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Gingival Exudatome Dynamics Implicate Inhibition of the Alternative Complement Pathway in the Protective Action of the C3 Inhibitor Cp40 in Nonhuman Primate Periodontitis
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2018-08-29 , DOI: 10.1021/acs.jproteome.8b00263 Nagihan Bostanci 1 , Kai Bao 1 , Xiaofei Li 2 , Tomoki Maekawa 2 , Jonas Grossmann 3 , Christian Panse 3 , Ruel A. Briones 4 , Ranillo R. G. Resuello 5 , Joel V. Tuplano 5 , Cristina A. G. Garcia 4 , Edimara S. Reis 6 , John D. Lambris 6 , George Hajishengallis 2
Journal of Proteome Research ( IF 3.8 ) Pub Date : 2018-08-29 , DOI: 10.1021/acs.jproteome.8b00263 Nagihan Bostanci 1 , Kai Bao 1 , Xiaofei Li 2 , Tomoki Maekawa 2 , Jonas Grossmann 3 , Christian Panse 3 , Ruel A. Briones 4 , Ranillo R. G. Resuello 5 , Joel V. Tuplano 5 , Cristina A. G. Garcia 4 , Edimara S. Reis 6 , John D. Lambris 6 , George Hajishengallis 2
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Periodontitis is a prevalent chronic inflammatory disease associated with dysbiosis. Although complement inhibition has been successfully used to treat periodontitis in animal models, studies globally analyzing inflamed tissue proteins to glean insight into possible mechanisms of action are missing. Using quantitative shotgun proteomics, we aimed to investigate differences in composition of inflammatory gingival tissue exudate (“gingival crevicular fluid”; GCF), before and after local administration of an inhibitor of the central complement component, C3, in nonhuman primates. The C3 inhibitor, Cp40 (also known as AMY-101) was administered locally in the maxillary gingival tissue of cynomolgus monkeys with established periodontitis, either once a week (1×-treatment; n = 5 animals) or three times per week (3×-treatment; n = 10 animals), for 6 weeks followed by another 6 weeks of observation in the absence of treatment. 45 GCF samples were processed for FASP digestion and liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis. Data were processed using the ProgenesisQI software. The statistical significance of differences between the groups was determined by RM-ANOVA, and a protein expression change was considered as a true regulation at >2-fold and p < 0.05. The human orthologues were subjected to Gene Ontology analyses using PANTHER. Data are available via ProteomeXchange with identifier PXD009502. 573 proteins with >2 peptides were longitudinally quantified. Both 3× and 1× administration of Cp40 resulted in significant down-regulation of dozens of proteins during the 6-week course of treatment as compared to baseline. Following drug withdrawal at 6 weeks, more than 50% of the down-regulated proteins showed increased levels at week 12. The top scored pathway was “complement activation, alternative pathway”, and several proteins involved in this pathway were down-regulated at 6 weeks. We mapped the proteomic fingerprint changes in local tissue exudate of cynomolgus monkey periodontitis in response to C3 inhibition and identified the alternative pathway of complement activation and leukocyte degranulation as main targets, which are thus likely to play significant roles in periodontal disease pathogenesis. Label-free quantitative proteomics strategies utilizing GCF are powerful tools for the identification of treatment targets and providing insights into disease mechanisms.
中文翻译：
牙龈渗出物动力学暗示在非人类灵长类牙周炎的C3抑制剂Cp40的保护作用中替代补体途径的抑制作用。
牙周炎是与营养不良相关的普遍的慢性炎症性疾病。尽管补体抑制已成功地用于动物模型的牙周炎治疗，但缺少对发炎的组织蛋白进行整体分析以了解可能的作用机制的全球研究。我们使用定量的shot弹枪蛋白质组学，旨在研究在非人灵长类动物中局部给予中央补体成分C3抑制剂前后，炎性牙龈组织渗出液（“牙龈沟液”； GCF）的成分差异。C3抑制剂Cp40（也称为AMY-101）在患有牙周炎的食蟹猴的上颌牙龈组织中局部给药，每周一次（1次治疗；n＝ 5只动物）或每周3次（3次治疗；n＝ 10只动物），持续6周，然后在不进行治疗的情况下再观察6周。处理了45个GCF样品以进行FASP消化和液相色谱-串联质谱（LC-MS / MS）分析。使用ProgenesisQI软件处理数据。通过RM-ANOVA确定组间差异的统计学显着性，蛋白质表达变化被认为是> 2倍和p的真实调控。<0.05。使用PANTHER对人类直系同源物进行了基因本体分析。数据可通过ProteomeXchange获得，其标识符为PXD009502。纵向定量了具有> 2个肽的573种蛋白质。与基线相比，在6周的治疗过程中，Cp40的3x和1x给药均导致数十种蛋白质的显着下调。在第6周停药后，超过50％的下调蛋白质在第12周显示水平升高。得分最高的途径是“补体激活，替代途径”，该途径中涉及的几种蛋白质在6时被下调周。我们绘制了响应C3抑制的食蟹猴牙周炎局部组织渗出液中的蛋白质组指纹图谱，并确定了补体激活和白细胞脱粒的替代途径为主要靶标，因此可能在牙周疾病的发病机理中发挥重要作用。利用GCF的无标签定量蛋白质组学策略是用于确定治疗目标并提供对疾病机制的见识的强大工具。
更新日期：2018-08-29
中文翻译：
牙龈渗出物动力学暗示在非人类灵长类牙周炎的C3抑制剂Cp40的保护作用中替代补体途径的抑制作用。
牙周炎是与营养不良相关的普遍的慢性炎症性疾病。尽管补体抑制已成功地用于动物模型的牙周炎治疗，但缺少对发炎的组织蛋白进行整体分析以了解可能的作用机制的全球研究。我们使用定量的shot弹枪蛋白质组学，旨在研究在非人灵长类动物中局部给予中央补体成分C3抑制剂前后，炎性牙龈组织渗出液（“牙龈沟液”； GCF）的成分差异。C3抑制剂Cp40（也称为AMY-101）在患有牙周炎的食蟹猴的上颌牙龈组织中局部给药，每周一次（1次治疗；n＝ 5只动物）或每周3次（3次治疗；n＝ 10只动物），持续6周，然后在不进行治疗的情况下再观察6周。处理了45个GCF样品以进行FASP消化和液相色谱-串联质谱（LC-MS / MS）分析。使用ProgenesisQI软件处理数据。通过RM-ANOVA确定组间差异的统计学显着性，蛋白质表达变化被认为是> 2倍和p的真实调控。<0.05。使用PANTHER对人类直系同源物进行了基因本体分析。数据可通过ProteomeXchange获得，其标识符为PXD009502。纵向定量了具有> 2个肽的573种蛋白质。与基线相比，在6周的治疗过程中，Cp40的3x和1x给药均导致数十种蛋白质的显着下调。在第6周停药后，超过50％的下调蛋白质在第12周显示水平升高。得分最高的途径是“补体激活，替代途径”，该途径中涉及的几种蛋白质在6时被下调周。我们绘制了响应C3抑制的食蟹猴牙周炎局部组织渗出液中的蛋白质组指纹图谱，并确定了补体激活和白细胞脱粒的替代途径为主要靶标，因此可能在牙周疾病的发病机理中发挥重要作用。利用GCF的无标签定量蛋白质组学策略是用于确定治疗目标并提供对疾病机制的见识的强大工具。
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