Abstract
The inflammasome acts as a key platform for the activation of pro-inflammatory cytokines. Adiponectin exhibits potent anti-inflammatory properties. However, the effect of adiponectin on the modulation of the inflammasome has not been explored. Herein, we show that globular adiponectin (gAcrp) suppressed lipopolysaccharide (LPS)-primed inflammasomes activation in murine peritoneal macrophages judged by prevention of interleukin-1β (IL-1β) maturation, caspase-1 activation, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck formation, and pyroptotic cell death. Interestingly, pretreatment with 3-methyl adenine, a pharmacological inhibitor of autophagy, abrogated the suppressive effects of gAcrp on IL-1β secretion and caspase-1 activation, indicating the crucial role of autophagy induction in gAcrp-modulation of the inflammasome activation. In addition, inhibition of 5′Adenosine monophaspahate (AMP)-activated protein kinase (AMPK) signaling abolished suppressive effect of gAcrp on inflammasomes activation. Furthermore, autophagy induction or inhibition of the inflammasome activation by gAcrp was not observed in macrophages deficient in AMPK. Taken together, these results indicate that adiponectin inhibits LPS-primed inflammasomes activation in macrophages via autophagy induction and AMPK signaling-dependent mechanisms.
Highlights
The inflammasome, a multimeric cytosolic protein complex comprising-caspase-1, nucleotide-binding oligomerization domain-like receptor (NLR) protein, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), is activated upon recognition of various danger signals, including exogenous pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs) [1]
Inhibition of the inflammasome directly led to the suppression of inflammation in adipose tissues and improved insulin-sensitivity in obese patients with type 2 diabetes [5], and blockade of interleukin-1β (IL-1β) resulted in a reduction in gout symptoms [6], suggesting that modulation of inflammasomes could be a promising strategy for the treatment of various inflammatory diseases
To investigate the possible regulatory effect of adiponectin on inflammasomes, we first examined whether globular adiponectin inhibits maturation and secretion of IL-1β by macrophages
Summary
The inflammasome, a multimeric cytosolic protein complex comprising (pro)-caspase-1, nucleotide-binding oligomerization domain-like receptor (NLR) protein, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), is activated upon recognition of various danger signals, including exogenous pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs) [1]. Depletion of autophagy-related gene products has been shown to enhance accumulation of dysfunctional mitochondrial DNA (mtDNA), resulting in the secretion of inflammatory cytokines [16]. These reports collectively suggest the prominent role of autophagy in the modulation of inflammatory conditions. In addition to its well-known metabolic effects, adiponectin exhibited potent anti-inflammatory properties mediated via multiple mechanisms, including inhibition of NF-κB signaling and inflammatory cytokine production, and/or induction of anti-inflammatory genes such as heme oxygenase-1 [18,19,20]. Accumulating evidence has indicated that the anti-inflammatory effects by globular adiponectin can be mediated by the induction of autophagy. Autophagy induction and AMPK signaling play pivotal roles in the suppression of inflammasomes activation by globular adiponectin
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