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In this study, we investigated roles of the NLRP3-IL-1β signaling pathway in the transition of acute to chronic neuroinflammation using the peripheral LPS-induced mouse model [17, 21, 23]. We uncovered several unique changes of microglial NLRP3-generated IL-1β in response to LPS treatment in vitro and in vivo, including a delayed increase in the production and release of mature IL-1β compared with most other proinflammatory cytokines, and differential regulated precursor processing pattern in response to different doses of LPS. Moreover, genetic or pharmacological inhibition of either NLRP3 or IL-1R1 did not prevent the initiation of acute neuroinflammation but abolished long-term chronic neuroinflammation and subsequent neurodegeneration. To the best of our knowledge, this study provides the first evidence showing a novel role of NLRP3-IL-1β in mediating the transition from acute to chronic neuroinflammation incited by sepsis.
Roles of IL-1β in mediating infection-induced acute sickness behaviors, the pathophysiological interactions between brain and immune systems, are well known [76,77,78,79]. However, information is limited regarding involvement of IL-1β in the long-term consequences in the brain after severe systemic infections. Previous reports indicate that IL-1β causes neurotoxicity per se or exacerbates pre-existing inflammatory response [80, 81]. However, the concentrations of IL-1β used in these studies were several orders of magnitude higher than the maximal amount that can be produced from brain. Thus, the pathophysiological function of IL-1β remains unclear. In this study, we provided strong evidence demonstrating a novel role of this cytokine in sepsis-induced long-term neuropathology. This conclusion was mainly based on the results from the following two studies. 1e1e36bf2d