Paciullo Francesco, Fallarino Francesca, Bianconi Vanessa, Mannarino Massimo R, Sahebkar Amirhossein, Pirro Matteo
Department of Medicine, Unit of Internal Medicine, University of Perugia, Perugia, Italy.
Department of Experimental Medicine, Unit of Pharmacology, University of Perugia, Perugia, Italy.
J Cell Physiol. 2017 Sep;232(9):2330-2338. doi: 10.1002/jcp.25767. Epub 2017 Jan 31.
Sepsis, a complex and dynamic syndrome resulting from microbial invasion and immune system dysregulation, is associated with an increased mortality, reaching up to 35% worldwide. Cholesterol metabolism is often disturbed during sepsis, with low plasma cholesterol levels being associated with poor prognosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of the low-density lipoprotein receptor (LDLR), thus regulating intracellular and plasma cholesterol levels. PCSK9 is often upregulated during sepsis and might have a detrimental effect on immune host response and survival. Accordingly, PCSK9 reduces lipopolysaccharide uptake and clearance by human hepatocytes. Moreover, PCSK9 upregulation exacerbates organ dysfunction and tissue inflammation during sepsis, whereas a protective effect of PCSK9 deficiency has been documented in septic patients. Although a possible detrimental impact of PCSK9 on survival has been described, some beneficial effects of PCSK9 on immune response may be hypothesized. First, PCSK9 is associated with increased plasma cholesterol levels, which might be protective during sepsis. Second, PCSK9, by stimulating LDLR degradation and inhibiting reverse cholesterol transport (RCT), might promote preferential cholesterol accumulation in macrophages and other immune cells; these events might improve lipid raft composition and augment toll-like receptor function thus supporting inflammatory response. Hence, a more clear definition of the role of PCSK9 in septic states might provide additional insight in the understanding of the sepsis-associated immune dysregulation and enhance therapeutic outcomes.
脓毒症是一种由微生物入侵和免疫系统失调引起的复杂动态综合征，其死亡率较高，在全球范围内高达35%。脓毒症期间胆固醇代谢常受干扰，血浆胆固醇水平低与预后不良相关。前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）促进低密度脂蛋白受体（LDLR）的降解，从而调节细胞内和血浆胆固醇水平。脓毒症期间PCSK9常上调，可能对免疫宿主反应和生存产生不利影响。因此，PCSK9减少人肝细胞对脂多糖的摄取和清除。此外，PCSK9上调会加重脓毒症期间的器官功能障碍和组织炎症，而PCSK9缺乏在脓毒症患者中具有保护作用。尽管已描述了PCSK9对生存可能的不利影响，但可以推测PCSK9对免疫反应有一些有益作用。首先，PCSK9与血浆胆固醇水平升高有关，这在脓毒症期间可能具有保护作用。其次，PCSK9通过刺激LDLR降解和抑制逆向胆固醇转运（RCT），可能促进巨噬细胞和其他免疫细胞中胆固醇的优先积累；这些事件可能改善脂筏组成并增强Toll样受体功能，从而支持炎症反应。因此，更明确地定义PCSK9在脓毒症状态中的作用可能为理解脓毒症相关的免疫失调提供更多见解，并提高治疗效果。
