Dennehy Kevin M, Ferwerda Gerben, Faro-Trindade Inês, Pyz Elwira, Willment Janet A, Taylor Philip R, Kerrigan Ann, Tsoni S Vicky, Gordon Siamon, Meyer-Wentrup Friederike, Adema Gosse J, Kullberg Bart-Jan, Schweighoffer Edina, Tybulewicz Victor, Mora-Montes Hector M, Gow Neil A R, Williams David L, Netea Mihai G, Brown Gordon D
Institute of Infectious Disease and Molecular Medicine, Clinical Laboratory Sciences Division of Immunology, University of Cape Town, Cape Town, South Africa.
Eur J Immunol. 2008 Feb;38(2):500-6. doi: 10.1002/eji.200737741.
Recognition of microbial components by germ-line encoded pattern recognition receptors (PRR) initiates immune responses to infectious agents. We and others have proposed that pairs or sets of PRR mediate host immunity. One such pair comprises the fungal beta-glucan receptor, Dectin-1, which collaborates through an undefined mechanism with Toll-like receptor 2 (TLR2) to induce optimal cytokine responses in macrophages. We show here that Dectin-1 signaling through the spleen tyrosine kinase (Syk) pathway is required for this collaboration, which can also occur with TLR4, 5, 7 and 9. Deficiency of either Syk or the TLR adaptor MyD88 abolished collaborative responses, which include TNF, MIP-1alpha and MIP-2 production, and which are comparable to the previously described synergy between TLR2 and TLR4. Collaboration of the Syk and TLR/MyD88 pathways results in sustained degradation of the inhibitor of kappaB (IkappaB), enhancing NFkappaB nuclear translocation. These findings establish the first example of Syk- and MyD88-coupled PRR collaboration, further supporting the concept that paired receptors collaborate to control infectious agents.
由种系编码的模式识别受体（PRR）识别微生物成分可启动针对感染因子的免疫反应。我们和其他人提出，PRR的对或组介导宿主免疫。这样的一对受体包括真菌β-葡聚糖受体Dectin-1，它通过一种未明确的机制与Toll样受体2（TLR2）协作，以在巨噬细胞中诱导最佳的细胞因子反应。我们在此表明，通过脾酪氨酸激酶（Syk）途径的Dectin-1信号传导是这种协作所必需的，这种协作也可与TLR4、5、7和9发生。Syk或TLR衔接蛋白MyD88的缺陷消除了包括TNF、MIP-1α和MIP-2产生在内的协作反应，这些反应与先前描述的TLR2和TLR4之间的协同作用相当。Syk和TLR/MyD88途径的协作导致κB抑制蛋白（IkappaB）的持续降解，增强NFkappaB核转位。这些发现确立了Syk和MyD88偶联的PRR协作的首个例子，进一步支持了成对受体协作以控制感染因子的概念。
