MicroRNA-34a Negatively Regulates Efferocytosis by Tissue Macrophages in Part via SIRT1
Alexandra L McCubbrey, Joshua D Nelson, Valerie R Stolberg, Pennelope K Blakely, Lisa McCloskey, William J Janssen, Christine M Freeman, Jeffrey L Curtis, Alexandra L McCubbrey, Joshua D Nelson, Valerie R Stolberg, Pennelope K Blakely, Lisa McCloskey, William J Janssen, Christine M Freeman, Jeffrey L Curtis
Abstract
Apoptotic cell (AC) clearance (efferocytosis) is an evolutionarily conserved process essential for immune health, particularly to maintain self-tolerance. Despite identification of many recognition receptors and intracellular signaling components of efferocytosis, its negative regulation remains incompletely understood and has not previously been known to involve microRNAs (miRs). In this article, we show that miR-34a (gene ID 407040), well recognized as a p53-dependent tumor suppressor, mediates coordinated negative regulation of efferocytosis by resident murine and human tissue macrophages (Mø). The miR-34a expression varied greatly between Mø from different tissues, correlating inversely with their capacity for AC uptake. Transient or genetic knockdown of miR-34a increased efferocytosis, whereas miR-34a overexpression decreased efferocytosis, without altering recognition of live, necrotic, or Ig-opsonized cells. The inhibitory effect of miR-34a was mediated both by reduced expression of Axl, a receptor tyrosine kinase known to recognize AC, and of the deacetylase silent information regulator T1, which had not previously been linked to efferocytosis by tissue Mø. Exposure to AC downregulated Mø miR-34a expression, resulting in a positive feedback loop that increased subsequent capacity to engulf AC. These findings demonstrate that miR-34a both specifically regulates and is regulated by efferocytosis. Given the ability of efferocytosis to polarize ingesting Mø uniquely and to reduce their host-defense functions, dynamic negative regulation by miR-34a provides one means of fine-tuning Mø behavior toward AC in specific tissue environments with differing potentials for microbial exposure.
Copyright © 2016 by The American Association of Immunologists, Inc.
Figures
![Figure 1. miR-34a negatively regulates efferocytosis](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4724467/bin/nihms740397f1.jpg)
Figure 2. miR-34a negatively regulates efferocytosis by…
Figure 2. miR-34a negatively regulates efferocytosis by human AMø
AMø were harvested by bronchoalveolar lavage…
Figure 3. miR-34a negatively regulates binding to…
Figure 3. miR-34a negatively regulates binding to AC but not uptake of other targets
A–D.…
Figure 4. miR-34a regulates Mø expression of…
Figure 4. miR-34a regulates Mø expression of Axl, but altered Axl expression is not required…
Figure 5. miR-34a negatively regulates Mø SIRT1…
Figure 5. miR-34a negatively regulates Mø SIRT1 expression and SIRT1 enhances efferocytosis
A. Total RNA…
Figure 6. Efferocytosis down-regulates miR-34a, creating a…
Figure 6. Efferocytosis down-regulates miR-34a, creating a positive-feedback loop for secondary engulfment
A. Resident AMø…
- Pentose Phosphate Pathway Regulates Tolerogenic Apoptotic Cell Clearance and Immune Tolerance.He D, Mao Q, Jia J, Wang Z, Liu Y, Liu T, Luo B, Zhang Z. He D, et al. Front Immunol. 2022 Jan 10;12:797091. doi: 10.3389/fimmu.2021.797091. eCollection 2021. Front Immunol. 2022. PMID: 35082786 Free PMC article.
- miR-34a repression of SIRT1 regulates apoptosis.Yamakuchi M, Ferlito M, Lowenstein CJ. Yamakuchi M, et al. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13421-6. doi: 10.1073/pnas.0801613105. Epub 2008 Aug 28. Proc Natl Acad Sci U S A. 2008. PMID: 18755897 Free PMC article.
- MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1.Zhao T, Li J, Chen AF. Zhao T, et al. Am J Physiol Endocrinol Metab. 2010 Jul;299(1):E110-6. doi: 10.1152/ajpendo.00192.2010. Epub 2010 Apr 27. Am J Physiol Endocrinol Metab. 2010. PMID: 20424141 Free PMC article.
