Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas, USA.
J Leukoc Biol. 2012 Feb;91(2):259-65. doi: 10.1189/jlb.0511239. Epub 2011 Dec 2.
Chemokines exert their function by binding the GPCR class of receptors on leukocytes and cell surface GAGs in target tissues. Most chemokines reversibly exist as monomers and dimers, but very little is known regarding the molecular mechanisms by which the monomer-dimer equilibrium modulates in vivo function. For the chemokine CXCL8, we recently showed in a mouse lung model that monomers and dimers are active and that the monomer-dimer equilibrium of the WT plays a crucial role in regulating neutrophil recruitment. In this study, we show that monomers and dimers are also active in the mouse peritoneum but that the role of monomer-dimer equilibrium is distinctly different between these tissues and that mutations in GAG-binding residues render CXCL8 less active in the peritoneum but more active in the lung. We propose that tissue-specific differences in chemokine gradient formation, resulting from tissue-specific differences in GAG interactions, are responsible for the observed differences in neutrophil recruitment. Our observation of differential roles played by the CXCL8 monomer-dimer equilibrium and GAG interactions in different tissues is novel and reveals an additional level of complexity of how chemokine dimerization regulates in vivo recruitment.
趋化因子通过与白细胞上的 GPCR 类受体和靶组织细胞表面 GAG 结合来发挥作用。大多数趋化因子以单体和二聚体的形式可逆存在，但对于单体-二聚体平衡如何调节体内功能的分子机制知之甚少。对于趋化因子 CXCL8，我们最近在小鼠肺模型中表明，单体和二聚体都是有活性的，WT 的单体-二聚体平衡在调节中性粒细胞募集中起着至关重要的作用。在这项研究中，我们表明单体和二聚体在小鼠腹膜中也具有活性，但单体-二聚体平衡在这些组织中的作用明显不同，并且 GAG 结合残基的突变使 CXCL8 在腹膜中活性降低，但在肺中活性增加。我们提出，由于 GAG 相互作用的组织特异性差异，趋化因子梯度形成的组织特异性差异是导致中性粒细胞募集观察到差异的原因。我们观察到 CXCL8 单体-二聚体平衡和 GAG 相互作用在不同组织中发挥不同作用，这是新颖的，揭示了趋化因子二聚化如何调节体内招募的另一个复杂层次。
