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Abstract
Adenosine triphosphate (ATP) is released by bacteria and host cells during bacterial infection as well as sterile tissue injury, acting as an inducer of inflammasome activation. Previous studies have shown that ATP treatment leads to AMP-activated protein kinase (AMPK) activation. However, it is unclear whether AMPK signaling has been involved in the regulation of ATP-induced inflammasome activation and subsequent pyroptosis. In this study, we aimed to investigate this issue in lipopolysaccharide-activated murine macrophages. Our results showed that AMPK signaling was activated in murine macrophages upon ATP treatment, which was accompanied by inflammasome activation and pyroptosis as evidenced by rapid cell membrane rupture as well as mature interleukin (IL)-1β and active caspase-1p10 release. The ATP-induced inflammasome activation and pyroptosis were markedly suppressed by an AMPK inhibitor compound C or small-interfering RNA-mediated knockdown of AMPKα, but could be greatly enhanced by metformin (a well-known AMPK agonist). Importantly, metformin administration increased the mortality of mice with bacterial sepsis, which was likely because metformin treatment enhanced the systemic inflammasome activation as indicated by elevated serum and hepatic IL-1β levels. Collectively, these data indicated that the AMPK signaling positively regulated ATP-induced inflammasome activation and pyroptosis in macrophages, highlighting the possibility of AMPK-targeting therapies for inflammatory diseases involving inflammasome activation.
Highlights
Inflammasomes are large multimeric protein complexes present in the cytosol of immune cells to sense and respond to pathogen infection or tissue injury
Many studies have focused on how inflammasomes are assembled and activated, little is known about the regulatory signaling of NLRP3 inflammasome activation upon extracellular adenosine triphosphate (ATP) stimulation
As dramatic metabolic changes occur during macrophage activation [22], it is of great interest whether AMPK, a key regulator of energy metabolism, regulates ATP-induced inflammasome activation in LPS-primed macrophages
Summary
Inflammasomes are large multimeric protein complexes present in the cytosol of immune cells to sense and respond to pathogen infection or tissue injury. Their activation constitutes a first line of defense against microbial infection [1]. One of the most extensively investigated inflammasomes is nucleotide and oligomerization domain, leucine-rich repeat containing protein family, pyrin containing domain 3 (NLRP3) in innate immune cells including macrophages. The full activation of NLRP3 inflammasome requires two steps. The first step is to prime the macrophages with pathogen-associated molecular patterns (PAMPs) which are recognized by specific pattern recognition receptors (PRRs) [2]. Lipopolysaccharide (LPS), a well-known PAMP expressed on Gram-negative bacteria, binds to and activates toll-like receptor 4 leading to the upregulation
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