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Posttranslational modifications by ADAM10 shape myeloid antigen-presenting cell homeostasis in the splenic marginal zone.
- Source :
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Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Sep 21; Vol. 118 (38). - Publication Year :
- 2021
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Abstract
- The spleen contains phenotypically and functionally distinct conventional dendritic cell (cDC) subpopulations, termed cDC1 and cDC2, which each can be divided into several smaller and less well-characterized subsets. Despite advances in understanding the complexity of cDC ontogeny by transcriptional programming, the significance of posttranslational modifications in controlling tissue-specific cDC subset immunobiology remains elusive. Here, we identified the cell-surface-expressed A-disintegrin-and-metalloproteinase 10 (ADAM10) as an essential regulator of cDC1 and cDC2 homeostasis in the splenic marginal zone (MZ). Mice with a CD11c-specific deletion of ADAM10 (ADAM10 <superscript>ΔCD11c</superscript> ) exhibited a complete loss of splenic ESAM <superscript>hi</superscript> cDC2A because ADAM10 regulated the commitment, differentiation, and survival of these cells. The major pathways controlled by ADAM10 in ESAM <superscript>hi</superscript> cDC2A are Notch, signaling pathways involved in cell proliferation and survival (e.g., mTOR, PI3K/AKT, and EIF2 signaling), and EBI2-mediated localization within the MZ. In addition, we discovered that ADAM10 is a molecular switch regulating cDC2 subset heterogeneity in the spleen, as the disappearance of ESAM <superscript>hi</superscript> cDC2A in ADAM10 <superscript>ΔCD11c</superscript> mice was compensated for by the emergence of a Clec12a <superscript>+</superscript> cDC2B subset closely resembling cDC2 generally found in peripheral lymph nodes. Moreover, in ADAM10 <superscript>ΔCD11c</superscript> mice, terminal differentiation of cDC1 was abrogated, resulting in severely reduced splenic Langerin <superscript>+</superscript> cDC1 numbers. Next to the disturbed splenic cDC compartment, ADAM10 deficiency on CD11c <superscript>+</superscript> cells led to an increase in marginal metallophilic macrophage (MMM) numbers. In conclusion, our data identify ADAM10 as a molecular hub on both cDC and MMM regulating their transcriptional programming, turnover, homeostasis, and ability to shape the anatomical niche of the MZ.<br />Competing Interests: The authors declare no competing interest.
- Subjects :
- ADAM10 Protein physiology
Amyloid Precursor Protein Secretases physiology
Animals
Antigen-Presenting Cells metabolism
CD11c Antigen metabolism
Cell Differentiation
Cell Proliferation
Female
Homeostasis
Lymphoid Tissue metabolism
Macrophages metabolism
Male
Membrane Proteins physiology
Mice
Mice, Inbred C57BL
Myeloid Cells metabolism
Phosphatidylinositol 3-Kinases metabolism
Protein Processing, Post-Translational genetics
Protein Processing, Post-Translational physiology
Signal Transduction
Spleen cytology
Spleen metabolism
ADAM10 Protein metabolism
Amyloid Precursor Protein Secretases metabolism
Dendritic Cells metabolism
Membrane Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 118
- Issue :
- 38
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 34526403
- Full Text :
- https://doi.org/10.1073/pnas.2111234118