Macrophage ADAM17 deficiency augments CD36-dependent apoptotic cell uptake and the linked anti-inflammatory phenotype
MetadataShow full item record
<italic>Rationale:</italic> Phagocytosis of apoptotic cells (efferocytosis) is mediated by apoptotic cell 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 is unclear. <italic>Objective:</italic> To test the hypothesis that ADAM17-mediated cleavage of apoptotic cell receptors limits efferocytosis <italic>in vivo</italic>. <italic>Methods and Results:</italic> <italic>In vivo</italic> comparison of macrophage uptake of apoptotic cells in wildtype and Adam17-null hematopoietic chimeras demonstrates that ADAM17 deficiency leads to a 60% increase in efferocytosis and an enhanced anti-inflammatory phenotype. <italic>In vitro</italic> 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. Soluble CD36 from macrophage-conditioned media is comprised of two ~47 and ~52 kDa species based on Western blotting, and mass spectrometry identifies two non-tryptic, N-terminal peptides in the ~47 kDa species and one non-tryptic, C-terminal peptide in the ~52 kDa fraction, which represent probable cleavage sites. Levels of soluble CD36 are decreased in Adam17-null conditioned media, providing the first evidence for involvement of ADAM17 in CD36 cleavage. Importantly, blockade of CD36 <italic>in vivo</italic> abrogates enhanced efferocytosis in macrophages lacking ADAM17. <italic>Conclusions:</italic> Our studies demonstrate the importance of ADAM17-mediated proteolysis for <italic>in vivo</italic> efferocytosis regulation, and suggest a possible mechanistic link between chronic inflammation and defective efferocytosis.
- Pathology