Abstract
BackgroundJapanese Encephalitis virus (JEV) is a common cause of acute and epidemic viral encephalitis. JEV infection is associated with microglial activation resulting in the production of pro-inflammatory cytokines including Interleukin-1 β (IL-1β) and Interleukin-18 (IL-18). The Pattern Recognition Receptors (PRRs) and the underlying mechanism by which microglia identify the viral particle leading to the production of these cytokines is unknown.Methodology/Principal FindingsFor our studies, we have used murine model of JEV infection as well as BV-2 mouse microglia cell line. In this study, we have identified a signalling pathway which leads to the activation of caspase-1 as the key enzyme responsible for the maturation of both IL-1β and IL-18 in NACHT, LRR and PYD domains-containing protein-3 (NLRP3) dependent manner. Depletion of NLRP3 results in the reduction of caspase-1 activity and subsequent production of these cytokines.Conclusion/SignificanceOur results identify a mechanism mediated by Reactive Oxygen Species (ROS) production and potassium efflux as the two danger signals that link JEV infection to caspase-1 activation resulting in subsequent IL-1β and IL-18 maturation.
Highlights
Microglia are the resident macrophages of the Central Nervous System (CNS), which are monocytic in origin and migrate to the CNS during early embryonic development [1,2]
Japanese Encephalitis Virus (JEV), a single-stranded RNA virus, is one of the common arboviruses that causes severe brain pathology [4] manifesting with fever, headache, vomiting and signs of meningeal irritation resulting in high mortality [5] and is responsible for a majority of encephalitis cases in Asiatic region [6]
We did not observe a complete abrogation of these cytokines upon KCl treatment, these findings suggest that NLRP3 inflammasome activation may require potassium efflux as an additional danger signal upon Japanese Encephalitis virus (JEV) infection
Summary
Microglia are the resident macrophages of the Central Nervous System (CNS), which are monocytic in origin and migrate to the CNS during early embryonic development [1,2]. During infection in the CNS, JEV initiates a potent inflammatory response including microglial activation which subsequently results in the production of several pro- and anti-inflammatory cytokines including IL-1b and IL-18 [7,8]. Both IL-1b and IL-18 play an important role in fever, septic shock and inflammatory diseases [9]. JEV infection is associated with microglial activation resulting in the production of pro-inflammatory cytokines including Interleukin-1 b (IL1b) and Interleukin-18 (IL-18). The Pattern Recognition Receptors (PRRs) and the underlying mechanism by which microglia identify the viral particle leading to the production of these cytokines is unknown
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