Dectin-1 Regulates IL-10 Production via a MSK1/2 and CREB Dependent Pathway and Promotes the Induction of Regulatory Macrophage Markers

Abstract

In response to infection by fungal pathogens, the innate immune system recognises specific fungal pathogen associated molecular patterns (PAMPs) via pattern recognition receptors including the C-type lectin dectin-1 and members of the Toll Like Receptor (TLR) family. Stimulation of these receptors leads to the induction of both pro- and anti-inflammatory cytokines. The protein kinases MSK1 and 2 are known to be important in limiting inflammatory cytokine production by macrophages in response to the TLR4 agonist LPS. In this study we show that MSKs are also activated in macrophages by the fungal derived ligand zymosan, as well as the dectin-1 specific agonists curdlan and depleted zymosan, via the ERK1/2 and p38α MAPK pathways. Furthermore, we show that MSKs regulate dectin-1 induced IL-10 production, and that this regulation is dependent on the ability of MSKs to phosphorylate the transcription factor CREB. IL-10 secreted in response to zymosan was able to promote STAT3 phosphorylation via an autocrine feedback loop. Consistent with the decreased IL-10 secretion in MSK1/2 knockout macrophages, these cells also had decreased STAT3 tyrosine phosphorylation relative to wild type controls after stimulation with zymosan. We further show that the reduction in IL-10 production in the MSK1/2 macrophages results in increased secretion of IL-12p40 in response to zymosan relative to wild type controls. The production of high levels of IL-10 but low levels of IL-12 has previously been associated with an M2b or ‘regulatory’ macrophage phenotype, which was initially described in macrophages stimulated with a combination of immune complexes and LPS. We found that zymosan, via dectin-1 activation, also leads to the expression of SphK1 and LIGHT, markers of a regulatory like phenotype in mouse macrophages. The expression of these makers was further reinforced by the high level of IL-10 secreted in response to zymosan stimulation.

Dectin-1-mediated Signaling Leads to Characteristic Gene Expressions and Cytokine Secretion via Spleen Tyrosine Kinase (Syk) in Rat Mast Cells

“…Consistent with previous studies in macrophages and DCs, gene expressions of TNF-␣ (12, 13, 15), IL-4/IL-13 (38,39), early growth response transcription factor 3 (40,41), and suppressor of cytokine signaling 1 (42) were also up-regulated in curdlan-stimulated mast cells. Interestingly, curdlan did not stimulate gene expressions that were previously reported in macrophages and DCs, such as IL-1␤ (43, 44), IL-2 (18), [18][19][20], and IL-12 (18,20). Alternatively, gene expressions of IL-3, MCP-1, Nfkbiz were up-regulated by curdlan-stimulated mast cells, although those have not been reported in macrophages and DCs.…”

“…Upon ligand binding, hemITAM of Dectin-1 is phosphorylated by Src family protein-tyrosine kinases and recruits spleen tyrosine kinase (Syk) (10), which initiates a signaling cascade leading to nuclear factor-B (NF-B) (13,14), nuclear factor of activated T-cells (NFAT) (15,16), and MAPK activation (17)(18)(19). Traditional ITAM sequences, such as those found in Fc receptors, consist of a tandem repeat of YXX(I/L) sequences (where X is any amino acid), which, upon ligand binding and receptor clustering, become tyrosine-phosphorylated by Src kinases.…”

Neuroinflammation triggered by β-glucan/dectin-1 signaling enables CNS axon regeneration

“…Stimulus-specific transcriptional programs downstream of PRRs can modulate the macrophage phenotype (33). Transcription factors activated in a dectin-1/ CARD9-dependent manner include NF-κB (19,20), IRF5 (34), and CREB (21,24,35). Dectin-1/CARD9-dependent activation of CREB downstream of curdlan coincides with enhanced regenerative growth of injured RGCs.…”

“…Dectin-1-mediated activation of the MAP kinase pathway in bone marrow (BM)-derived macrophages leads to activation of cAMP response element-binding protein (CREB) (24). Biochemical analysis of eye lysates revealed rapid activation of extracellular signal-regulated protein kinase (Erk1/2) and CREB in WT mice, but not in dectin-1 −/− mice, at 6 h after ONC and i.o.…”

Dynamic Modulation of Innate Immune Response by Varying Dosages of Lipopolysaccharide (LPS) in Human Monocytic Cells

“…While FoxO1 contributes to the expression of pro-inflammatory mediators (23,29), CREB is largely involved in the expression of anti-inflammatory mediators (25,41). Pharmacological activation of Akt corresponds with suppression of FoxO1 (42), which, in light of GSK3 suppression by Akt (26), points to a connection between GSK3 and FoxO1 activity.…”