- MiR-34a contributes to diabetes-related cochlear hair cell apoptosis via SIRT1/HIF-1α signaling.Lin Y, Shen J, Li D, Ming J, Liu X, Zhang N, Lai J, Shi M, Ji Q, Xing Y. Lin Y, et al. Gen Comp Endocrinol. 2017 May 15;246:63-70. doi: 10.1016/j.ygcen.2017.02.017. Epub 2017 Mar 2. Gen Comp Endocrinol. 2017. PMID: 28263817
- microRNA-34a aggravates coxsackievirus B3-induced apoptosis of cardiomyocytes through the SIRT1-p53 pathway.Jiang D, Li M, Yu Y, Shi H, Chen R. Jiang D, et al. J Med Virol. 2019 Sep;91(9):1643-1651. doi: 10.1002/jmv.25482. Epub 2019 May 21. J Med Virol. 2019. PMID: 30968966
- Senescence: Pathogenic Driver in Chronic Obstructive Pulmonary Disease.Rivas M, Gupta G, Costanzo L, Ahmed H, Wyman AE, Geraghty P. Rivas M, et al. Medicina (Kaunas). 2022 Jun 17;58(6):817. doi: 10.3390/medicina58060817. Medicina (Kaunas). 2022. PMID: 35744080 Free PMC article. Review.
- MicroRNAs as Regulators of Phagocytosis.Gierlikowski W, Gierlikowska B. Gierlikowski W, et al. Cells. 2022 Apr 19;11(9):1380. doi: 10.3390/cells11091380. Cells. 2022. PMID: 35563685 Free PMC article. Review.
- Pentose Phosphate Pathway Regulates Tolerogenic Apoptotic Cell Clearance and Immune Tolerance.He D, Mao Q, Jia J, Wang Z, Liu Y, Liu T, Luo B, Zhang Z. He D, et al. Front Immunol. 2022 Jan 10;12:797091. doi: 10.3389/fimmu.2021.797091. eCollection 2021. Front Immunol. 2022. PMID: 35082786 Free PMC article.
- Activators of SIRT1 in the kidney and protective effects of SIRT1 during acute kidney injury (AKI) (effect of SIRT1 activators on acute kidney injury).Raji-Amirhasani A, Khaksari M, Darvishzadeh Mahani F, Hajializadeh Z. Raji-Amirhasani A, et al. Clin Exp Nephrol. 2021 Aug;25(8):807-821. doi: 10.1007/s10157-021-02057-0. Epub 2021 Mar 29. Clin Exp Nephrol. 2021. PMID: 33779856 Review.
- A macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus.Simion V, Zhou H, Haemmig S, Pierce JB, Mendes S, Tesmenitsky Y, Pérez-Cremades D, Lee JF, Chen AF, Ronda N, Papotti B, Marto JA, Feinberg MW. Simion V, et al. Nat Commun. 2020 Dec 1;11(1):6135. doi: 10.1038/s41467-020-19664-2. Nat Commun. 2020. PMID: 33262333 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Apoptosis / genetics*
- Apoptosis / immunology
- Flow Cytometry
- Gene Knockdown Techniques
- Humans
- Macrophages / immunology*
- Mice
- Mice, Inbred C57BL
- MicroRNAs / immunology*
- Phagocytosis / genetics*
- Phagocytosis / immunology
- Reverse Transcriptase Polymerase Chain Reaction
- Sirtuin 1 / immunology*
- Transfection
- MIRN34 microRNA, human
- MIRN34a microRNA, mouse
- MicroRNAs
- SIRT1 protein, human
- Sirt1 protein, mouse
- Sirtuin 1
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 2. miR-34a negatively regulates efferocytosis by…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4724467/bin/nihms740397f2.jpg)
![Figure 3. miR-34a negatively regulates binding to…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4724467/bin/nihms740397f3.jpg)
![Figure 4. miR-34a regulates Mø expression of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4724467/bin/nihms740397f4.jpg)
Figure 5. miR-34a negatively regulates Mø SIRT1…
Figure 5. miR-34a negatively regulates Mø SIRT1 expression and SIRT1 enhances efferocytosis
A. Total RNA…
Figure 6. Efferocytosis down-regulates miR-34a, creating a…
Figure 6. Efferocytosis down-regulates miR-34a, creating a positive-feedback loop for secondary engulfment
A. Resident AMø…
- Pentose Phosphate Pathway Regulates Tolerogenic Apoptotic Cell Clearance and Immune Tolerance.He D, Mao Q, Jia J, Wang Z, Liu Y, Liu T, Luo B, Zhang Z. He D, et al. Front Immunol. 2022 Jan 10;12:797091. doi: 10.3389/fimmu.2021.797091. eCollection 2021. Front Immunol. 2022. PMID: 35082786 Free PMC article.
- miR-34a repression of SIRT1 regulates apoptosis.Yamakuchi M, Ferlito M, Lowenstein CJ. Yamakuchi M, et al. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13421-6. doi: 10.1073/pnas.0801613105. Epub 2008 Aug 28. Proc Natl Acad Sci U S A. 2008. PMID: 18755897 Free PMC article.
- MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1.Zhao T, Li J, Chen AF. Zhao T, et al. Am J Physiol Endocrinol Metab. 2010 Jul;299(1):E110-6. doi: 10.1152/ajpendo.00192.2010. Epub 2010 Apr 27. Am J Physiol Endocrinol Metab. 2010. PMID: 20424141 Free PMC article.
- MiR-34a contributes to diabetes-related cochlear hair cell apoptosis via SIRT1/HIF-1α signaling.Lin Y, Shen J, Li D, Ming J, Liu X, Zhang N, Lai J, Shi M, Ji Q, Xing Y. Lin Y, et al. Gen Comp Endocrinol. 2017 May 15;246:63-70. doi: 10.1016/j.ygcen.2017.02.017. Epub 2017 Mar 2. Gen Comp Endocrinol. 2017. PMID: 28263817
- microRNA-34a aggravates coxsackievirus B3-induced apoptosis of cardiomyocytes through the SIRT1-p53 pathway.Jiang D, Li M, Yu Y, Shi H, Chen R. Jiang D, et al. J Med Virol. 2019 Sep;91(9):1643-1651. doi: 10.1002/jmv.25482. Epub 2019 May 21. J Med Virol. 2019. PMID: 30968966
- Senescence: Pathogenic Driver in Chronic Obstructive Pulmonary Disease.Rivas M, Gupta G, Costanzo L, Ahmed H, Wyman AE, Geraghty P. Rivas M, et al. Medicina (Kaunas). 2022 Jun 17;58(6):817. doi: 10.3390/medicina58060817. Medicina (Kaunas). 2022. PMID: 35744080 Free PMC article. Review.
- MicroRNAs as Regulators of Phagocytosis.Gierlikowski W, Gierlikowska B. Gierlikowski W, et al. Cells. 2022 Apr 19;11(9):1380. doi: 10.3390/cells11091380. Cells. 2022. PMID: 35563685 Free PMC article. Review.
- Pentose Phosphate Pathway Regulates Tolerogenic Apoptotic Cell Clearance and Immune Tolerance.He D, Mao Q, Jia J, Wang Z, Liu Y, Liu T, Luo B, Zhang Z. He D, et al. Front Immunol. 2022 Jan 10;12:797091. doi: 10.3389/fimmu.2021.797091. eCollection 2021. Front Immunol. 2022. PMID: 35082786 Free PMC article.
- Activators of SIRT1 in the kidney and protective effects of SIRT1 during acute kidney injury (AKI) (effect of SIRT1 activators on acute kidney injury).Raji-Amirhasani A, Khaksari M, Darvishzadeh Mahani F, Hajializadeh Z. Raji-Amirhasani A, et al. Clin Exp Nephrol. 2021 Aug;25(8):807-821. doi: 10.1007/s10157-021-02057-0. Epub 2021 Mar 29. Clin Exp Nephrol. 2021. PMID: 33779856 Review.
- A macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus.Simion V, Zhou H, Haemmig S, Pierce JB, Mendes S, Tesmenitsky Y, Pérez-Cremades D, Lee JF, Chen AF, Ronda N, Papotti B, Marto JA, Feinberg MW. Simion V, et al. Nat Commun. 2020 Dec 1;11(1):6135. doi: 10.1038/s41467-020-19664-2. Nat Commun. 2020. PMID: 33262333 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Apoptosis / genetics*
- Apoptosis / immunology
- Flow Cytometry
- Gene Knockdown Techniques
- Humans
- Macrophages / immunology*
- Mice
- Mice, Inbred C57BL
- MicroRNAs / immunology*
- Phagocytosis / genetics*
- Phagocytosis / immunology
- Reverse Transcriptase Polymerase Chain Reaction
- Sirtuin 1 / immunology*
- Transfection
- MIRN34 microRNA, human
- MIRN34a microRNA, mouse
- MicroRNAs
- SIRT1 protein, human
- Sirt1 protein, mouse
- Sirtuin 1
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 5. miR-34a negatively regulates Mø SIRT1…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4724467/bin/nihms740397f5.jpg)
Figure 6. Efferocytosis down-regulates miR-34a, creating a…
Figure 6. Efferocytosis down-regulates miR-34a, creating a positive-feedback loop for secondary engulfment
A. Resident AMø…
- Pentose Phosphate Pathway Regulates Tolerogenic Apoptotic Cell Clearance and Immune Tolerance.He D, Mao Q, Jia J, Wang Z, Liu Y, Liu T, Luo B, Zhang Z. He D, et al. Front Immunol. 2022 Jan 10;12:797091. doi: 10.3389/fimmu.2021.797091. eCollection 2021. Front Immunol. 2022. PMID: 35082786 Free PMC article.
