A novel proteolytic cascade generates an extracellular matrix-derived chemoattractant in chronic neutrophilic inflammation
A novel proteolytic cascade generates an extracellular matrix-derived chemoattractant in chronic neutrophilic inflammation
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DOI：
10.4049/jimmunol.180.8.5662
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发表时间：
2008-04-15
影响因子：
4.4
通讯作者：
Blalock, J. Edwin
中科院分区：
文献类型：
--
作者：
Gaggar, Amit;Jackson, Patricia L.;Blalock, J. Edwin
慢性嗜酸性炎症是包括囊性纤维化（CF）在内的多种肺部疾病的表现。越来越多的证据表明，细胞外基质蛋白质片段，如胶原蛋白和弹性蛋白，在气道炎症动物模型中炎症细胞向肺的募集中起重要作用。不幸的是，这些肽与人类疾病的关联以及针对这些炎症途径的治疗靶点的鉴定仍然难以捉摸。在这项研究中，我们证明了一种新的细胞外基质衍生的中性粒细胞化学引诱物，脯氨酸-甘氨酸-脯氨酸（PGP），通过CXC受体1和2对中性粒细胞的行为，类似于N-乙酰化脯氨酸-甘氨酸-脯氨酸（N-α-PGP）。我们描述了特定的多步蛋白水解途径参与PGP生成胶原蛋白，涉及基质金属蛋白酶8和9和脯氨酰内肽酶，丝氨酸蛋白酶，我们确定了一个新的作用，在炎症。PGP的产生与体内蛋白酶给药后气道中性粒细胞计数密切相关。使用CF作为模型，我们表明CF痰中PGP肽水平升高，并且在CF住院治疗急性肺加重期间PGP水平下降，指出其作为这种疾病的新生物标志物的作用。最后，我们证明，CF分泌物能够产生PGP从胶原蛋白离体，这一代显着衰减使用针对基质金属蛋白酶8，基质金属蛋白酶9，或脯氨酰内肽酶的抑制剂。这些实验突出了独特的蛋白酶与调节先天免疫的结构蛋白的相互作用，并支持这些肽作为慢性嗜肺性肺病的新型生物标志物和治疗靶点的作用。
Chronic neutrophilic inflammation is a manifestation of a variety of lung diseases including cystic fibrosis (CF). There is increasing evidence that fragments of extracellular matrix proteins, such as collagen and elastin, play an important role in inflammatory cell recruitment to the lung in animal models of airway inflammation. Unfortunately, the association of these peptides with human disease and the identification of therapeutic targets directed toward these inflammatory pathways have remained elusive. In this study, we demonstrate that a novel extracellular matrix-derived neutrophil chemoattractant, proline-glycine-proline (PGP), acts through CXC receptors 1 and 2 on neutrophils, similar to N-acetylated proline-glycine-proline (N-alpha-PGP). We describe the specific multistep proteolytic pathway involved in PGP generation from collagen, involving matrix metalloproteases 8 and 9 and prolyl endopeptidase, a serine protease for which we identify a novel role in inflammation. PGP generation correlates closely with airway neutrophil counts after administration of proteases in vivo. Using CF as a model, we show that CF sputum has elevated levels of PGP peptides and that PGP levels decline during the course of CF inpatient therapy for acute pulmonary exacerbation, pointing to its role as a novel biomarker for this disease. Finally, we demonstrate that CF secretions are capable of generating PGP from collagen ex vivo and that this generation is significantly attenuated by the use of inhibitors directed toward matrix metalloprotease 8, matrix metalloprotease 9, or prolyl endopeptidase. These experiments highlight unique protease interactions with structural proteins regulating innate immunity and support a role for these peptides as novel biomarkers and therapeutic targets for chronic, neutrophilic lung diseases.