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Targeting Mir-106-3P Facilitates Functional Recovery Via Inactivating Inflammatory Microglia and Interfering Glial Scar Component Deposition After Neural Injury

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Targeting Mir-106-3P Facilitates Functional Recovery Via Inactivating Inflammatory Microglia and Interfering Glial Scar Component Deposition After Neural Injury European Review for Medical and Pharmacological Sciences 2019; 23: 9000-9008 Targeting miR-106-3p facilitates functional recovery via inactivating inflammatory microglia and interfering glial scar component deposition after neural injury Y.-H. YANG1, J. ZHU2 1Department of Spine Section, Baoji Hospital of TCM, Baoji, China 2CT/Nuclear Magnetic Chamber, Tongchuan Mining Bureau Center Hospital, Tongchuan, China CONCLUSIONS: Abstract. – OBJECTIVE: The aim of this The silence of miR-106-3p study was to elucidate whether the knockdown promotes the recovery of the locomotor func- of microRNA-106-3p (miR-106-3p) could mediate tion and protects the environment of the neuro- the nerve regeneration and functional recovery tization by inactivating inflammatory microglia after the spinal cord injury (SCI) and its poten- and reducing the scar formation following SCI. tial mechanism. MATERIALS AND METHODS: Microglia were Key Words: extracted from the cerebral cortex of the neo- Spinal cord injury (SCI), MiR-106-3p inhibition, Glial natal rats and cultured in vitro. Subsequently, scar, Functional recovery. biomarkers of M1-type and M2-type in microg- lia transfected with miR-106-3p inhibitor were measured. Furthermore, in vivo SCI model in rats was successfully constructed, and SCI rats Introduction were intrathecally injected with miR-106-3p in- hibitor or negative control. The expressions of The acute mechanical compression of the spi- the pro-inflammatory factors in the SCI rats or nal cord induces the destruction of the blood-spi- controls were detected by the enzyme-linked nal barrier, microvasculature rupture, and neuro- immunosorbent assay (ELISA). The glial scar nal damage, which is called primary spinal cord marker and extracellular matrix were visualized 1 by Western blotting and immunofluorescence, injury (PSCI) . On the basis of PSCI, the hypoxic respectively. To observe the nerve function in tissues, erythrocytes deposition, and damaged rats, the movement evaluation was conducted cell debris may trigger a cascade of the patholog- using Basso-Beattie-Bresnahan (BBB) locomo- ical reactions arranging from the inflammatory tor rating scale. response to scar generation. This can eventual- RESULTS: In the inflammatory microglia, miR- ly contribute to a secondary spinal cord injury 106-3p was markedly up-regulated. Western blot- (SSCI), where a large number of leukocytes are ting exhibited the downregulation of M1-type 2,3 cells and the upregulation of M2-type cells after recruited and the glial cells are activated . Mi- silencing miR-106-3p. In SCI rats, we discovered croglia are known as a group of immunological that the miR-106-3p level in the injured spinal macrophages native of the neural tissues. Under cord was up-regulated within one week following normal circumstance, microglia normally guide injury. Meanwhile, the levels of the pro-inflam- the normal function of the neural network of the matory factors were significantly reduced in SCI adult central nervous system in a resting state4-6. rats with the miR-106-3p knockdown. At 7 days after the injury, the area of the astrocyte scar in However, the infection and lesion of the neural the injured spinal cord was remarkably reduced tissues quickly stimulate microglia activation, by in vivo knockdown of miR-106-3p. Moreover, which also plays a double-edged role7. Type M1 the extracellular matrix components secreted in microglia are considered as the pro-inflammato- the scar were also significantly inhibited. Howev- ry cells that can secrete reactive oxygen species er, the glial secretion of the neurotrophic factors (ROS), inducible nitric oxide synthase (iNOS), as relatively increased in the SCI rats with the miR- 106-3p knockdown. Neurological function recov- well as pro-inflammatory factors, including tu- ery was pronounced in SCI rats with the miR-106- mor necrosis factor alpha (TNF-α), interleukin-6 3p knockdown relative to controls. (IL-6), and monocyte chemoattractant protein-1 9000 Corresponding Author: Jian Zhu, BM; e-mail: [email protected] MiR-106-3p in primary spinal cord injury (MCP-1)8-10. Generally, the cytotoxic effects of matrixes were down-regulated, while the neuro- type M1 microglia on neurons and oligodendro- trophic factors were relatively up-regulated after cytes aggravate neural tissue damage11. Com- the knockdown of miR-106-3p. Furthermore, the pared with M1, the type M2 microglia are grant- silence of miR-106-3p ameliorated the chronic ed to phagocytosis of cell debris. Meanwhile, inflammation and glial-fibrotic scar formation they secrete abundant anti-inflammatory cyto- during the progression of the damage recovering. kines ranging from IL-10, transforming growth factor β (TGF-β), IL-4, IL-13, and neurotrophic factors12. Miron et al13 have demonstrated that the Materials and Methods type M2 microglia promote the proliferation and