Abstract
Advanced glycation end products (AGEs) are adducts formed on proteins by glycation with reducing sugars, such as glucose, and tend to form and accumulate under hyperglycemic conditions. AGE accumulation alters protein function and has been implicated in the pathogenesis of many degenerative diseases such as diabetic complications. AGEs have also been shown to promote the production of pro-inflammatory cytokines, but the roles of AGEs in inflammasome signaling have not been explored in detail. Here, we present evidence that AGEs attenuate activation of the NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs) as determined by caspase-1 processing and interleukin-1β production. AGEs also dampened the assembly of the NLRP3 inflammasome, but did not affect the NLRC4 or AIM2 inflammasome activation. Moreover, our data indicated that AGE treatment inhibited Toll-like receptor (TLR)-dependent production of pro-inflammatory cytokines in BMDMs. This immunosuppressive effect of AGE was not associated with a receptor for AGEs (RAGE)-mediated signaling. Instead, AGE treatment markedly suppressed lipopolysaccharide-induced M1 polarization of macrophages. Furthermore, AGEs significantly dampened innate immune responses including NLRP3 inflammasome activation and type-I interferon production in macrophages upon influenza virus infection. These observations collectively suggest that AGEs could impair host NLRP3 inflammasome-mediated innate immune defenses against RNA virus infection leading to an increased susceptibility to infection.
Highlights
Advanced glycation end products (AGEs) are adducts formed on proteins by glycation with reducing sugars, such as glucose, and tend to form and accumulate under hyperglycemic conditions
AGEs impair host innate responses in macrophages in response to influenza virus infection As our data demonstrated that AGE pretreatment caused a severe reduction in the assembly and activation of NLRP3 inflammasomes, we further examined whether AGEs could affect host inflammasome activation in macrophages upon influenza virus infection
Accumulating recent evidence has demonstrated that deregulated NLRP3 inflammasome activity is closely associated with the progression of multiple metabolic and degenerative disorders (19 –21)
Summary
To examine the effect of AGEs on inflammasome signaling, we first prepared AGEs by incubating bovine serum albumin (BSA) with a high concentration of glucose for 8 weeks, as described previously [22]. The reaction mixture containing glucose alone (without BSA) did not suppress caspase-1 activation after LPS/ ATP stimulation (Fig. 3H) These findings indicate that AGE pretreatment drives lower responsiveness to NLRP3-activated stimulation in macrophages. Lated phosphorylation and degradation of IB in BMDMs, indicating that AGEs negatively regulated NF-B signaling under our conditions (Fig. 5B) We further verified this finding in HEK293 cells stably expressing TLR4, in which LPS stimulation caused a robust activation of NF-B as determined by performing an NF-B–luciferase reporter assay. AGEs showed a remarkable suppression of ATP-triggered activation of caspase-1 in NLRP3-reconstituted macrophages (Fig. 6F) These findings suggest that AGEs could interfere with the LPS-promoted priming step and the signal 2-induced activation step for the activation of NLRP3 inflammasome. These findings suggest that AGEs could impair the host innate immune defense in macrophages against dsRNA-mediated virus infection
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