Heparin-bound chemokine CXCL8 monomer and dimer are impaired for CXCR1 and CXCR2 activation: implications for gradients and neutrophil trafficking.
Heparin-bound chemokine CXCL8 monomer and dimer are impaired for CXCR1 and CXCR2 activation: implications for gradients and neutrophil trafficking.
复制标题
DOI：
10.1098/rsob.170168
复制
发表时间：
2017-11
期刊：
影响因子：
5.8
通讯作者：
Rajarathnam K
中科院分区：
文献类型：
--
作者：
Joseph PRB;Sawant KV;Rajarathnam K
趋化因子CXCL 8通过将中性粒细胞募集到感染部位而在宿主免疫应答中起关键作用。CXCL 8以单体和二聚体形式存在，并通过与糖胺聚糖（GAG）相互作用并激活CXCR 1和CXCR 2受体来介导募集。CXCL 8单体和二聚体如何与受体和GAG相互作用介导运输尚不清楚。特别地，已经牵涉到趋触性（由GAG结合的趋化因子介导）和趋化性（由可溶性趋化因子介导）梯度，并且激活受体的是游离的还是GAG结合的CXCL 8单体和/或二聚体仍然未知。使用溶液NMR光谱，我们现在已经表征了肝素结合的CXCL 8单体和二聚体与CXCR 1和CXCR 2受体N-结构域的结合。我们的数据提供了令人信服的证据，肝素结合的单体和二聚体不能结合任何受体。细胞测定还表明，肝素结合的CXCL 8的受体活性受损。考虑到二聚体以更高的亲和力结合GAG，二聚体将主要以GAG结合形式存在，单体以游离形式存在。我们得出结论，GAG相互作用决定了游离CXCL 8的水平，并且是游离的而不是GAG结合的CXCL 8激活受体并介导血液中性粒细胞向感染组织的募集。
Chemokine CXCL8 plays a pivotal role in host immune response by recruiting neutrophils to the infection site. CXCL8 exists as monomers and dimers, and mediates recruitment by interacting with glycosaminoglycans (GAGs) and activating CXCR1 and CXCR2 receptors. How CXCL8 monomer and dimer interactions with both receptors and GAGs mediate trafficking is poorly understood. In particular, both haptotactic (mediated by GAG-bound chemokine) and chemotactic (mediated by soluble chemokine) gradients have been implicated, and whether it is the free or the GAG-bound CXCL8 monomer and/or dimer that activates the receptor remains unknown. Using solution NMR spectroscopy, we have now characterized the binding of heparin-bound CXCL8 monomer and dimer to CXCR1 and CXCR2 receptor N-domains. Our data provide compelling evidence that heparin-bound monomers and dimers are unable to bind either of the receptors. Cellular assays also indicate that heparin-bound CXCL8 is impaired for receptor activity. Considering dimer binds GAGs with higher affinity, dimers will exist predominantly in the GAG-bound form and the monomer in the free form. We conclude that GAG interactions determine the levels of free CXCL8, and that it is the free, and not GAG-bound, CXCL8 that activates the receptors and mediates recruitment of blood neutrophils to the infected tissue.
登录
查看更多内容
影响因子：
2.9
作者：
Kuschert, GSV;Coulin, F;Wells, TNC
通讯作者：
Wells, TNC
影响因子：
8
作者：
Joseph, Prem Raj B.;Rajarathnam, Krishna
通讯作者：
Rajarathnam, Krishna
影响因子：
6.7
作者：
Colditz, Ian G.;Schneider, Martin A.;Rot, Antal
通讯作者：
Rot, Antal
影响因子：
3.7
作者：
Das ST;Rajagopalan L;Guerrero-Plata A;Sai J;Richmond A;Garofalo RP;Rajarathnam K
通讯作者：
Rajarathnam K
影响因子：
3.1
作者：
da Silva, Fabiano Pinheiro;Soriano, Francisco Garcia
通讯作者：
Soriano, Francisco Garcia