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C-type Lectin Receptor Dectin-3 Mediates Trehalose 6,6′-Dimycolate (TDM)-induced Mincle Expression through CARD9/Bcl10/MALT1-dependent Nuclear Factor (NF)-κB Activation*
- Publication Year :
- 2014
- Publisher :
- American Society for Biochemistry and Molecular Biology, 2014.
-
Abstract
- Previous studies indicate that both Dectin-3 (also called MCL or Clec4d) and Mincle (also called Clec4e), two C-type lectin receptors, can recognize trehalose 6,6′-dimycolate (TDM), a cell wall component from mycobacteria, and induce potent innate immune responses. Interestingly, stimulation of Dectin-3 by TDM can also induce Mincle expression, which may enhance the host innate immune system to sense Mycobacterium infection. However, the mechanism by which Dectin-3 induces Mincle expression is not fully defined. Here, we show that TDM-induced Mincle expression is dependent on Dectin-3-mediated NF-κB, but not nuclear factor of activated T-cells (NFAT), activation, and Dectin-3 induces NF-κB activation through the CARD9-BCL10-MALT1 complex. We found that bone marrow-derived macrophages from Dectin-3-deficient mice were severely defective in the induction of Mincle expression in response to TDM stimulation. This defect is correlated with the failure of TDM-induced NF-κB activation in Dectin-3-deficient bone marrow-derived macrophages. Consistently, inhibition of NF-κB, but not NFAT, impaired TDM-induced Mincle expression, whereas NF-κB, but not NFAT, binds to the Mincle promoter. Dectin-3-mediated NF-κB activation is dependent on the CARD9-Bcl10-MALT1 complex. Finally, mice deficient for Dectin-3 or CARD9 produced much less proinflammatory cytokines and keyhole limpet hemocyanin (KLH)-specific antibodies after immunization with an adjuvant containing TDM. Overall, this study provides the mechanism by which Dectin-3 induces Mincle expression in response to Mycobacterium infection, which will have significant impact to improve adjuvant and design vaccine for antimicrobial infection.
- Subjects :
- Immunology
Biology
Biochemistry
Models, Biological
Proinflammatory cytokine
Adjuvants, Immunologic
C-type lectin
Animals
Humans
Lectins, C-Type
Receptors, Immunologic
Promoter Regions, Genetic
Molecular Biology
Adaptor Proteins, Signal Transducing
Innate immune system
Cord factor
NFATC Transcription Factors
NF-kappa B
Transcription Factor RelA
Membrane Proteins
NFAT
Cell Biology
B-Cell CLL-Lymphoma 10 Protein
Cell biology
Neoplasm Proteins
CARD Signaling Adaptor Proteins
Mice, Inbred C57BL
Protein Subunits
Gene Expression Regulation
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
Caspases
biology.protein
Cord Factors
Cytokines
Signal transduction
Protein Multimerization
Keyhole limpet hemocyanin
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....3cd8f0d029825a248db58ac28745bc7a