Aljohmani Ahmad, Yildiz Daniela
Institute of Experimental and Clinical Pharmacology and Toxicology, PZMS, ZHMB, Saarland University, Homburg, Germany.
Front Cardiovasc Med. 2020 Dec 16;7:608281. doi: 10.3389/fcvm.2020.608281. eCollection 2020.
Despite recent advances in treatment strategies, infectious diseases are still under the leading causes of death worldwide. Although the activation of the inflammatory cascade is one prerequisite of defense, persistent and exuberant immune response, however, may lead to chronicity of inflammation predisposing to a temporal or permanent tissue damage not only of the site of infection but also among different body organs. The initial response to invading pathogens is mediated by the recognition through various pattern-recognition receptors along with cellular engulfment resulting in a coordinated release of soluble effector molecules and cytokines aiming to terminate the external stimuli. Members of the 'a disintegrin and metalloproteinase' (ADAM) family have the capability to proteolytically cleave transmembrane molecules close to the plasma membrane, a process called ectodomain shedding. In fact, in infectious diseases dysregulation of numerous ADAM substrates such as junction molecules (e.g., E-cadherin, VE-cadherin, JAM-A), adhesion molecules (e.g., ICAM-1, VCAM-1, L-selectin), and chemokines and cytokines (e.g., CXCL16, TNF-α) has been observed. The alpha-cleavage by ADAM proteases represents a rate limiting step for downstream regulated intramembrane proteolysis (RIPing) of several substrates, which influence cellular differentiation, cell signaling pathways and immune modulation. Both the substrates mentioned above and RIPing crucially contribute to a systematic damage in cardiovascular, endocrine, and/or gastrointestinal systems. This review will summarize the current knowledge of ADAM function and the subsequent RIPing in infectious diseases (e.g., pathogen recognition and clearance) and discuss the potential long-term effect on pathophysiological changes such as cardiovascular diseases.
尽管近年来治疗策略取得了进展，但传染病仍是全球主要死因之一。虽然炎症级联反应的激活是防御的一个先决条件，但持续且过度的免疫反应可能导致炎症慢性化，不仅使感染部位，还会使不同身体器官易发生暂时或永久性组织损伤。对入侵病原体的初始反应是通过各种模式识别受体进行识别并伴随细胞吞噬来介导的，从而导致可溶性效应分子和细胞因子的协同释放，旨在终止外部刺激。“去整合素和金属蛋白酶”（ADAM）家族成员能够在靠近质膜处蛋白水解切割跨膜分子，这一过程称为胞外域脱落。事实上，在传染病中，已观察到许多ADAM底物的失调，如连接分子（如E-钙黏蛋白、VE-钙黏蛋白、JAM-A）、黏附分子（如ICAM-1、VCAM-1、L-选择素）以及趋化因子和细胞因子（如CXCL16、TNF-α）。ADAM蛋白酶的α切割是几种底物下游调节性膜内蛋白水解（RIPing）的限速步骤，这些底物会影响细胞分化、细胞信号通路和免疫调节。上述底物和RIPing都对心血管、内分泌和/或胃肠道系统的系统性损伤起着关键作用。本综述将总结当前关于ADAM功能以及传染病中后续RIPing（如病原体识别和清除）的知识，并讨论其对心血管疾病等病理生理变化的潜在长期影响。
