The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner
The NRF2/KEAP1 pathway protects healthy cells from malignant transformation and maintains cellular homeostasis. Up to 30% of human lung tumors gain constitutive NRF2 activity which contributes to cancer cell survival and chemoresistance, but the effects of NRF2 activation in immune cells within the...
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MDPI AG
2023-01-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/1/116 |
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| author | Jessica A. Moerland Ana S. Leal Beth Lockwood Elena Y. Demireva Huirong Xie Teresa Krieger-Burke Karen T. Liby |
| author_facet | Jessica A. Moerland Ana S. Leal Beth Lockwood Elena Y. Demireva Huirong Xie Teresa Krieger-Burke Karen T. Liby |
| author_sort | Jessica A. Moerland |
| collection | DOAJ |
| description | The NRF2/KEAP1 pathway protects healthy cells from malignant transformation and maintains cellular homeostasis. Up to 30% of human lung tumors gain constitutive NRF2 activity which contributes to cancer cell survival and chemoresistance, but the effects of NRF2 activation in immune cells within the tumor microenvironment are underexplored. Macrophages can promote cancer progression or regression depending on context, and NRF2 activation affects macrophage activity. The NRF2 activator CDDO-Methyl ester (CDDO-Me or bardoxolone methyl) reprogrammed Nrf2 wild-type (WT) tumor-educated bone marrow-derived macrophages (TE-BMDMs) from a tumor-promoting to a tumor-inhibiting phenotype, marked by an increase in M1 markers TNFα, IL-6, and MHC-II and a decrease in the tumor-promoting factors VEGF, CCL2, and CD206. No changes were observed in Nrf2 knockout (KO) TE-BMDMs. CDDO-Me decreased tumor burden (<i>p</i> < 0.001) and improved pathological grade (<i>p</i> < 0.05) in WT but not Nrf2 KO A/J mice. Tumor burden in Nrf2 KO mice was 4.6-fold higher (<i>p</i> < 0.001) than in WT mice, irrespective of treatment. CDDO-Me increased the number of lung-infiltrating macrophages in WT mice but lowered CD206 expression in these cells (<i>p</i> < 0.0001). In summary, Nrf2 KO exacerbates lung tumorigenesis in A/J mice, and CDDO-Me promotes an Nrf2-dependent, anti-cancer macrophage phenotype. |
| first_indexed | 2024-03-09T13:47:14Z |
| format | Article |
| id | doaj.art-758e751f9a254e85957c4cb170a579c6 |
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| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T13:47:14Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
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| series | Antioxidants |
| spelling | doaj.art-758e751f9a254e85957c4cb170a579c62023-11-30T20:58:32ZengMDPI AGAntioxidants2076-39212023-01-0112111610.3390/antiox12010116The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent MannerJessica A. Moerland0Ana S. Leal1Beth Lockwood2Elena Y. Demireva3Huirong Xie4Teresa Krieger-Burke5Karen T. Liby6Department of Pharmacology & Toxicology, College of Osteopathic Medicine, Michigan State University, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI 48824, USADepartment of Pharmacology & Toxicology, College of Osteopathic Medicine, Michigan State University, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI 48824, USADepartment of Pharmacology & Toxicology, College of Osteopathic Medicine, Michigan State University, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI 48824, USATransgenic and Genome Editing Facility, Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI 48824, USATransgenic and Genome Editing Facility, Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI 48824, USAIn Vivo Core Facility, Michigan State University, East Lansing, MI 48824, USADepartment of Pharmacology & Toxicology, College of Osteopathic Medicine, Michigan State University, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI 48824, USAThe NRF2/KEAP1 pathway protects healthy cells from malignant transformation and maintains cellular homeostasis. Up to 30% of human lung tumors gain constitutive NRF2 activity which contributes to cancer cell survival and chemoresistance, but the effects of NRF2 activation in immune cells within the tumor microenvironment are underexplored. Macrophages can promote cancer progression or regression depending on context, and NRF2 activation affects macrophage activity. The NRF2 activator CDDO-Methyl ester (CDDO-Me or bardoxolone methyl) reprogrammed Nrf2 wild-type (WT) tumor-educated bone marrow-derived macrophages (TE-BMDMs) from a tumor-promoting to a tumor-inhibiting phenotype, marked by an increase in M1 markers TNFα, IL-6, and MHC-II and a decrease in the tumor-promoting factors VEGF, CCL2, and CD206. No changes were observed in Nrf2 knockout (KO) TE-BMDMs. CDDO-Me decreased tumor burden (<i>p</i> < 0.001) and improved pathological grade (<i>p</i> < 0.05) in WT but not Nrf2 KO A/J mice. Tumor burden in Nrf2 KO mice was 4.6-fold higher (<i>p</i> < 0.001) than in WT mice, irrespective of treatment. CDDO-Me increased the number of lung-infiltrating macrophages in WT mice but lowered CD206 expression in these cells (<i>p</i> < 0.0001). In summary, Nrf2 KO exacerbates lung tumorigenesis in A/J mice, and CDDO-Me promotes an Nrf2-dependent, anti-cancer macrophage phenotype.https://www.mdpi.com/2076-3921/12/1/116Nrf2Keap1Nrf2 regulatorslung cancermacrophagesCDDO-Methyl ester |
| spellingShingle | Jessica A. Moerland Ana S. Leal Beth Lockwood Elena Y. Demireva Huirong Xie Teresa Krieger-Burke Karen T. Liby The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner Antioxidants Nrf2 Keap1 Nrf2 regulators lung cancer macrophages CDDO-Methyl ester |
| title | The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner |
| title_full | The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner |
| title_fullStr | The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner |
| title_full_unstemmed | The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner |
| title_short | The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner |
| title_sort | triterpenoid cddo methyl ester redirects macrophage polarization and reduces lung tumor burden in a nrf2 dependent manner |
| topic | Nrf2 Keap1 Nrf2 regulators lung cancer macrophages CDDO-Methyl ester |
| url | https://www.mdpi.com/2076-3921/12/1/116 |
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