Neuropathic Pain Via Mirnamentioning

confidence: 67%

Concise review: Current understanding of extracellular vesicles to treat neuropathic pain

Zhang

Jia

et al. 2023

Front. Aging Neurosci.

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“…Several miRNAs controlling BNB properties are regulated in pain. While barrier‐impairing miR‐155 is increased in CCI, possibly via tissue plasminogen receptor, 41 a reduction in miR‐183 results in FOXO1‐mediated claudin‐5 reduction and subsequent endoneurial disruption 42 . CRPS patients show altered systemic levels of barrier‐relevant miRNAs: both miR‐183 and miR‐223 are decreased in plasma‐derived exosomes.…”

Section: Discussionmentioning

confidence: 99%

“…While barrier-impairing miR-155 is increased in CCI, possibly via tissue plasminogen receptor, 41 a reduction in miR-183 results in FOXO1-mediated claudin-5 reduction and subsequent endoneurial disruption. 42 CRPS patients show altered systemic levels of barrierrelevant miRNAs: both miR-183 and miR-223 are decreased in plasma-derived exosomes. Moreover, low miR-223 levels correlate with edema formation and a more severe clinical picture.…”

Section: Discussionmentioning

confidence: 99%

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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“…We had excluded several interesting studies done on animal models. 10,15,17,19,31,41,47,51,52,[54][55][56] In animal models, it is common to analyse miRNA expression directly on tissues involved in nociceptive pathways (eg, DRG, spinal cord, and supra-spinal areas). 52,54,55 However, these tissues are not accessible in human participants, which could lead to a discrepancy between animal models and human participants.…”

Section: Limitationsmentioning

confidence: 99%

The role of micro-RNAs in neuropathic pain—a scoping review

Kovanur Sampath,

Belcher,

Hales

et al. 2023

PR9

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Neuropathic pain can be caused by a lesion or disease of the somatosensory system characterised by pathological neuro-immune alterations. At a molecular level, microRNAs (miRNAs) act as regulators of gene expression orchestrating both immune and neuronal processes. Thus, miRNAs may act as essential modulators of processes for the establishment and maintenance of neuropathic pain. The objective/aims of this scoping review was to explore and chart the literature to identify miRNAs that are dysregulated in neuropathic pain. The following databases were searched from inception to March 2023: PubMed, EBSCO, CINAHL, Cochrane Library, and SCOPUS. Two independent reviewers screened, extracted data, and independently assessed the risk of bias in included studies. The JBI critical appraisal checklist was used for critical appraisal. A narrative synthesis was used to summarise the evidence. Seven studies (total of 384 participants) that met our eligibility criteria were included in this scoping review. Our review has identified different miRNAs that are commonly involved in the chronic neuropathic pain conditions including miR-132, miR-101, and miR-199a. Our review findings further suggest that expression of miRNAs to be significantly associated with increased diabetic disease duration, HbA1C levels, and fibrinogen levels. Our review findings suggest that there is clear association between miRNA expression and chronic neuropathic pain conditions. Therefore, increasing the specificity by selecting a candidate miRNA and identifying its target mRNA is an area of future research.

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Microvascular Barrier Protection by microRNA-183 via FoxO1 Repression: A Pathway Disturbed in Neuropathy and Complex Regional Pain Syndrome

Cited by 12 publications

References 80 publications

Concise review: Current understanding of extracellular vesicles to treat neuropathic pain

Concise review: Current understanding of extracellular vesicles to treat neuropathic pain

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

The role of micro-RNAs in neuropathic pain—a scoping review

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