Chemokine CXCL1-Mediated Neutrophil Trafficking in the Lung: Role of CXCR2 Activation.
Chemokine CXCL1-Mediated Neutrophil Trafficking in the Lung: Role of CXCR2 Activation.
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DOI：
10.1159/000430914
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发表时间：
2015
影响因子：
5.3
通讯作者：
Rajarathnam K
中科院分区：
文献类型：
--
作者：
Sawant KV;Xu R;Cox R;Hawkins H;Sbrana E;Kolli D;Garofalo RP;Rajarathnam K
趋化因子CXCL 1及其受体CXCR 2通过募集和激活中性粒细胞以杀死组织部位的微生物而在宿主免疫应答中起关键作用。这一过程中的失调与引起疾病的附带组织损伤有关。CXCL 1可逆地以单体和二聚体形式存在，并且已经提出不同的单体和二聚体活性以及单体-二聚体平衡调节中性粒细胞功能。然而，连接CXCL 1/CXCR 2轴和中性粒细胞“有益”和“破坏性”表型的分子机制尚不清楚。在这项研究中，我们通过CXCL 1 WT（以单体和二聚体形式存在）和非解离二聚体来表征小鼠肺部中性粒细胞的运输及其后果。然而，与二聚体相比，WT在低剂量下更具活性，WT和二聚体在高剂量下均引起大量中性粒细胞外排。重要的是，由WT或二聚体引起的强中性粒细胞募集对肺组织完整性无害，并且进一步地，不能与表面CXCR 2水平相关。我们的结论是，CXCL 1单体/二聚体分布和受体相互作用是高度耦合的，并调节中性粒细胞的运输，并且疾病背景下的损伤是靶组织不适当的CXCR 2激活的结果，而不是由于中性粒细胞在募集过程中施加的机械力造成的。
Chemokine CXCL1 and its receptor CXCR2 play a crucial role in host immune response by recruiting and activating neutrophils for microbial killing at the tissue site. Dysregulation in this process has been implicated in collateral tissue damage causing disease. CXCL1 reversibly exists as monomers and dimers, and it has been proposed that distinct monomer and dimer activities and monomer-dimer equilibrium regulate neutrophil function. However, the molecular mechanisms linking CXCL1/CXCR2 axis and neutrophil ‘beneficial’ and ‘destructive’ phenotypes are not known. In this study, we characterized neutrophil trafficking and its consequence in the mouse lung by CXCL1 WT (exists as monomer and dimer) and a non-dissociating dimer. Whereas WT, compared to dimer, was more active at low doses, both WT and dimer elicited large neutrophil efflux at high doses. Importantly, robust neutrophil recruitment elicited by WT or dimer was not detrimental to lung tissue integrity, and further, could not be correlated to surface CXCR2 levels. We conclude that CXCL1 monomer/dimer distribution and receptor interactions are highly coupled and regulate neutrophil trafficking, and that injury in the context of disease is a consequence of inappropriate CXCR2 activation at the target tissue and not due to mechanical forces exerted by neutrophils during recruitment.