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Updated: May 12, 2026
Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
Macrophage ADAM17 deficiency augments CD36-dependent apoptotic cell uptake and the linked anti-inflammatory phenotype
Will S Driscoll1, Tomas Vaisar, Jingjing Tang
1Department of Pathology, Division of Metabolism, Endocrinology, and Nutrition, University of Washington School of Medicine, Seattle, WA 98104, USA.
Rationale:
Apoptotic cell phagocytosis (efferocytosis) is mediated by specific receptors and is essential for resolution of inflammation. In chronic inflammation, apoptotic cell clearance is dysfunctional and soluble levels of several apoptotic cell receptors are elevated. Reports have identified proteolytic cleavage as a mechanism capable of releasing soluble apoptotic cell receptors, but the functional implications of their proteolysis are unclear.
Objective:
To test the hypothesis that ADAM17-mediated cleavage of apoptotic cell receptors limits efferocytosis in vivo.
Methods And Results:
In vivo comparison of macrophage efferocytosis in wild-type and Adam17-null hematopoietic chimeras demonstrates that ADAM17 deficiency leads to a 60% increase in efferocytosis and an enhanced anti-inflammatory phenotype in a model of peritonitis. In vitro uptake of phosphatidylserine liposomes identifies the dual-pass apoptotic cell receptor CD36 as a major contributor to enhanced efferocytosis, and CD36 surface levels are elevated on macrophages from Adam17-null mice. Further, temporal elevation of CD36 expression with inflammation may also contribute to its impact. Soluble CD36 from macrophage-conditioned media comprises 2 species based on Western blotting, and mass spectrometry identifies 3 N-terminal peptides that represent probable cleavage sites. Levels of soluble CD36 are decreased in Adam17-null conditioned media, providing evidence for involvement of ADAM17 in CD36 cleavage. Importantly, enhanced efferocytosis in vivo by macrophages lacking ADAM17 is CD36 dependent and accelerates macrophage clearance from the peritoneum, thus promoting resolution of inflammation and highlighting the impact of increased apoptotic cell uptake.
Conclusions:
Our studies demonstrate the importance of ADAM17-mediated proteolysis for in vivo efferocytosis regulation and suggest a possible mechanistic link between chronic inflammation and defective efferocytosis.
Insights
ADAM17 protease activity limits the clearance of apoptotic cells (efferocytosis). Blocking ADAM17 enhances efferocytosis, promoting inflammation resolution and suggesting a link to chronic inflammatory diseases.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Apoptotic cell phagocytosis (efferocytosis) is crucial for resolving inflammation.
- Dysfunctional efferocytosis and elevated soluble apoptotic cell receptors are observed in chronic inflammation.
- Proteolytic cleavage releases soluble apoptotic cell receptors, but its functional role is unclear.
Purpose of the Study:
- To investigate the hypothesis that ADAM17-mediated cleavage of apoptotic cell receptors restrains efferocytosis in vivo.
- To elucidate the role of ADAM17 in regulating efferocytosis and inflammation resolution.
Main Methods:
- Comparison of efferocytosis in wild-type and Adam17-null hematopoietic chimeras.
- In vitro uptake assays using phosphatidylserine liposomes.
- Analysis of CD36 expression, soluble CD36 levels, and identification of cleavage sites via mass spectrometry.
Main Results:
- ADAM17 deficiency increased efferocytosis by 60% and promoted an anti-inflammatory phenotype in a peritonitis model.
- The apoptotic cell receptor CD36 was identified as a key mediator of enhanced efferocytosis in Adam17-null macrophages.
- ADAM17 was implicated in CD36 cleavage, as evidenced by decreased soluble CD36 in Adam17-null conditioned media.
- Enhanced efferocytosis in Adam17-null macrophages was CD36-dependent and accelerated peritoneal clearance, promoting inflammation resolution.
Conclusions:
- ADAM17-mediated proteolysis plays a significant role in regulating efferocytosis in vivo.
- These findings suggest a mechanistic link between ADAM17 activity, defective efferocytosis, and chronic inflammation.
