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

Abstract

A simultaneous engagement of different pathogen recognition receptors provides a tailor-made adaptive immunity for an efficient defense against distinct pathogens. For example, cross-talk of TLR and C-type lectin signaling effectively shapes distinct gene expression patterns by integrating the signals at the level of NF-κB. In this study, we extend this principle to a strong synergism between the dectin-1 agonist curdlan and an inflammatory growth factor, GM-CSF. Both together act in synergy in inducing a strong inflammatory signature that converts immature dendritic cells (DCs) to potent effector DCs. A variety of cytokines (IL-1β, IL-6, TNF-α, IL-2, and IL-12p70), costimulatory molecules (CD80, CD86, CD40, and CD70), chemokines (CXCL1, CXCL2, CXCL3, CCL12, CCL17), as well as receptors and molecules involved in fugal recognition and immunity such as Mincle, dectin-1, dectin-2, and pentraxin 3 are strongly upregulated in DC treated simultaneously with curdlan and GM-CSF. The synergistic effect of both stimuli resulted in strong IκBα phosphorylation, its rapid degradation, and enhanced nuclear translocation of all NF-κB subunits. We further identified MAPK ERK as one possible integration site of both signals, because its phosphorylation was clearly augmented when curdlan was coapplied with GM-CSF. Our data demonstrate that the immunomodulatory activity of curdlan requires an additional signal provided by GM-CSF to successfully initiate a robust β-glucan–specific cytokine and chemokine response. The integration of both signals clearly prime and tailor a more effective innate and adaptive response against invading microbes and fungi.

Cytokine‐dependent regulation of dendritic cell differentiation in the splenic microenvironment

“…In contrast to the suppressive activity of IFN-γ on CCL17 production, other cytokines have been reported to enhance CCL17, in particular IL-4, GM-CSF, and TNF, although this was also found to be cell type-dependent [5,25,26,29]. We therefore tested the ability of these cytokines to further induce CCL17 production in splenic DCs derived from either CCL17 E/+ -or CCL17 Figure 3A.…”

“…In contrast to visceral and peripheral LN (PLN), the spleen harbors mainly lymphoid organ resident DCs with the exception of circulating plasmacytoid DCs [4]. Under inflammatory conditions monocytes are able to differentiate into mature DCs through the recognition of PAMPs in conjunction with GM-CSF (Csf-2) [5,6]. GM-CSF has been implicated in the formation of inflammatory DCs in vivo [7], and was also shown to enhance CD103 expression and the ability of CD8α + DCs to cross-present antigens to CD8 + T cells [8][9][10].…”

“…Stimulation of NKT cells by α-GalCer induces rapid and highlevel production of a wide range of cytokines, such as IFN-γ, IL-4, IL-13, IL-17, TNF, and GM-CSF, promoting Th1 and Th2 as well as Th17 responses [31,32]. CCL17 production, in turn, was shown previously to be inducible in certain DC subsets in vitro mainly by IL-4, IL-13, TNF, and GM-CSF [5,25,26,38]. Furthermore, Stat5 and Stat6 were identified as transcription factors, which induce CCL17 expression [25,39,40].…”

Curdlan blocks the immune suppression by myeloid-derived suppressor cells and reduces tumor burden

“…mucosal T cells. Min et al [41] found that curdlan has a synergistic effect with GM-CSF to promote the maturation of dendritic cells. In addition, Chiba et al [42] demonstrated that dectin-1 expressed by DCs and macrophages could recognize N-glycan structures on tumor cells and signals to activate IRF5 pathway, thereby activating NK cells to kill tumor cells.…”

Modulação do inflamassoma por componentes de cápsula secretados pelo Cryptococcus neoformans

“…Existem vários relatos de uma produção aumentada de citocinas frente a dois estímulos ao NF-κB, dando base para a afirmação supracitada (GAO et. al., 2001;MIN et. al., 2012).…”