Apoptosis Signal-regulating Kinase 1 Silencing on Astroglial Inflammasomes in an Experimental Model of Ischemic Stroke

• Published in: Neuroscience 2018-10, Vol.390, p.218-230
• Main Authors: Cheon, So Yeong, Kim, Eun Jung, Kim, So Yeon, Kim, Jeong Min, Kam, Eun Hee, Park, Jong-Kwang, Koo, Bon-Nyeo
• Format: Article
• Language: English
• Subjects: Animals; apoptosis signal-regulating kinase 1; astrocyte; Astrocytes - metabolism; Brain Ischemia - metabolism; Cell Line; Disease Models, Animal; inflammasomes; Inflammasomes - metabolism; Inflammation - metabolism; inflammatory response; ischemic stroke; Male; MAP Kinase Kinase Kinase 5 - metabolism; Mice, Inbred C57BL; Proteins - metabolism; Stroke - metabolism
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2018.08.020

•ASK1 silencing reduced I/R-induced NLRP2 inflammasome and pro-inflammatory IL-1β and IL-18.•ASK1 silencing reduced apoptotic cell death in ischemic brain.•ASK1 inhibition reduced OGD/R-induced NLRP2 inflammasome components in cultured astrocytes.•ASK1 inhibition decreased pro-inflammatory IL-1β and IL-18 levels in cultured astrocytes. Activation of the inflammasome complex contributes to the inflammatory response and cell death under pathologic conditions. The nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 2 (NLRP2) inflammasome is activated in astrocytes after cerebral ischemia, which can aggravate ischemic damage. Apoptosis signal-regulating kinase 1 (ASK1) is an early activator and immune-regulator after ischemic injury, that can lead to cell death. The objective of the present study was to evaluate the role of ASK1 in controlling NLRP2 inflammasomes in astrocytes after cerebral ischemia. In a mouse model of ischemic stroke, the levels of NLRP2 inflammasome components, and interleukin (IL)-1β and IL-18, were quantified in different brain regions. In addition, an astrocyte cell line was subjected to oxygen-glucose deprivation and reperfusion (OGD/R) injury, and the levels of NLRP2 inflammasome factors, IL-1β and IL-18 were evaluated. Ischemic brain injury activated astrocytes. The levels of NLRP2 inflammasome components, IL-1β and IL-18 productions, and cell death increased in the cortex and striatum after ischemic injury. In cultured astrocytes, NLRP2 inflammasome components, IL-1β and IL-18 levels were upregulated after OGD/R. ASK1 silencing or inhibition efficiently reduced NLRP2 inflammasome components and pro-inflammatory cytokine levels in mice and cultured astrocytes. Our findings identify a key role for ASK1 in regulating astroglial inflammasomes after cerebral ischemia. We suggest ASK1 as one of the main targets for astroglial inflammasomes in ischemic stroke.