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Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2006 Dec 26; Vol. 103 (52), pp. 19794-9. Date of Electronic Publication: 2006 Dec 13. - Publication Year :
- 2006
-
Abstract
- Macrophage pattern recognition receptors (PRRs) play key roles in innate immunity, but they also may contribute to disease processes under certain pathological conditions. We recently showed that engagement of the type A scavenger receptor (SRA), a PRR, triggers JNK-dependent apoptosis in endoplasmic reticulum (ER)-stressed macrophages. In advanced atherosclerotic lesions, the SRA, activated JNK, and ER stress are observed in macrophages, and macrophage death in advanced atheromata leads to plaque necrosis. Herein, we show that SRA ligands trigger apoptosis in ER-stressed macrophages by cooperating with another PRR, Toll-like receptor 4 (TLR4), to redirect TLR4 signaling from prosurvival to proapoptotic. Common SRA ligands activate both TLR4 signaling and engage the SRA. The TLR4 effect results in activation of the proapoptotic MyD88-JNK branch of TLR4, whereas the SRA effect silences the prosurvival IRF-3-IFN-beta branch of TLR4. The normal cell-survival effect of LPS-induced TLR4 activation is converted into an apoptosis response by immunoneutralization of IFN-beta, and the apoptosis effect of SRA ligands is converted into a cell-survival response by reconstitution with IFN-beta. Thus, combinatorial signaling between two distinct PRRs results in a functional outcome-macrophage apoptosis that does not occur with either PRR alone. PRR-induced macrophage death may play important roles in advanced atherosclerosis and in other innate immunity-related processes in which the balance between macrophage survival and death is critical.
- Subjects :
- Animals
Calcium metabolism
Cell Survival
Cells, Cultured
Cytoplasm metabolism
Endoplasmic Reticulum metabolism
Enzyme Activation
Female
Interferon Regulatory Factor-3 metabolism
Interferon-beta metabolism
JNK Mitogen-Activated Protein Kinases metabolism
Ligands
Macrophages drug effects
Mice
Mice, Inbred C57BL
Mice, Knockout
NF-kappa B metabolism
Polysaccharides pharmacology
Receptors, Pattern Recognition deficiency
Receptors, Pattern Recognition genetics
Scavenger Receptors, Class A metabolism
Apoptosis drug effects
Macrophages cytology
Macrophages metabolism
Receptors, Pattern Recognition metabolism
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 103
- Issue :
- 52
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 17167049
- Full Text :
- https://doi.org/10.1073/pnas.0609671104