differentiation of oligodendrocytes and can also Primary Microglia Culture and Treatment be involved in re-myelinization. Therefore, M2 To extract primary microglia, the 3-day-old phenotypic microglia exert a neuroprotective role neonatal rats were first sacrificed. Briefly, the in reducing the inflammatory response and facil- cerebral cortex of rats was dissolved in tyrosine itating the nerve repair14,15. Besides, the astrocytes solution. After centrifugation, the purified mi- surrounding the injured site in the brain trans- croglia were cultured in Dulbecco’s Modified form to reactive astrocytes in response to SCI. Eagle’s Medium (DMEM; Gibco, Rockville, MD, The latter further mature into scarring-like astro- USA) containing 10% fetal bovine serum (FBS; cytes and eventually accumulate dense glial scars Gibco, Rockville, MD, USA) and 1% streptomy- around the injured area16,17. These reactive astro- cin and penicillin. Until the density of the cell cytes are also known as type A1 astrocytes. They reached 90%, lipopolysaccharide-induced cells do not provide nutritional support and protection (100 ng/mL LPS for 24 h incubation) were trans- for the remaining neurons after injury. Moreover, fected with miR-106-3p inhibitor or negative con- they cannot possess the phagocytic ability to trol for 24 h. clean myelin debris18,19. Instead, they murder the damaged neurons and oligodendrocytes20. Con- Animals and Grouping trarily, the reactive astrocytes express a class of A total of 84 male Sprague Dawley (SD) rats extracellular matrix molecules called chondroitin (aged at 6 weeks and weighing from 200-220 g) sulfate proteoglycans (CSPGs), which inhibit the were sacrificed to construct the SCI model. All sprouting of neuraxon21. In addition, there are rats were caged separately, with free access to many non-neural type cells with various ori- conventional food and water. The environmen- gins, and they possess strong heterogeneity in tal conditions were controlled at 22-24°C, with the blocked lesion area after the inflammatory 50%-65% of humidity and in a 12 h/12 h artificial reaction, including pericytes, fibroblasts from the circadian cycle. All rats were divided into three spinal membrane, and other sources, as well as groups, including: the Sham group, SCI group, various immune cells derived from the periph- and inhibitor group. The rats in the Sham group eral blood. This can ruggedize scar structure via only received laminectomy. The rats in the SCI laminin and fibronectin secretion22. Shi et al23 group and inhibitor group underwent SCI, and have demonstrated that the multiple microRNAs intrathecally injected with normal saline or miR- (miRNAs) are altered in SCI, serving as critical 106-3p inhibitor, respectively. This study was ap- factors in the pathological mechanism of SCI. proved by the Animal Ethics Committee of Baoji For instances, miR-17-5p regulates the reactive Hospital of the TCM Animal Center. astrocyte proliferation in SCI mice24. Jin et al25 have considered that miR-136 controls the apop- Operative Procedure and Treatment tosis of neurocytes in spinal cord ischemic injury. Firstly, rats were anesthetized with 10% para- Gao et al26 have indicated that miR-137 inhibits formaldehyde at a dose of 4 mL/kg and prepared inflammatory response and apoptosis after SCI for skin disinfection at the operation area. The via targeting MK2. SCI procedures were performed as follows: after In the current study, we monitored the increase localization of the spinous process of T10, the skin of miR-106-3p in the inflammatory microglia was cut open, and the fascia muscle tissues were and the inhibitory effect of miR-106-3p in glial separated to expose the intact T10 lamina. Lami- inflammation. In the SCI model, we discovered nectomy was performed to strip the upper lamina significantly reduced inflammatory factors and of the spinal cord, followed by a complete expose reactive astrocytes in the injured site. Fibrous of the spinal cord. ALLEN bump equipment (10 g 9001 Y.-H. Yang, J. Zhu × 5 cm) was then performed to damage the spinal utes. 0.2 mL of chloroform was added into tissue/ cord tissues. The successful SCI modeling caused cell lysis corresponding to every 1 mL of TRIzol. spinal cord hemorrhage and delayed the extension The mixture was violently shaken for 15 seconds of the hind-limbs and tail swing in rats. Next, the and incubated at room temperature for 3 minutes. rats were intrathecally injected with miR-106-3p After centrifugation for 15 minutes (10000 RPM, inhibitor or normal saline. The incision was su- 4°C), the upper water phase was collected, and tured, and the skin was sterilized. The auxiliary the isopropyl alcohol was added. The mixture urination was conducted three times a day until was vibrated and placed at room temperature for recovery of urination reflex. 10 minutes. After centrifugation for 10 minutes (10000 RPM, 4°C), RNA precipitation was col- Western Blotting lected, and the supernatant was discarded. After The total protein was extracted from spinal washing RNA precipitation with 75% ethanol, the cord tissues or differently treated microglia on ice mixture was centrifuged (10000 RPM and 4°C) using a total protein extraction kit containing pro- for 5 minutes.
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