Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NF-kappaB activation in dendritic cells.
Dendritic cells (DCs) play a key role in immune homeostasis and maintenance of self-tolerance. Tolerogenic DCs can be established by an encounter with apoptotic cells (ACs) and subsequent inhibition of maturation and effector functions. The receptor(s) and signaling pathway(s) involved in AC-induced inhibition of DCs have yet to be defined. We demonstrate that pretreatment with apoptotic but not necrotic cells inhibits activation of IkappaB kinase (IKK) and downstream NF-kappaB. Notably, receptor tyrosine kinase Mer (MerTK) binding of ACs is required for mediating this effect. Monocyte-derived DCs lacking MerTK expression (MerTKKD) or treated with blocking MerTK-specific antibodies (Abs) are resistant to AC-induced inhibition and continue to activate NF-kappaB 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-kappaB pathways in AC-induced inhibition of monocyte-derived DCs.
Sen
Pradip
P
Department of Microbiology and Immunology, Mary Ellen Jones Bldg, Rm 804, Campus Box 7290, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599-7290, USA.
Wallet
Mark A
MA
Yi
Zuoan
Z
Huang
Yingsu
Y
Henderson
Michael
M
Mathews
Clayton E
CE
Earp
H Shelton
HS
Matsushima
Glenn
G
Baldwin
Albert S
AS
Tisch
Roland M
RM
D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D000076202:c-Mer Tyrosine Kinase
D000906:Antibodies; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase