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Differential use of CARD9 by dectin-1 in macrophages and dendritic cells
Helen S Goodridge1, Takahiro Shimada, Andrea J Wolf
1Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Insights
Dectin-1 and CARD9 signaling are crucial for anti-fungal responses. However, their ability to induce TNF-alpha varies significantly across different immune cells, suggesting complex regulatory mechanisms.
Area of Science:
- Immunology
- Cell Biology
- Innate Immunity
Background:
- Pattern recognition receptors TLR2 and Dectin-1 are vital for macrophage and dendritic cell (DC) responses to fungi.
- Proinflammatory cytokine induction relies on signals from both TLR2 and Dectin-1.
- CARD9 has been identified as a key mediator in innate anti-fungal immunity.
Purpose of the Study:
- To investigate the role of Dectin-1-CARD9 signaling in TNF-alpha induction across various immune cell types.
- To understand the variations in Dectin-1-CARD9 signaling efficiency in different macrophage and DC populations.
- To elucidate the mechanisms underlying the regulation of Dectin-1-CARD9-mediated cytokine production.
Main Methods:
- Utilized murine bone marrow-derived macrophages and dendritic cells (DC).
- Stimulated cells via Dectin-1 and analyzed NF-kappaB activation and TNF-alpha production.
- Examined the effects of priming with GM-CSF or IFN-gamma on Dectin-1-CARD9 signaling.
- Investigated CARD9 recruitment to phagosomes and its interaction with TLR signaling.
Main Results:
- Dectin-1-CARD9 signals failed to activate NF-kappaB and induce TNF-alpha in naive murine bone marrow-derived macrophages.
- Priming with GM-CSF or IFN-gamma enabled Dectin-1-CARD9-mediated TNF-alpha induction in macrophages.
- Significant variations in TNF-alpha production were observed in different macrophage/DC populations upon Dectin-1 ligation.
- CARD9 was recruited to phagosomes and enhanced TLR-induced cytokine production, even when Dectin-1 signaling was insufficient.
Conclusions:
- The efficacy of Dectin-1-CARD9 signaling for TNF-alpha induction is cell-type specific.
- Additional inhibitory factors likely restrict Dectin-1-CARD9 signaling in certain immune cells.
- CARD9 plays a crucial role in enhancing TLR-mediated cytokine production, independent of Dectin-1's direct signaling capacity in some contexts.
Abstract:
The pattern recognition receptors TLR2 and Dectin-1 play key roles in coordinating the responses of macrophages and dendritic cells (DC) to fungi. Induction of proinflammatory cytokines is instructed by signals from both TLR2 and Dectin-1. A recent report identified a role for CARD9 in innate anti-fungal responses, demonstrating CARD9-Bcl10-mediated activation of NF-kappaB and proinflammatory cytokine induction in murine bone marrow-derived DC stimulated via Dectin-1. We now report that Dectin-1-CARD9 signals fail to activate NF-kappaB and drive TNF-alpha induction in murine bone marrow-derived macrophages. However, priming of bone marrow-derived macrophages with GM-CSF or IFN-gamma permits Dectin-1-CARD9-mediated TNF-alpha induction. Analysis of other macrophage/DC populations revealed further variation in the ability of Dectin-1-CARD9 signaling to drive TNF-alpha production. Resident peritoneal cells and alveolar macrophages produce TNF-alpha upon Dectin-1 ligation, while thioglycollate-elicited peritoneal macrophages and Flt3L-derived DC do not. We present data demonstrating that CARD9 is recruited to phagosomes via its CARD domain where it enhances TLR-induced cytokine production even in cells in which Dectin-1 is insufficient to drive cytokine production. In such cells, Dectin-1, CARD9, and Bcl10 levels are not limiting, and data indicate that these cells express additional factors that restrict Dectin-1-CARD9 signaling for TNF-alpha induction.
