Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes
- Author
- Sophia Maschalidi (UGent) , Parul Mehrotra (UGent) , Burcu Nur Keçeli (UGent) , Hannah De Cleene (UGent) , Kim Lecomte (UGent) , Renée Van der Cruyssen (UGent) , Pauline Janssen, Jonathan Pinney, Geert van Loo (UGent) , Dirk Elewaut (UGent) , Ann Massie, Esther Hoste (UGent) and Kodi Ravichandran (UGent)
- Organization
- Project
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- Deciphering metabolite-based communication between dying cells and the tissue neighborhood
- Molecular mechanisms of cellular crosstalk in skin regeneration and cancer
- Clearance of dying cells and their relevance to health an disease
- Refining cancer cell death and danger signals for the improvement of immunotherapy
- MIMICRY - Modulating Immunity and the Microbiome for effective CRC Immunotherapy
- NF-kB, autofagie en ER stress in de homeostase en pathologie van de darm.
- Abstract
- Chronic non-healing wounds are a major complication of diabetes, which affects 1 in 10 people worldwide. Dying cells in the wound perpetuate the inflammation and contribute to dysregulated tissue repair1-3. Here we reveal that the membrane transporter SLC7A11 acts as a molecular brake on efferocytosis, the process by which dying cells are removed, and that inhibiting SLC7A11 function can accelerate wound healing. Transcriptomics of efferocytic dendritic cells in mouse identified upregulation of several SLC7 gene family members. In further analyses, pharmacological inhibition of SLC7A11, or deletion or knockdown of Slc7a11 using small interfering RNA enhanced efferocytosis in dendritic cells. Slc7a11 was highly expressed in dendritic cells in skin, and single-cell RNA sequencing of inflamed skin showed that Slc7a11 was upregulated in innate immune cells. In a mouse model of excisional skin wounding, inhibition or loss of SLC7A11 expression accelerated healing dynamics and reduced the apoptotic cell load in the wound. Mechanistic studies revealed a link between SLC7A11, glucose homeostasis and diabetes. SLC7A11-deficient dendritic cells were dependent on aerobic glycolysis using glucose derived from glycogen stores for increased efferocytosis; also, transcriptomics of efferocytic SLC7A11-deficient dendritic cells identified increased expression of genes linked to gluconeogenesis and diabetes. Further, Slc7a11 expression was higher in the wounds of diabetes-prone db/db mice, and targeting SLC7A11 accelerated their wound healing. The faster healing was also linked to the release of the TGFβ family member GDF15 from efferocytic dendritic cells. In sum, SLC7A11 is a negative regulator of efferocytosis, and removing this brake improves wound healing, with important implications for wound management in diabetes.
- Keywords
- Multidisciplinary, SYSTEM X(C)(-), ANTIGEN, DIFFERENTIATION, HOMEOSTASIS, EXPRESSION, SCLEROSIS, SUPPORT, SKIN
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8755271
- MLA
- Maschalidi, Sophia, et al. “Targeting SLC7A11 Improves Efferocytosis by Dendritic Cells and Wound Healing in Diabetes.” NATURE, vol. 606, no. 7915, 2022, pp. 776–84, doi:10.1038/s41586-022-04754-6.
- APA
- Maschalidi, S., Mehrotra, P., Keçeli, B. N., De Cleene, H., Lecomte, K., Van der Cruyssen, R., … Ravichandran, K. (2022). Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes. NATURE, 606(7915), 776–784. https://doi.org/10.1038/s41586-022-04754-6
- Chicago author-date
- Maschalidi, Sophia, Parul Mehrotra, Burcu Nur Keçeli, Hannah De Cleene, Kim Lecomte, Renée Van der Cruyssen, Pauline Janssen, et al. 2022. “Targeting SLC7A11 Improves Efferocytosis by Dendritic Cells and Wound Healing in Diabetes.” NATURE 606 (7915): 776–84. https://doi.org/10.1038/s41586-022-04754-6.
- Chicago author-date (all authors)
- Maschalidi, Sophia, Parul Mehrotra, Burcu Nur Keçeli, Hannah De Cleene, Kim Lecomte, Renée Van der Cruyssen, Pauline Janssen, Jonathan Pinney, Geert van Loo, Dirk Elewaut, Ann Massie, Esther Hoste, and Kodi Ravichandran. 2022. “Targeting SLC7A11 Improves Efferocytosis by Dendritic Cells and Wound Healing in Diabetes.” NATURE 606 (7915): 776–784. doi:10.1038/s41586-022-04754-6.
- Vancouver
- 1.Maschalidi S, Mehrotra P, Keçeli BN, De Cleene H, Lecomte K, Van der Cruyssen R, et al. Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes. NATURE. 2022;606(7915):776–84.
- IEEE
- [1]S. Maschalidi et al., “Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes,” NATURE, vol. 606, no. 7915, pp. 776–784, 2022.
@article{8755271,
abstract = {{Chronic non-healing wounds are a major complication of diabetes, which affects 1 in 10 people worldwide. Dying cells in the wound perpetuate the inflammation and contribute to dysregulated tissue repair1-3. Here we reveal that the membrane transporter SLC7A11 acts as a molecular brake on efferocytosis, the process by which dying cells are removed, and that inhibiting SLC7A11 function can accelerate wound healing. Transcriptomics of efferocytic dendritic cells in mouse identified upregulation of several SLC7 gene family members. In further analyses, pharmacological inhibition of SLC7A11, or deletion or knockdown of Slc7a11 using small interfering RNA enhanced efferocytosis in dendritic cells. Slc7a11 was highly expressed in dendritic cells in skin, and single-cell RNA sequencing of inflamed skin showed that Slc7a11 was upregulated in innate immune cells. In a mouse model of excisional skin wounding, inhibition or loss of SLC7A11 expression accelerated healing dynamics and reduced the apoptotic cell load in the wound. Mechanistic studies revealed a link between SLC7A11, glucose homeostasis and diabetes. SLC7A11-deficient dendritic cells were dependent on aerobic glycolysis using glucose derived from glycogen stores for increased efferocytosis; also, transcriptomics of efferocytic SLC7A11-deficient dendritic cells identified increased expression of genes linked to gluconeogenesis and diabetes. Further, Slc7a11 expression was higher in the wounds of diabetes-prone db/db mice, and targeting SLC7A11 accelerated their wound healing. The faster healing was also linked to the release of the TGFβ family member GDF15 from efferocytic dendritic cells. In sum, SLC7A11 is a negative regulator of efferocytosis, and removing this brake improves wound healing, with important implications for wound management in diabetes.}},
author = {{Maschalidi, Sophia and Mehrotra, Parul and Keçeli, Burcu Nur and De Cleene, Hannah and Lecomte, Kim and Van der Cruyssen, Renée and Janssen, Pauline and Pinney, Jonathan and van Loo, Geert and Elewaut, Dirk and Massie, Ann and Hoste, Esther and Ravichandran, Kodi}},
issn = {{0028-0836}},
journal = {{NATURE}},
keywords = {{Multidisciplinary,SYSTEM X(C)(-),ANTIGEN,DIFFERENTIATION,HOMEOSTASIS,EXPRESSION,SCLEROSIS,SUPPORT,SKIN}},
language = {{eng}},
number = {{7915}},
pages = {{776--784}},
title = {{Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes}},
url = {{http://doi.org/10.1038/s41586-022-04754-6}},
volume = {{606}},
year = {{2022}},
}
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