High glucose enhances the activation of NLRP3 inflammasome by ambient fine particulate matter in alveolar macrophages
Abstract 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 ambi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Particle and Fibre Toxicology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12989-023-00552-8 |
| _version_ | 1797637107822362624 |
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| author | Yiqun Mo Luke Mo Yue Zhang Yuanbao Zhang Jiali Yuan Qunwei Zhang |
| author_facet | Yiqun Mo Luke Mo Yue Zhang Yuanbao Zhang Jiali Yuan Qunwei Zhang |
| author_sort | Yiqun Mo |
| collection | DOAJ |
| description | Abstract 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 (PM2.5)-induced macrophage activation and secretion of the proinflammatory cytokine, IL-1β, 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 PM2.5 led to upregulation of IL-1β, activation of the NLRP3 inflammasome, increased nuclear translocation of the transcription factor NF-κB, 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 PM2.5 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 PM2.5-induced upregulation of IL-1β, activation of the NLRP3 inflammasome, and nuclear translocation of NF-κB. In addition, enhancement of PM2.5-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-1β cannot be cleaved to IL-1β or cells are insensitive to IL-1β, respectively. Conclusions This study demonstrated that exposure of mouse alveolar macrophages to PM2.5 in a high glucose setting enhanced PM2.5-induced production of IL-1β through activation of the NLRP3 inflammasome and nuclear translocation of NF-κB due to PM2.5-induced oxidative stress, leading to MMP-9 upregulation. The key role of NADPH oxidase in PM2.5-induced ROS generation and activation of the IL-1β secretion pathway and the importance of IL-1β secretion and signaling in PM2.5-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. |
| first_indexed | 2024-03-11T12:44:38Z |
| format | Article |
| id | doaj.art-5da5c2b8873b405daec2a0b7157c1555 |
| institution | Directory Open Access Journal |
| issn | 1743-8977 |
| language | English |
| last_indexed | 2024-03-11T12:44:38Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Particle and Fibre Toxicology |
| spelling | doaj.art-5da5c2b8873b405daec2a0b7157c15552023-11-05T12:05:22ZengBMCParticle and Fibre Toxicology1743-89772023-11-0120111910.1186/s12989-023-00552-8High glucose enhances the activation of NLRP3 inflammasome by ambient fine particulate matter in alveolar macrophagesYiqun Mo0Luke Mo1Yue Zhang2Yuanbao Zhang3Jiali Yuan4Qunwei Zhang5Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of LouisvilleDepartment of Epidemiology and Population Health, School of Public Health and Information Sciences, University of LouisvilleNorthwestern University Feinberg School of MedicineDepartment of Epidemiology and Population Health, School of Public Health and Information Sciences, University of LouisvilleDepartment of Epidemiology and Population Health, School of Public Health and Information Sciences, University of LouisvilleDepartment of Epidemiology and Population Health, School of Public Health and Information Sciences, University of LouisvilleAbstract 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 (PM2.5)-induced macrophage activation and secretion of the proinflammatory cytokine, IL-1β, 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 PM2.5 led to upregulation of IL-1β, activation of the NLRP3 inflammasome, increased nuclear translocation of the transcription factor NF-κB, 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 PM2.5 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 PM2.5-induced upregulation of IL-1β, activation of the NLRP3 inflammasome, and nuclear translocation of NF-κB. In addition, enhancement of PM2.5-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-1β cannot be cleaved to IL-1β or cells are insensitive to IL-1β, respectively. Conclusions This study demonstrated that exposure of mouse alveolar macrophages to PM2.5 in a high glucose setting enhanced PM2.5-induced production of IL-1β through activation of the NLRP3 inflammasome and nuclear translocation of NF-κB due to PM2.5-induced oxidative stress, leading to MMP-9 upregulation. The key role of NADPH oxidase in PM2.5-induced ROS generation and activation of the IL-1β secretion pathway and the importance of IL-1β secretion and signaling in PM2.5-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.https://doi.org/10.1186/s12989-023-00552-8Ambient fine particulate matter (PM2.5)Alveolar macrophageHigh glucoseNLRP3 inflammasomeIL-1βMMP-9 |
| spellingShingle | Yiqun Mo Luke Mo Yue Zhang Yuanbao Zhang Jiali Yuan Qunwei Zhang High glucose enhances the activation of NLRP3 inflammasome by ambient fine particulate matter in alveolar macrophages Particle and Fibre Toxicology Ambient fine particulate matter (PM2.5) Alveolar macrophage High glucose NLRP3 inflammasome IL-1β MMP-9 |
| title | High glucose enhances the activation of NLRP3 inflammasome by ambient fine particulate matter in alveolar macrophages |
| title_full | High glucose enhances the activation of NLRP3 inflammasome by ambient fine particulate matter in alveolar macrophages |
| title_fullStr | High glucose enhances the activation of NLRP3 inflammasome by ambient fine particulate matter in alveolar macrophages |
| title_full_unstemmed | High glucose enhances the activation of NLRP3 inflammasome by ambient fine particulate matter in alveolar macrophages |
| title_short | High glucose enhances the activation of NLRP3 inflammasome by ambient fine particulate matter in alveolar macrophages |
| title_sort | high glucose enhances the activation of nlrp3 inflammasome by ambient fine particulate matter in alveolar macrophages |
| topic | Ambient fine particulate matter (PM2.5) Alveolar macrophage High glucose NLRP3 inflammasome IL-1β MMP-9 |
| url | https://doi.org/10.1186/s12989-023-00552-8 |
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