Stiffness-tuned and ROS-sensitive hydrogel incorporating complement C5a receptor antagonist modulates antibacterial activity of macrophages for periodontitis treatment.
Stiffness-tuned and ROS-sensitive hydrogel incorporating complement C5a receptor antagonist modulates antibacterial activity of macrophages for periodontitis treatment.
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DOI：
10.1016/j.bioactmat.2023.01.011
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发表时间：
2023-07
影响因子：
18.9
通讯作者：
Cao, Yang
中科院分区：
文献类型：
--
作者：
Gan, Ziqi;Xiao, Zecong;Zhang, Zhen;Li, Yang;Liu, Chao;Chen, Xin;Liu, Yuanbo;Wu, Dongle;Liu, Chufeng;Shuai, Xintao;Cao, Yang
关键词：
无可否认，牙周炎是一种由微生物驱动的难治性感染性疾病，其中牙龈卟啉单胞菌（Pg）发挥着关键作用。 Pg可以选择性地损害牙周巨噬细胞的抗菌反应，包括其吞噬和杀菌活性，而不干扰其促炎活性，最终导致微生物区系紊乱、破坏性牙周炎症和牙槽骨丢失。在这里，开发了一种可注射的 ROS 敏感水凝胶，用于将活性骨髓源性巨噬细胞（以下称为异位巨噬细胞）和补体 C5a 受体拮抗剂（C5A）释放到牙龈缝隙。通过适当调整水凝胶的硬度，这些巨噬细胞的吞噬活性大大增强，在弹性模量为 106 kPa 时达到最佳性能。同时，C5A避免了Pg不必要的C5a受体激活，以确保异位和原位巨噬细胞的细菌杀灭活性。此外，ROS敏感水凝胶还表现出另一个显着特征，即降低牙周生态位中的ROS水平，这有助于减轻牙周炎症和减少骨质流失。这项研究强调了利用具有定制生物力学特性的水凝胶来重塑治疗细胞功能的潜力，这有望在牙周炎治疗之外获得广泛的应用。牙龈卟啉单胞菌在牙周炎中起着关键作用。坚硬的水凝胶机械地激活巨噬细胞，以更好地吞噬病原体。 C5a受体阻断确保了巨噬细胞的杀菌活性。牙周龛中积累的ROS被ROS响应水凝胶直接去除。
Periodontitis is admittedly a microbe-driven intractable infectious disease, in which Porphyromonas gingivalis (Pg) plays a keystone role. Pg can selectively impair the antimicrobial responses of periodontal resident macrophages including their phagocytic and bactericidal activity without interfering their proinflammatory activity, which leads to microflora disturbance, destructive periodontal inflammation and alveolar bone loss eventually. Here, an injectable ROS-sensitive hydrogel is developed for releasing active bone marrow-derived macrophages (named ex-situ macrophages hereafter) and a complement C5a receptor antagonist (C5A) to the gingival crevice. Through appropriately tuning the hydrogel stiffness, the phagocytic activity of these macrophages is greatly enhanced, reaching an optimal performance at the elastic modulus of 106 kPa. Meanwhile, C5A avoids undesired C5a receptor activation by Pg to ensure the bacterial killing activity of both the ex-situ and in-situ macrophages. Besides, the ROS-sensitive hydrogels show another distinct feature of decreasing the ROS level in periodontal niche, which contributes to the alleviated periodontal inflammation and attenuated bone loss as well. This study highlights the potential of utilizing hydrogels with tailored biomechanical properties to remodel the functions of therapeutic cells, which is expected to find wide applications even beyond periodontitis treatment. Porphyromonas gingivalis plays a keystone role in periodontitis. Stiff hydrogel mechanically activates macrophages for better engulfing pathogens. C5a receptor blockade ensures the bactericidal activity of macrophages. Accumulated ROS in periodontal niche is directly removed by ROS-responsive hydrogel.
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影响因子：
3.7
作者：
Hajishengallis G
通讯作者：
Hajishengallis G
影响因子：
2.4
作者：
Guilak, Farshid;Butler, David L.;Goldstein, Steven A.;Baaijens, Frank P. T.
通讯作者：
Baaijens, Frank P. T.
DOI：
10.4049/jimmunol.1202339
发表时间：
2012-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Abe T;Hosur KB;Hajishengallis E;Reis ES;Ricklin D;Lambris JD;Hajishengallis G
通讯作者：
Hajishengallis G
影响因子：
5.4
作者：
De Caro, Viviana;Murgia, Denise;Campisi, Giuseppina
通讯作者：
Campisi, Giuseppina
影响因子：
7.7
作者：
Guvendiren, Murat;Burdick, Jason A.
通讯作者：
Burdick, Jason A.