The TLR2-MyD88-NOD2-RIPK2 signalling axis regulates a balanced pro-inflammatory and IL-10-mediated anti-inflammatory cytokine response to Gram-positive cell walls
The TLR2-MyD88-NOD2-RIPK2 signalling axis regulates a balanced pro-inflammatory and IL-10-mediated anti-inflammatory cytokine response to Gram-positive cell walls
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DOI：
10.1111/j.1462-5822.2008.01189.x
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发表时间：
2008-10-01
影响因子：
3.4
通讯作者：
Murray, Peter J.
中科院分区：
文献类型：
--
作者：
Moreira, Lilian O.;El Kasmi, Karim C.;Murray, Peter J.
肺炎链球菌的全身性感染与结构复杂的细胞壁碎片（PnCW）的强烈促炎反应有关，PnCW在细胞生长和抗生素诱导的自溶过程中脱落。与先前的研究一致，PnCW诱导的炎症细胞因子的产生依赖于TLR2，但不依赖于细胞质NLR蛋白NOD2。然而，在促炎反应的同时，我们发现PnCW还能诱导巨噬细胞大量分泌抗炎IL-10。这种反应依赖于TLR2，但也涉及NOD2，因为缺乏NOD2会减少细胞壁反应中IL-10的分泌，并转化为对IL-10调节的靶基因表达的下游影响减弱。pncw介导的通过TLR2产生IL-10需要RIPK2 （NOD2功能所需的激酶）和MyD88，但与已知的zymosan不同的是，没有检测到ERK通路的激活。由于NOD2突变与异常免疫应答有关，激活TLR2-NOD2-RIPK2通路对IL-10分泌的时间和定量影响可能会影响对革兰氏阳性菌的促炎和抗炎应答之间的平衡。
Systemic infection with Streptococcus pneumoniae is associated with a vigorous pro-inflammatory response to structurally complex cell wall fragments (PnCW) that are shed during cell growth and antibiotic-induced autolysis. Consistent with previous studies, inflammatory cytokine production induced by PnCW was dependent on TLR2 but independent of NOD2, a cytoplasmic NLR protein. However, in parallel with the pro-inflammatory response, we found that PnCW also induced prodigious secretion of anti-inflammatory IL-10 from macrophages. This response was dependent on TLR2, but also involved NOD2 as absence of NOD2-reduced IL-10 secretion in response to cell wall and translated into diminished downstream effects on IL-10-regulated target gene expression. PnCW-mediated production of IL-10 via TLR2 required RIPK2 a kinase required for NOD2 function, and MyD88 but differed from that known for zymosan in that ERK pathway activation was not detected. As mutations in NOD2 are linked to aberrant immune responses, the temporal and quantitative effects of activation of the TLR2-NOD2-RIPK2 pathway on IL-10 secretion may affect the balance between pro- and anti-inflammatory responses to Gram-positive bacteria.