Submitted April 14, 2006
Accepted August 4, 2006
Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NF-
B activation in dendritic cells
Pradip Sen, Mark A Wallet, Zuoan Yi, Yingsu Huang, Michael Henderson, Clayton E Mathews, H. Shelton Earp, Glenn Matsushima, Albert S Baldwin Jr., and Roland M Tisch*
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, NC
Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA
Lineberger Comprehensive Cancer Center/Department of Medicine and Pharmacology, UNC, Chapel Hill, NC
Department of Microbiology and Immunology/Lineberger Comprehensive Center/Neuroscience Center, UNC
Lineberger Comprehensive Cancer Center/Department of Biology, UNC, Chapel Hill, NC
Department of Microbiology and Immunology/Lineberger Comprehensive Center, UNC, Chapel Hill, NC
* Corresponding author; email: rmtisch{at}med.unc.edu.
Dendritic cells (DC) play a key role in immune homeostasis and maintenance of self-tolerance. Tolerogenic DC can be established by an encounter with apoptotic cells (AC) and subsequent inhibition of maturation and effector functions. The receptor(s) and signaling pathway(s) involved in AC-induced inhibition of DC have yet to be defined. We demonstrate that pretreatment with apoptotic but not necrotic cells, inhibits activation of I
B kinase (IKK) and downstream NF-B. Notably, receptor tyrosine kinase Mer (MerTK) binding of AC is required for mediating this effect. Monocyte-derived DC lacking MerTK expression (MerTKKD) or treated with blocking MerTK-specific Ab are resistant to AC-induced inhibition and continue to activate NF-B, and secrete proinflammatory cytokines. Blocking MerTK activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway prevents AC-induced inhibition. These results demonstrate an essential role for MerTK-mediated regulation of the PI3K/AKT and NF-B pathways in AC-induced inhibition of monocyte-derived DC.
