Upstream stimulating factor 2 aggravates neuropathic pain induced in spinal nerve ligation-induced mice via regulating SNHG5/miR-181b-5p.

BACKGROUND: Upstream stimulating factor 2 (USF2) belongs to basic-Helix-Loop-Helix-Leucine Zipper transcription factor family, regulating expression of genes involved in immune response or energy metabolism network. Role of USF2 in neuropathic pain was evaluated. METHODS: Mice were intraspinally injected with adenovirus for knockdown of USF2 (Ad-shUSF2), and then subjected to spinal nerve ligation (SNL) to induce neuropathic pain. Distribution and expression of USF2 was detected by western blot and immunofluorescence. Mechanical and thermal pain sensitivity were examined by paw withdrawal thresholds (PWT) and paw withdrawal latency (PWL). Chromatin immunoprecipitation (ChIP) and luciferase activity assays were performed to detect binding ability between USF2 and SNHG5. RESULTS: The expression of USF2 was elevated and colocalized with astrocytes and microglia in L5 dorsal root ganglion (DRG) of SNL-induced mice. Injection of Ad-shUSF2 attenuated SNL-induced decrease of PWT and PWL in mice. Knockdown of USF2 increased level of IL-10, but decreased TNF-α, IL-1ß, and IL-6 in SNL-induced mice. Silence of USF2 enhanced protein expression of CD206, while reduced expression of CD16 and CD32 in SNL-induced mice. USF2 bind to promoter of SNHG5, and weakened SNL-induced up-regulation of SNHG5. SNHG5 bind to miR-181b-5p, and miR-181b-5p to interact with CXCL5. CONCLUSION: Silence of USF2 ameliorated neuropathic pain, suppressed activation of M1 microglia and inhibited inflammation in SNL-induced mice through regulation of SNHG5/miR-181b-5p/CXCL5 axis. Therefore, USF2/SNHG5/miR-181b-5p/CXCL5 might be a promising target for neuropathic pain. However, the effect of USF2/SNHG5/miR-181b-5p/CXCL5 on neuropathic pain should also be investigated in further research.

CD44 connects autophagy decline and ageing in the vascular endothelium.

The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and ageing in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in ageing vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and ageing phenotypes. Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature ageing characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature ageing of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and ageing.