Dectin-1 regulates IL-10 production via a MSK1/2 and CREB dependent pathway and promotes the induction of regulatory macrophage markers

Suzanne E Elcombe, Shaista Naqvi, Mirjam W M Van Den Bosch, Kirsty F Mackenzie, Francesca Cianfanelli, Gordon D Brown, J Simon C Arthur

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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 p38a 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.
Original languageEnglish
Article numbere60086
Number of pages15
JournalPloS ONE
Volume8
Issue number3
DOIs
Publication statusPublished - 22 Mar 2013

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zymosan
Zymosan
Macrophages
interleukin-10
Interleukin-10
macrophages
Phosphorylation
agonists
phosphorylation
cytokines
curdlan
secretion
Interleukin-12 Subunit p40
Cytokines
C-Type Lectins
Phenotype
Pattern Recognition Receptors
phenotype
receptors
antigen-antibody complex

Cite this

Elcombe, S. E., Naqvi, S., Van Den Bosch, M. W. M., Mackenzie, K. F., Cianfanelli, F., Brown, G. D., & Arthur, J. S. C. (2013). Dectin-1 regulates IL-10 production via a MSK1/2 and CREB dependent pathway and promotes the induction of regulatory macrophage markers. PloS ONE, 8(3), [e60086]. https://doi.org/10.1371/journal.pone.0060086

Dectin-1 regulates IL-10 production via a MSK1/2 and CREB dependent pathway and promotes the induction of regulatory macrophage markers. / Elcombe, Suzanne E; Naqvi, Shaista; Van Den Bosch, Mirjam W M; Mackenzie, Kirsty F; Cianfanelli, Francesca; Brown, Gordon D; Arthur, J Simon C.

In: PloS ONE, Vol. 8, No. 3, e60086, 22.03.2013.

Research output: Contribution to journalArticle

Elcombe, Suzanne E ; Naqvi, Shaista ; Van Den Bosch, Mirjam W M ; Mackenzie, Kirsty F ; Cianfanelli, Francesca ; Brown, Gordon D ; Arthur, J Simon C. / Dectin-1 regulates IL-10 production via a MSK1/2 and CREB dependent pathway and promotes the induction of regulatory macrophage markers. In: PloS ONE. 2013 ; Vol. 8, No. 3.
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