The Induction of Inflammation by Dectin-1 In Vivo Is Dependent on Myeloid Cell Programming and the Progression of Phagocytosis

Abstract

Dectin-1 is the archetypal signaling, non-Toll-like pattern recognition receptor that plays a protective role in immune defense to Candida albicans as the major leukocyte receptor for β-glucans. Dectin-1-deficiency is associated with impaired recruitment of inflammatory leukocytes and inflammatory mediator production at the site of infection. In this study, we have used mice to define the mechanisms that regulate the dectin-1-mediated inflammatory responses. Myeloid cell activation by dectin-1 is controlled by inherent cellular programming, with distinct macrophage and dendritic cell populations responding differentially to the engagement of this receptor. The inflammatory response is further modulated by the progression of the phagocytosis, with “frustrated phagocytosis” resulting in dramatically augmented inflammatory responses. These studies demonstrate that dectin-1 in isolation is sufficient to drive a potent inflammatory response in a context-dependent manner. This has implications for the mechanism by which myeloid cells are activated during fungal infections and the processes involved in the therapeutic manipulation of the immune system via exogenous dectin-1 stimulation or blockade.

Synergism between Curdlan and GM-CSF Confers a Strong Inflammatory Signature to Dendritic Cells

“…These results are in accordance with a previous work of Rosas et al (44), which demonstrated the crucial effect of GM-CSF in cellular programming of a proinflammatory dectin-1-mediated response in macrophages. Using both curdlan and glucan microparticles, the authors showed that macrophages do not mount a significant proinflammatory cytokine response upon dectin-1 engagement, which can be dramatically boosted via GM-CSF costimulation (44). They speculated about a GM-CSF-mediated alteration of the downstream signaling components of the Syk/ CARD9 and NF-kB pathways, but the exact mechanism of action was not clarified.…”

Conventional Dendritic Cells Mount a Type I IFN Response againstCandidaspp. Requiring Novel Phagosomal TLR7-Mediated IFN-β Signaling

“…Under our experimental conditions, the IFN-I response to Candida is highly cell-typespecific within innate immune cells, because peritoneal or BMDMs as well as neutrophils or splenic DCs challenged by Candida fail to release detectable amounts of IFN-b. Thus, our results are consistent with reports about distinct and cell-typespecific cytokine responses between BMDMs and myeloid dendritic cells (44)(45)(46), suggesting that different innate immune cells may have distinct repertoires to sense and to respond to microbial PAMPs, depending on the differentiation procedure used to obtain the cells in vitro or the host tissue environment in vivo. This may help to fine-tune the host defense and immune surveillance.…”

CLEC5A is critical for dengue virus–induced inflammasome activation in human macrophages

“…45 While thioglycollate-elicted peritoneal M did not respond to ␤-glucan, exogenous GM-CSF rendered cells producing high amount of cytokines to ␤-glucan, suggesting M differentiation in vivo might be polarized by GM-CSF and had distinct response than primary M in response to ␤-glucan stimulation. 45 Goodridge et al reported that zymosan can induce higher amount of TNF-␣ in GM-CSF-derived BMDC than in BMM (cultured by M-CSF), and ␤-glucan can only induce TNF-␣ secretion from BMDCs, but not BMM . This observation suggests that GM-CSF can activate NF-B to produce TNF-␣ induction on ␤-glucan stimulation, 46 and GM-CSF is a potent cytokine to modulate cell functions in vivo.…”

“…45,46 Rosas et al found that bone marrow-derived dendritic cells (cultured by GM-CSF) produced higher amounts of cytokines than BMM (cultured by M-CSF) in response to pathogenic fungi and its derivatives. 45 While thioglycollate-elicted peritoneal M did not respond to ␤-glucan, exogenous GM-CSF rendered cells producing high amount of cytokines to ␤-glucan, suggesting M differentiation in vivo might be polarized by GM-CSF and had distinct response than primary M in response to ␤-glucan stimulation. 45 Goodridge et al reported that zymosan can induce higher amount of TNF-␣ in GM-CSF-derived BMDC than in BMM (cultured by M-CSF), and ␤-glucan can only induce TNF-␣ secretion from BMDCs, but not BMM .…”