Background and aims Atherosclerosis (AS), an arterial vasculature disease, is characterized by abnormal lipid accumulation and inflammatory response. ADP ribosylation factor like GTPase 11 (ARL11) is linked to multifarious processes in cells. This study aims to clarify the underlying mechanism of ARL11 in AS. Methods ApoE -/- mice fed with high-fat diet were used as the mouse models of AS. Gene expression in AS was determined by mRNA-sequencing. The ARL11 expression was detected by real-time PCR, western blot and immunofluorescence. The M1 polarization of macrophages was indicated by TNF-α and IL-6 levels detected by ELISA and iNOS expression determined by real-time PCR and western blot. The role of ARL11 during AS was explored through loss-of-function. Results There were 1301 upregulated and 1110 downregulated genes during AS. These differently expressed genes (DEGs) were mainly enriched in pathways and terms which are involved in inflammation. Moreover, Arl11 was highly expressed in AS models. Downregulation of Arl11 decreased the lipid deposition and atherosclerotic plaques in the aortas of AS mice, and declined inflammatory cytokines and M1 polarization of macrophages induced by IFN-γ. Furthermore, ARL11 interacted with JAK2 and p-JAK2 and modulated their degradation, thus inhibiting the activation of JAK2/STAT1 pathway. Conclusions : ARL11 promoted the development of AS via interacting with JAK2 and activating JAK2/STAT1 pathway. Thus, silencing ARL11 may prevent the process of AS and be a novel way to treat AS.
Spinal cord injury (SCI) is a severe central nervous system injury and microglia are major participants in neuroinflammation after injury. ADP-ribosylation factor-like GTPase 11 (ARL11) is a GTP-binding protein. Whether ARL11 is involved in the SCI progression is unknown. In the impactor-induced moderate SCI mouse model, ARL11 protein and mRNA expression were significantly increased in the injury site. LPS (100 ng/mL) and IFN-γ (20 ng/mL) were incubated with BV2 cells (immortalized mouse microglial cell line) to drive them into an M1-like phenotype. ARL11 up-regulation was also observed in activated microglia in SCI mice and LPS and IFN-γ treated BV2 cells. Basso Mouse Scale scores and inclined plate test revealed that ARL11 deletion promoted motor function recovery in SCI mice. Pathological examination showed ARL11 knockdown reduced spinal cord tissue damage, increased neuron numbers, and inhibited neuronal apoptosis in SCI mice. ARL11 knockdown notably inhibited IL-1β and IL-6 production in vivo and in vitro. Furthermore, ARL11 deletion significantly inhibited iNOS protein and mRNA expression in vivo and in vitro, and COX-2 expression in vivo . Mechanism studies revealed that ARL11 silencing decreased phosphorylated ERK1/2 protein expression. Additionally, ELF1 knockdown significantly inhibited ARL11 protein and mRNA expression in vitro . ELF1 acted as a transcription activator in regulating ARL11 expression by binding to the promoter. In conclusion, ARL11 knockdown protects neurons by inhibiting M1 microglia-induced neuroinflammation, thereby promoting motor functional recovery in SCI mice. This may occur in part under the regulation of ELF1. Our study provides a new molecular target for SCI treatment.
危险品化学品经营许可证（带存储）