PMID- 29051224 OWN - NLM STAT- MEDLINE DCOM- 20180125 LR - 20210205 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 292 IP - 50 DP - 2017 Dec 15 TI - Advanced glycation end products impair NLRP3 inflammasome-mediated innate immune responses in macrophages. PG - 20437-20448 LID - 10.1074/jbc.M117.806307 [doi] AB - 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-1beta 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. CI - (c) 2017 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Son, Seunghwan AU - Son S AD - From the Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science. FAU - Hwang, Inhwa AU - Hwang I AD - From the Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science. FAU - Han, Seung Hyeok AU - Han SH AD - the Department of Internal Medicine, Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul 03722, Korea and. FAU - Shin, Jeon-Soo AU - Shin JS AD - From the Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science. FAU - Shin, Ok Sarah AU - Shin OS AD - the Department of Biomedical Sciences, College of Medicine, Korea University Guro Hospital, Seoul 08308, Korea. FAU - Yu, Je-Wook AU - Yu JW AD - From the Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, jewookyu@yuhs.ac. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171019 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Biomarkers) RN - 0 (Glycation End Products, Advanced) RN - 0 (IL1B protein, mouse) RN - 0 (Inflammasomes) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharides) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Reactive Oxygen Species) RN - 0 (interleukin-6, mouse) RN - EC 3.4.22.36 (Caspase 1) SB - IM MH - Animals MH - Biomarkers/metabolism MH - Bone Marrow Cells/cytology/drug effects/immunology/metabolism MH - Caspase 1/genetics/metabolism MH - Cells, Cultured MH - *Down-Regulation/drug effects MH - Gene Expression Regulation/drug effects MH - Genes, Reporter/drug effects MH - Glycation End Products, Advanced/*metabolism MH - *Immunity, Innate/drug effects MH - Inflammasomes/drug effects/immunology/*metabolism MH - Interleukin-1beta/genetics/metabolism MH - Interleukin-6/genetics/metabolism MH - Lipopolysaccharides/antagonists & inhibitors/toxicity MH - *Macrophage Activation/drug effects MH - Macrophages/cytology/drug effects/immunology/*metabolism MH - Mice MH - Mice, Inbred C57BL MH - NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/drug effects MH - Specific Pathogen-Free Organisms PMC - PMC5733583 OTO - NOTNLM OT - NLRP3 OT - glycation OT - inflammasome OT - innate immunity OT - macrophage COIS- The authors declare that they have no conflicts of interest with the contents of this article EDAT- 2017/10/21 06:00 MHDA- 2018/01/26 06:00 PMCR- 2018/12/15 CRDT- 2017/10/21 06:00 PHST- 2017/07/10 00:00 [received] PHST- 2017/10/10 00:00 [revised] PHST- 2017/10/21 06:00 [pubmed] PHST- 2018/01/26 06:00 [medline] PHST- 2017/10/21 06:00 [entrez] PHST- 2018/12/15 00:00 [pmc-release] AID - S0021-9258(20)32780-0 [pii] AID - M117.806307 [pii] AID - 10.1074/jbc.M117.806307 [doi] PST - ppublish SO - J Biol Chem. 2017 Dec 15;292(50):20437-20448. doi: 10.1074/jbc.M117.806307. Epub 2017 Oct 19.