- miR-34a repression of SIRT1 regulates apoptosis.Yamakuchi M, Ferlito M, Lowenstein CJ. Yamakuchi M, et al. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13421-6. doi: 10.1073/pnas.0801613105. Epub 2008 Aug 28. Proc Natl Acad Sci U S A. 2008. PMID: 18755897 Free PMC article.
- MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1.Zhao T, Li J, Chen AF. Zhao T, et al. Am J Physiol Endocrinol Metab. 2010 Jul;299(1):E110-6. doi: 10.1152/ajpendo.00192.2010. Epub 2010 Apr 27. Am J Physiol Endocrinol Metab. 2010. PMID: 20424141 Free PMC article.
- MiR-34a contributes to diabetes-related cochlear hair cell apoptosis via SIRT1/HIF-1α signaling.Lin Y, Shen J, Li D, Ming J, Liu X, Zhang N, Lai J, Shi M, Ji Q, Xing Y. Lin Y, et al. Gen Comp Endocrinol. 2017 May 15;246:63-70. doi: 10.1016/j.ygcen.2017.02.017. Epub 2017 Mar 2. Gen Comp Endocrinol. 2017. PMID: 28263817
- microRNA-34a aggravates coxsackievirus B3-induced apoptosis of cardiomyocytes through the SIRT1-p53 pathway.Jiang D, Li M, Yu Y, Shi H, Chen R. Jiang D, et al. J Med Virol. 2019 Sep;91(9):1643-1651. doi: 10.1002/jmv.25482. Epub 2019 May 21. J Med Virol. 2019. PMID: 30968966
- Senescence: Pathogenic Driver in Chronic Obstructive Pulmonary Disease.Rivas M, Gupta G, Costanzo L, Ahmed H, Wyman AE, Geraghty P. Rivas M, et al. Medicina (Kaunas). 2022 Jun 17;58(6):817. doi: 10.3390/medicina58060817. Medicina (Kaunas). 2022. PMID: 35744080 Free PMC article. Review.
- MicroRNAs as Regulators of Phagocytosis.Gierlikowski W, Gierlikowska B. Gierlikowski W, et al. Cells. 2022 Apr 19;11(9):1380. doi: 10.3390/cells11091380. Cells. 2022. PMID: 35563685 Free PMC article. Review.
- Pentose Phosphate Pathway Regulates Tolerogenic Apoptotic Cell Clearance and Immune Tolerance.He D, Mao Q, Jia J, Wang Z, Liu Y, Liu T, Luo B, Zhang Z. He D, et al. Front Immunol. 2022 Jan 10;12:797091. doi: 10.3389/fimmu.2021.797091. eCollection 2021. Front Immunol. 2022. PMID: 35082786 Free PMC article.
- Activators of SIRT1 in the kidney and protective effects of SIRT1 during acute kidney injury (AKI) (effect of SIRT1 activators on acute kidney injury).Raji-Amirhasani A, Khaksari M, Darvishzadeh Mahani F, Hajializadeh Z. Raji-Amirhasani A, et al. Clin Exp Nephrol. 2021 Aug;25(8):807-821. doi: 10.1007/s10157-021-02057-0. Epub 2021 Mar 29. Clin Exp Nephrol. 2021. PMID: 33779856 Review.
- A macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus.Simion V, Zhou H, Haemmig S, Pierce JB, Mendes S, Tesmenitsky Y, Pérez-Cremades D, Lee JF, Chen AF, Ronda N, Papotti B, Marto JA, Feinberg MW. Simion V, et al. Nat Commun. 2020 Dec 1;11(1):6135. doi: 10.1038/s41467-020-19664-2. Nat Commun. 2020. PMID: 33262333 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Animals
- Apoptosis / genetics*
- Apoptosis / immunology
- Flow Cytometry
- Gene Knockdown Techniques
- Humans
- Macrophages / immunology*
- Mice
- Mice, Inbred C57BL
- MicroRNAs / immunology*
- Phagocytosis / genetics*
- Phagocytosis / immunology
- Reverse Transcriptase Polymerase Chain Reaction
- Sirtuin 1 / immunology*
- Transfection
- MIRN34 microRNA, human
- MIRN34a microRNA, mouse
- MicroRNAs
- SIRT1 protein, human
- Sirt1 protein, mouse
- Sirtuin 1
- Full Text Sources
- Other Literature Sources
- Medical
- Research Materials
- Miscellaneous
![Figure 6. Efferocytosis down-regulates miR-34a, creating a…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4724467/bin/nihms740397f6.jpg)
Source: PubMed