Autophagy-mediated circHIPK2 promotes lipopolysaccharide-induced astrocytic inflammation via SIGMAR1

Circular RNAs (circRNAs) are a subclass of noncoding RNAs and widely involve in the occurrence of multiple human diseases. It is an urgent task to clarify circRNA upstream regulation mechanism and seek their biofunction. Our previous study has confirmed that circular RNA HIPK2 (circHIPK2) promotes astrocyte activation via SIGMAR1, sigma non-opioid intracellular receptor 1, in a mouse model of single high-dose lipopolysaccharide (LPS) injection. However, what mechanism circHIPK2 is regulated by and whether it is involved in the inflammatory response of astrocytes remain unclear. In this study, we reported that circHIPK2 and SIGMAR1 were significantly increased in mouse prefrontal cortex after multiple intraperitoneal injection of LPS, with the elevation of inflammatory mediators. Knockdown circHIPK2 in primary astrocytes suppressed the SIGMAR1 expression and inflammation. Pretreatment of autophagy inducer rapamycin on astrocytes suppressed the circHIPK2 expression and inactivated inflammatory response. These results implied that autophagy inducer rapamycin could suppress astrocytic inflammation by inactivating circHIPK2-SIGMAR1 axis. Autophagy may be a promising upstream administrator of circHIPK2 and therapeutic target for central nervous system inflammation.