PMID- 37919797 OWN - NLM STAT- MEDLINE DCOM- 20231106 LR - 20231106 IS - 1743-8977 (Electronic) IS - 1743-8977 (Linking) VI - 20 IP - 1 DP - 2023 Nov 2 TI - High glucose enhances the activation of NLRP3 inflammasome by ambient fine particulate matter in alveolar macrophages. PG - 41 LID - 10.1186/s12989-023-00552-8 [doi] LID - 41 AB - BACKGROUND: Epidemiological studies have demonstrated that individuals with preexisting conditions, including diabetes mellitus (DM), are more susceptible to air pollution. However, the underlying mechanisms remain unclear. In this study, we proposed that a high glucose setting enhances ambient fine particulate matter (PM(2.5))-induced macrophage activation and secretion of the proinflammatory cytokine, IL-1beta, through activation of the NLRP3 inflammasome, altering the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). RESULTS: Exposure of mouse alveolar macrophages to non-cytotoxic doses of PM(2.5) led to upregulation of IL-1beta, activation of the NLRP3 inflammasome, increased nuclear translocation of the transcription factor NF-kappaB, increased generation of reactive oxygen species (ROS), and increased expression and enzymatic activity of MMP-9; these effects were enhanced when cells were pretreated with high glucose. However, pretreatment in a high glucose setting alone did not induce significant changes. ROS generation following PM(2.5) exposure was abolished when cells were pretreated with ROS scavengers such as Trolox and superoxide dismutase (SOD), or with an NADPH oxidase inhibitor, DPI. Pretreatment of cells with DPI attenuated the effects of a high glucose setting on PM(2.5)-induced upregulation of IL-1beta, activation of the NLRP3 inflammasome, and nuclear translocation of NF-kappaB. In addition, enhancement of PM(2.5)-induced expression and enzymatic activity of MMP-9 following high glucose pretreatment was not observed in primary alveolar macrophages obtained from NLRP3 or IL-1R1 knockout (KO) mice, where pro-IL-1beta cannot be cleaved to IL-1beta or cells are insensitive to IL-1beta, respectively. CONCLUSIONS: This study demonstrated that exposure of mouse alveolar macrophages to PM(2.5) in a high glucose setting enhanced PM(2.5)-induced production of IL-1beta through activation of the NLRP3 inflammasome and nuclear translocation of NF-kappaB due to PM(2.5)-induced oxidative stress, leading to MMP-9 upregulation. The key role of NADPH oxidase in PM(2.5)-induced ROS generation and activation of the IL-1beta secretion pathway and the importance of IL-1beta secretion and signaling in PM(2.5)-induced increases in MMP-9 enzymatic activity were also demonstrated. This study provides a further understanding of the potential mechanisms underlying the susceptibility of individuals with DM to air pollution and suggests potential therapeutic targets. CI - (c) 2023. The Author(s). FAU - Mo, Yiqun AU - Mo Y AD - Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY, 40202, USA. FAU - Mo, Luke AU - Mo L AD - Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY, 40202, USA. FAU - Zhang, Yue AU - Zhang Y AD - Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA. FAU - Zhang, Yuanbao AU - Zhang Y AD - Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY, 40202, USA. FAU - Yuan, Jiali AU - Yuan J AD - Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY, 40202, USA. FAU - Zhang, Qunwei AU - Zhang Q AD - Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY, 40202, USA. Qunwei.Zhang@louisville.edu. LA - eng GR - ES023693/ES/NIEHS NIH HHS/United States GR - HL147856/HL/NHLBI NIH HHS/United States GR - R15 ES023693/ES/NIEHS NIH HHS/United States GR - R01 HL147856/HL/NHLBI NIH HHS/United States GR - R21 ES028911/ES/NIEHS NIH HHS/United States PT - Journal Article DEP - 20231102 PL - England TA - Part Fibre Toxicol JT - Particle and fibre toxicology JID - 101236354 RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Particulate Matter) RN - 0 (NF-kappa B) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - 0 (Reactive Oxygen Species) RN - IY9XDZ35W2 (Glucose) RN - EC 1.6.3.- (NADPH Oxidases) RN - 0 (Interleukin-1beta) SB - IM MH - Animals MH - Mice MH - *Inflammasomes/metabolism MH - *NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism MH - Macrophages, Alveolar/metabolism MH - Particulate Matter/toxicity MH - NF-kappa B/metabolism MH - Matrix Metalloproteinase 9 MH - Reactive Oxygen Species/metabolism MH - Glucose MH - NADPH Oxidases MH - Interleukin-1beta/genetics/metabolism PMC - PMC10621103 OTO - NOTNLM OT - Alveolar macrophage OT - Ambient fine particulate matter (PM2.5) OT - High glucose OT - IL-1beta OT - MMP-9 OT - NLRP3 inflammasome COIS- The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/11/03 06:44 MHDA- 2023/11/06 06:42 PMCR- 2023/11/02 CRDT- 2023/11/03 00:56 PHST- 2023/06/07 00:00 [received] PHST- 2023/10/23 00:00 [accepted] PHST- 2023/11/06 06:42 [medline] PHST- 2023/11/03 06:44 [pubmed] PHST- 2023/11/03 00:56 [entrez] PHST- 2023/11/02 00:00 [pmc-release] AID - 10.1186/s12989-023-00552-8 [pii] AID - 552 [pii] AID - 10.1186/s12989-023-00552-8 [doi] PST - epublish SO - Part Fibre Toxicol. 2023 Nov 2;20(1):41. doi: 10.1186/s12989-023-00552-8.