Calcium Dobesilate Modulates PKCδ-NADPH Oxidase- MAPK-NF-κB Signaling Pathway to Reduce <i>CD14</i>, <i>TLR4</i>, and <i>MMP9</i> Expression during Monocyte-to-Macrophage Differentiation: Potential Therapeutic Implications for Atherosclerosis
Monocyte-to-macrophage differentiation results in the secretion of various inflammatory mediators and oxidative stress molecules necessary for atherosclerosis pathogenesis. Consequently, this differentiation represents a potential clinical target in atherosclerosis. Calcium dobesilate (CaD), an esta...
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MDPI AG
2021-11-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/11/1798 |
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| author | Florence Njau Hermann Haller |
| author_facet | Florence Njau Hermann Haller |
| author_sort | Florence Njau |
| collection | DOAJ |
| description | Monocyte-to-macrophage differentiation results in the secretion of various inflammatory mediators and oxidative stress molecules necessary for atherosclerosis pathogenesis. Consequently, this differentiation represents a potential clinical target in atherosclerosis. Calcium dobesilate (CaD), an established vasoactive and angioprotective drug in experimental models of diabetic microvascular complications reduces oxidative stress and inhibits inflammation via diverse molecular targets; however, its effect on monocytes/macrophages is poorly understood. In this study, we investigated the anti-inflammatory mechanism of CaD during phorbol 12-myristate 13-acetate (PMA)-induced monocyte-to-macrophage differentiation in in vitro models of sepsis (LPS) and hyperglycemia, using THP-1 monocytic cell line. CaD significantly suppressed CD14, TLR4, and MMP9 expression and activity, lowering pro-inflammatory mediators, such as IL1β, TNFα, and MCP-1. The effects of CaD translated through to studies on primary human macrophages. CaD inhibited reactive oxygen species (ROS) generation, PKCδ, MAPK (ERK1/2 and p38) phosphorylation, NOX2/p47phox expression, and membrane translocation. We used hydrogen peroxide (H2O2) to mimic oxidative stress, demonstrating that CaD suppressed PKCδ activation via its ROS-scavenging properties. Taken together, we demonstrate for the first time that CaD suppresses CD14, TLR4, MMP9, and signature pro-inflammatory cytokines, in human macrophages, via the downregulation of PKCδ/NADPH oxidase/ROS/MAPK/NF-κB-dependent signaling pathways. Our data present novel mechanisms of how CaD alleviates metabolic and infectious inflammation. |
| first_indexed | 2024-03-10T05:45:20Z |
| format | Article |
| id | doaj.art-99557863ac5f4254ae7b9ed9f20f5502 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T05:45:20Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
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| series | Antioxidants |
| spelling | doaj.art-99557863ac5f4254ae7b9ed9f20f55022023-11-22T22:13:51ZengMDPI AGAntioxidants2076-39212021-11-011011179810.3390/antiox10111798Calcium Dobesilate Modulates PKCδ-NADPH Oxidase- MAPK-NF-κB Signaling Pathway to Reduce <i>CD14</i>, <i>TLR4</i>, and <i>MMP9</i> Expression during Monocyte-to-Macrophage Differentiation: Potential Therapeutic Implications for AtherosclerosisFlorence Njau0Hermann Haller1Division of Nephrology, Hannover Medical School, 30625 Hannover, GermanyDivision of Nephrology, Hannover Medical School, 30625 Hannover, GermanyMonocyte-to-macrophage differentiation results in the secretion of various inflammatory mediators and oxidative stress molecules necessary for atherosclerosis pathogenesis. Consequently, this differentiation represents a potential clinical target in atherosclerosis. Calcium dobesilate (CaD), an established vasoactive and angioprotective drug in experimental models of diabetic microvascular complications reduces oxidative stress and inhibits inflammation via diverse molecular targets; however, its effect on monocytes/macrophages is poorly understood. In this study, we investigated the anti-inflammatory mechanism of CaD during phorbol 12-myristate 13-acetate (PMA)-induced monocyte-to-macrophage differentiation in in vitro models of sepsis (LPS) and hyperglycemia, using THP-1 monocytic cell line. CaD significantly suppressed CD14, TLR4, and MMP9 expression and activity, lowering pro-inflammatory mediators, such as IL1β, TNFα, and MCP-1. The effects of CaD translated through to studies on primary human macrophages. CaD inhibited reactive oxygen species (ROS) generation, PKCδ, MAPK (ERK1/2 and p38) phosphorylation, NOX2/p47phox expression, and membrane translocation. We used hydrogen peroxide (H2O2) to mimic oxidative stress, demonstrating that CaD suppressed PKCδ activation via its ROS-scavenging properties. Taken together, we demonstrate for the first time that CaD suppresses CD14, TLR4, MMP9, and signature pro-inflammatory cytokines, in human macrophages, via the downregulation of PKCδ/NADPH oxidase/ROS/MAPK/NF-κB-dependent signaling pathways. Our data present novel mechanisms of how CaD alleviates metabolic and infectious inflammation.https://www.mdpi.com/2076-3921/10/11/1798atherosclerosiscalcium dobesilateinflammationmonocyte-macrophage differentiationoxidative stressPKCδ |
| spellingShingle | Florence Njau Hermann Haller Calcium Dobesilate Modulates PKCδ-NADPH Oxidase- MAPK-NF-κB Signaling Pathway to Reduce <i>CD14</i>, <i>TLR4</i>, and <i>MMP9</i> Expression during Monocyte-to-Macrophage Differentiation: Potential Therapeutic Implications for Atherosclerosis Antioxidants atherosclerosis calcium dobesilate inflammation monocyte-macrophage differentiation oxidative stress PKCδ |
| title | Calcium Dobesilate Modulates PKCδ-NADPH Oxidase- MAPK-NF-κB Signaling Pathway to Reduce <i>CD14</i>, <i>TLR4</i>, and <i>MMP9</i> Expression during Monocyte-to-Macrophage Differentiation: Potential Therapeutic Implications for Atherosclerosis |
| title_full | Calcium Dobesilate Modulates PKCδ-NADPH Oxidase- MAPK-NF-κB Signaling Pathway to Reduce <i>CD14</i>, <i>TLR4</i>, and <i>MMP9</i> Expression during Monocyte-to-Macrophage Differentiation: Potential Therapeutic Implications for Atherosclerosis |
| title_fullStr | Calcium Dobesilate Modulates PKCδ-NADPH Oxidase- MAPK-NF-κB Signaling Pathway to Reduce <i>CD14</i>, <i>TLR4</i>, and <i>MMP9</i> Expression during Monocyte-to-Macrophage Differentiation: Potential Therapeutic Implications for Atherosclerosis |
| title_full_unstemmed | Calcium Dobesilate Modulates PKCδ-NADPH Oxidase- MAPK-NF-κB Signaling Pathway to Reduce <i>CD14</i>, <i>TLR4</i>, and <i>MMP9</i> Expression during Monocyte-to-Macrophage Differentiation: Potential Therapeutic Implications for Atherosclerosis |
| title_short | Calcium Dobesilate Modulates PKCδ-NADPH Oxidase- MAPK-NF-κB Signaling Pathway to Reduce <i>CD14</i>, <i>TLR4</i>, and <i>MMP9</i> Expression during Monocyte-to-Macrophage Differentiation: Potential Therapeutic Implications for Atherosclerosis |
| title_sort | calcium dobesilate modulates pkcδ nadph oxidase mapk nf κb signaling pathway to reduce i cd14 i i tlr4 i and i mmp9 i expression during monocyte to macrophage differentiation potential therapeutic implications for atherosclerosis |
| topic | atherosclerosis calcium dobesilate inflammation monocyte-macrophage differentiation oxidative stress PKCδ |
| url | https://www.mdpi.com/2076-3921/10/11/1798 |
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