Abstract
Spinal cord ischemia-reperfusion (SCIR) injury is a serious complication of open surgical and endovascular aortic procedures. MicroRNA-132-3p (miR-132-3p) has been reported to be involved in the progression of various diseases, but its role in SCIR injury is unclear. Thus, we aimed in this study to investigate the mechanism of miR-132-3p in SCIR injury and explore its pathway as a therapeutic target for SCIR injury. We first constructed a SCIR injury rat model and documented motor function in the model. Reverse transcription quantitative polymerase chain reaction (RT-qPC)R and Western blot analysis were used to detect the expression of miR-132-3p and mitogen-activated protein kinase kinase kinase 3 (MEKK3) in SCIR injury rats. The interaction between miR-132-3p and MEKK3 was identified by dual-luciferase reporter gene assay. Then, the effects of miR-132-3p and MEKK3 on macrophage M1 polarization were evaluated in vitro and in vivo by altering their expression in macrophages of SCIR injury rats, with treatments altering the nuclear factor-kappaB (NF-κB) and c-Jun N-terminal kinase (JNK)/p38 signaling pathways using SP600125, SB203580, or PDTC. The SCIR injury rats had a high Tarlov score and low miR-132-3p expression along with high MEKK3 expression. miR-132-3p could directly bind to MEKK3, and that macrophage M1 polarization and inflammation could be inhibited by overexpression of miR-132-3p through downregulating MEKK3 and inactivating the NF-κB and p38/JNK signaling pathways. Besides, increased miR-132-3p expression could decrease the injured rat Tarlov score. Overall, our study demonstrated that miR-132-3p can suppress M1 polarization of macrophages and alleviate SCIR injury by blocking the MEKK3-dependent activation of the NF-κB and p38/JNK signaling pathway. Thus, miR-132-3p and its downstream pathways may be useful targets to alleviate the symptoms of SCIR injury.
Highlights
Spinal cord ischemia-reperfusion (SCIR) injury, may result from spinal cord blood flow interruption during aortic surgery, which occurs post-operatively with an incidence rate of 28% (Zhu et al, 2013)
Immunohistochemistry indicated an increase of the expression of macrophage marker CD68 in spinal cord tissues of SCIR injury rats in comparison with sham-operated rats (p < 0.05) (Figure 1C), which suggested the presence of macrophage infiltration at the site with SCI
Following the results demonstrating that miR-132-3p could regulate mitogen-activated protein kinase kinase kinase 3 (MEKK3) to inhibit M1 polarization of macrophages, we further investigated whether miR-132-3p regulated MEKK3 to modulate the downstream nuclear factor-kappaB (NF-κB) and p38/Jun N-terminal kinase (JNK) signaling pathways so as to affect the macrophage M1 polarization
Summary
Spinal cord ischemia-reperfusion (SCIR) injury, may result from spinal cord blood flow interruption during aortic surgery, which occurs post-operatively with an incidence rate of 28% (Zhu et al, 2013). Acute SCIR injury is related to some pathologic changes such as inflammation, neuronal apoptosis, and edema (Ning et al, 2012), and can give rise to neurological deficits such as acute or delayed paraplegia (Wyndaele, 2016). The inflammation caused by activation of macrophages and resident microglia plays a key role in spinal cord injury progression (David and Kroner, 2011). It has been documented that macrophages primarily remain in the proinflammatory M1 state in the injured spinal cord (Kroner et al, 2014). Effective procedures for the prevention and treatment of SCIR injury have not been well defined (Yin et al, 2014), which motivates our search for new therapeutic avenues
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