TY  - JOUR
A1  - Reinhold, Ann Kristin
A1  - Krug, Susanne M.
A1  - Salvador, Ellaine
A1  - Sauer, Reine S.
A1  - Karl-Schöller, Franziska
A1  - Malcangio, Marzia
A1  - Sommer, Claudia
A1  - Rittner, Heike L.
T1  - MicroRNA-21-5p functions via RECK/MMP9 as a proalgesic regulator of the blood nerve barrier in nerve injury
JF  - Annals of the New York Academy of Sciences
N2  - 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.
KW  - claudin-1
KW  - RECK
KW  - MMP9
KW  - CRPS
KW  - microRNA
KW  - neuropathic pain
KW  - blood nerve barrier
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318226
VL  - 1515
IS  - 1
SP  - 184
EP  - 195
ER  - 
TY  - JOUR
A1  - Chen, Jeremy Tsung-Chieh
A1  - Schmidt, Lea
A1  - Schürger, Christina
A1  - Hankir, Mohammed K.
A1  - Krug, Susanne M.
A1  - Rittner, Heike L.
T1  - Netrin-1 as a multitarget barrier stabilizer in the peripheral nerve after injury
JF  - International Journal of Molecular Sciences
N2  - The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; however, its role in regulating barrier integrity and pain processing after nerve injury is poorly understood. Here, we show that chronic constriction injury (CCI) in Wistar rats reduced netrin-1 protein and the netrin-1 receptor neogenin-1 (Neo1) in the sciatic nerve. Replacement of netrin-1 via systemic or local administration of the recombinant protein rescued injury-induced nociceptive hypersensitivity. This was prevented by siRNA-mediated knockdown of Neo1 in the sciatic nerve. Mechanistically, netrin-1 restored endothelial and myelin, but not perineural, barrier function as measured by fluorescent dye or fibrinogen penetration. Netrin-1 also reversed the decline in the tight junction proteins claudin-5 and claudin-19 in the sciatic nerve caused by CCI. Our findings emphasize the role of the endothelial and myelin barriers in pain processing after nerve damage and reveal that exogenous netrin-1 restores their function to mitigate CCI-induced hypersensitivity via Neo1. The netrin-1-neogenin-1 signaling pathway may thus represent a multi-target barrier protector for the treatment of neuropathic pain.
KW  - neuropathic pain
KW  - netrin-1
KW  - blood-nerve barrier
KW  - tight junction proteins
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261695
SN  - 1422-0067
VL  - 22
IS  - 18
ER  -