Dectin-1 regulates IL-10 production via a MSK1/2 and CREB dependent pathway and promotes the induction of regulatory macrophage markers.
Dectin-1 regulates IL-10 production via a MSK1/2 and CREB dependent pathway and promotes the induction of regulatory macrophage markers.
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DOI：
10.1371/journal.pone.0060086
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Arthur JS
中科院分区：
文献类型：
--
作者：
Elcombe SE;Naqvi S;Van Den Bosch MW;MacKenzie KF;Cianfanelli F;Brown GD;Arthur JS
作为对真菌病原体感染的响应，天然免疫系统通过模式识别受体识别特定的真菌病原体相关分子模式(PAMPs)，包括C型凝集素Dectin-1和Toll样受体(TLR)家族的成员。对这些受体的刺激可以诱导促炎和抗炎细胞因子的产生。已知蛋白激酶MSK1和MSK2在限制巨噬细胞对TLR4激动剂脂多糖的反应中产生炎性细胞因子具有重要作用。在这项研究中，我们发现，在巨噬细胞中，MSK也可以通过ERK1/2和p38αMAPK通路被真菌衍生的配体酵母多糖以及Dectin-1特异性激动剂Curdlan和耗尽的酵母多糖激活。此外，我们发现MSK调节Dectin-1诱导的IL-10的产生，并且这种调节依赖于MSK对转录因子CREB的磷酸化能力。酵母多糖刺激后分泌的IL-10可通过自分泌反馈环促进STAT3的磷酸化。与MSK1/2基因敲除的巨噬细胞IL-10分泌减少一致，这些细胞在酵母多糖刺激后，STAT3酪氨酸磷酸化水平也低于野生型对照细胞。我们进一步表明，与野生型对照相比，MSK1/2巨噬细胞中IL-10产生的减少导致酵母多糖增加了IL-12p40的分泌。高水平的IL-10和低水平的IL-12的产生以前被认为与M2B或“调节性”巨噬细胞表型有关，最初的描述是在免疫复合体和内毒素的组合刺激下的巨噬细胞。我们发现，酵母多糖通过Dectin-1的激活，也导致SphK1和LIGH的表达，这是小鼠巨噬细胞中调节样表型的标志。酵母多糖刺激后分泌的高水平IL-10进一步增强了这些标志物的表达。
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.
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影响因子：
4.4
作者：
Gerber, JS;Mosser, DM
通讯作者：
Mosser, DM
Dectin-1介导β-葡聚糖的生物学作用。
DOI：
10.1084/jem.20021890
发表时间：
2003-05-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Brown GD;Herre J;Williams DL;Willment JA;Marshall AS;Gordon S
通讯作者：
Gordon S
影响因子：
3.5
作者：
Arthur, JSC;Cohen, P
通讯作者：
Cohen, P
DOI：
10.1126/science.1221789
发表时间：
2012-06-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Iliev ID;Funari VA;Taylor KD;Nguyen Q;Reyes CN;Strom SP;Brown J;Becker CA;Fleshner PR;Dubinsky M;Rotter JI;Wang HL;McGovern DP;Brown GD;Underhill DM
通讯作者：
Underhill DM
影响因子：
5.3
作者：
Beardmore, VA;Hinton, HJ;Arthur, JSC
通讯作者：
Arthur, JSC