Bone Marrow Macrophages Induce Inflammation by Efferocytosis of Apoptotic Prostate Cancer Cells via HIF-1α Stabilization
The clearance of apoptotic cancer cells by macrophages, known as efferocytosis, fuels the bone-metastatic growth of prostate cancer cells via pro-inflammatory and immunosuppressive processes. However, the exact molecular mechanisms remain unclear. In this study, single-cell transcriptomics of bone m...
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| Format: | Article |
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MDPI AG
2022-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/23/3712 |
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| author | Veronica Mendoza-Reinoso Patricia M. Schnepp Dah Youn Baek John R. Rubin Ernestina Schipani Evan T. Keller Laurie K. McCauley Hernan Roca |
| author_facet | Veronica Mendoza-Reinoso Patricia M. Schnepp Dah Youn Baek John R. Rubin Ernestina Schipani Evan T. Keller Laurie K. McCauley Hernan Roca |
| author_sort | Veronica Mendoza-Reinoso |
| collection | DOAJ |
| description | The clearance of apoptotic cancer cells by macrophages, known as efferocytosis, fuels the bone-metastatic growth of prostate cancer cells via pro-inflammatory and immunosuppressive processes. However, the exact molecular mechanisms remain unclear. In this study, single-cell transcriptomics of bone marrow (BM) macrophages undergoing efferocytosis of apoptotic prostate cancer cells revealed a significant enrichment in their cellular response to hypoxia. Here, we show that BM macrophage efferocytosis increased hypoxia inducible factor-1alpha (HIF-1α) and STAT3 phosphorylation (p-STAT3 at Tyr705) under normoxic conditions, while inhibitors of p-STAT3 reduced HIF-1α. Efferocytosis promoted HIF-1α stabilization, reduced its ubiquitination, and induced HIF-1α and p-STAT3 nuclear translocation. HIF-1α stabilization in efferocytic BM macrophages resulted in enhanced expression of pro-inflammatory cytokine MIF, whereas BM macrophages with inactive HIF-1α reduced MIF expression upon efferocytosis. Stabilization of HIF-1α using the HIF-prolyl-hydroxylase inhibitor, Roxadustat, enhanced MIF expression in BM macrophages. Furthermore, BM macrophages treated with recombinant MIF protein activated NF-κB (p65) signaling and increased the expression of pro-inflammatory cytokines. Altogether, these findings suggest that the clearance of apoptotic cancer cells by BM macrophages triggers p-STAT3/HIF-1α/MIF signaling to promote further inflammation in the bone tumor microenvironment where a significant number of apoptotic cancer cells are present. |
| first_indexed | 2024-03-09T17:51:19Z |
| format | Article |
| id | doaj.art-5b0d4efb334b440bb74d6091d6258d3b |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T17:51:19Z |
| publishDate | 2022-11-01 |
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| record_format | Article |
| series | Cells |
| spelling | doaj.art-5b0d4efb334b440bb74d6091d6258d3b2023-11-24T10:42:33ZengMDPI AGCells2073-44092022-11-011123371210.3390/cells11233712Bone Marrow Macrophages Induce Inflammation by Efferocytosis of Apoptotic Prostate Cancer Cells via HIF-1α StabilizationVeronica Mendoza-Reinoso0Patricia M. Schnepp1Dah Youn Baek2John R. Rubin3Ernestina Schipani4Evan T. Keller5Laurie K. McCauley6Hernan Roca7Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USADepartment of Urology, Medical School, University of Michigan, Ann Arbor, MI 48109, USADepartment of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USADepartment of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USADepartment of Orthopaedic Surgery, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Urology, Medical School, University of Michigan, Ann Arbor, MI 48109, USADepartment of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USADepartment of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USAThe clearance of apoptotic cancer cells by macrophages, known as efferocytosis, fuels the bone-metastatic growth of prostate cancer cells via pro-inflammatory and immunosuppressive processes. However, the exact molecular mechanisms remain unclear. In this study, single-cell transcriptomics of bone marrow (BM) macrophages undergoing efferocytosis of apoptotic prostate cancer cells revealed a significant enrichment in their cellular response to hypoxia. Here, we show that BM macrophage efferocytosis increased hypoxia inducible factor-1alpha (HIF-1α) and STAT3 phosphorylation (p-STAT3 at Tyr705) under normoxic conditions, while inhibitors of p-STAT3 reduced HIF-1α. Efferocytosis promoted HIF-1α stabilization, reduced its ubiquitination, and induced HIF-1α and p-STAT3 nuclear translocation. HIF-1α stabilization in efferocytic BM macrophages resulted in enhanced expression of pro-inflammatory cytokine MIF, whereas BM macrophages with inactive HIF-1α reduced MIF expression upon efferocytosis. Stabilization of HIF-1α using the HIF-prolyl-hydroxylase inhibitor, Roxadustat, enhanced MIF expression in BM macrophages. Furthermore, BM macrophages treated with recombinant MIF protein activated NF-κB (p65) signaling and increased the expression of pro-inflammatory cytokines. Altogether, these findings suggest that the clearance of apoptotic cancer cells by BM macrophages triggers p-STAT3/HIF-1α/MIF signaling to promote further inflammation in the bone tumor microenvironment where a significant number of apoptotic cancer cells are present.https://www.mdpi.com/2073-4409/11/23/3712hypoxia-inducible factorefferocytosisbone marrow macrophagesinflammation |
| spellingShingle | Veronica Mendoza-Reinoso Patricia M. Schnepp Dah Youn Baek John R. Rubin Ernestina Schipani Evan T. Keller Laurie K. McCauley Hernan Roca Bone Marrow Macrophages Induce Inflammation by Efferocytosis of Apoptotic Prostate Cancer Cells via HIF-1α Stabilization Cells hypoxia-inducible factor efferocytosis bone marrow macrophages inflammation |
| title | Bone Marrow Macrophages Induce Inflammation by Efferocytosis of Apoptotic Prostate Cancer Cells via HIF-1α Stabilization |
| title_full | Bone Marrow Macrophages Induce Inflammation by Efferocytosis of Apoptotic Prostate Cancer Cells via HIF-1α Stabilization |
| title_fullStr | Bone Marrow Macrophages Induce Inflammation by Efferocytosis of Apoptotic Prostate Cancer Cells via HIF-1α Stabilization |
| title_full_unstemmed | Bone Marrow Macrophages Induce Inflammation by Efferocytosis of Apoptotic Prostate Cancer Cells via HIF-1α Stabilization |
| title_short | Bone Marrow Macrophages Induce Inflammation by Efferocytosis of Apoptotic Prostate Cancer Cells via HIF-1α Stabilization |
| title_sort | bone marrow macrophages induce inflammation by efferocytosis of apoptotic prostate cancer cells via hif 1α stabilization |
| topic | hypoxia-inducible factor efferocytosis bone marrow macrophages inflammation |
| url | https://www.mdpi.com/2073-4409/11/23/3712 |
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