Department of Biochemistry, College of Medicine, Ewha Womans University, Seoul 07084, Republic of Korea.
Department of Physiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea; Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea.
Int Immunopharmacol. 2024 Dec 25;143(Pt 2):113441. doi: 10.1016/j.intimp.2024.113441. Epub 2024 Oct 25.
The type 2 scavenger receptor CD36 functions not only as a long chain fatty acid transporter, but also as a pro-inflammatory mediator. Ceramide is the simple N-acylated form of sphingosine and exerts distinct biological activity depending on its acyl chain length. Six ceramide synthases (CerS) in mammals determine the chain length of ceramide species, and CerS6 mainly produces C16-ceramide. Endotoxin-induced septic shock shows high mortality, but the pathophysiologic role of sphingolipids involved in this process has been hardly investigated. This paper aims to highlight the different role of CerS isoforms in endotoxin-induced inflammatory responses and the regulatory role of CD36 in CerS6 protein degradation with an emphasis as the potential therapeutic candidates in humans. Lipopolysaccharide (LPS), the endotoxin of the Gram-negative bacterial cell wall, was treated to induce endotoxin-induced inflammation both in vitro and in vivo. CerS6-derived C16-ceramide propagated LPS-induced inflammatory responses activating various intracellular signaling pathways, such as mitogen-activated protein kinase and nuclear factor-κB, resulting in the formation of inflammasome complex and pro-inflammatory cytokines. Mechanistically, CerS6-derived C16-ceramide augmented inflammatory responses via endoplasmic reticulum stress, and CerS6 protein stability was regulated by CD36. Finally, CerS6 protein expression and LPS-induced lethality were strikingly reduced in CD36 knockout mice. Collectively, our findings show that CerS6-derived C16-ceramide plays a pivotal role in endotoxin-induced inflammation and suggest CerS6 and its regulator CD36 as possible targets for therapy under life-threatening inflammation such as septic shock.
Ⅱ型清道夫受体 CD36 不仅作为长链脂肪酸的转运蛋白，而且作为促炎介质发挥作用。神经酰胺是鞘氨醇的简单 N-酰化形式，根据其酰基链长度发挥不同的生物学活性。哺乳动物中的 6 种神经酰胺合酶（CerS）决定神经酰胺种类的链长，CerS6 主要产生 C16-神经酰胺。内毒素诱导的败血症休克死亡率高，但涉及该过程的鞘脂类的病理生理作用几乎没有被研究过。本文旨在强调不同 CerS 同工型在内毒素诱导的炎症反应中的作用，以及 CD36 在 CerS6 蛋白降解中的调节作用，并强调它们作为人类潜在治疗靶点的潜力。脂多糖（LPS）是革兰氏阴性细菌细胞壁的内毒素，用于在体外和体内诱导内毒素诱导的炎症。CerS6 衍生的 C16-神经酰胺促进 LPS 诱导的炎症反应，激活各种细胞内信号通路，如丝裂原活化蛋白激酶和核因子-κB，导致炎性小体复合物和促炎细胞因子的形成。从机制上讲，CerS6 衍生的 C16-神经酰胺通过内质网应激增强炎症反应，CerS6 蛋白稳定性受 CD36 调节。最后，在 CD36 敲除小鼠中，CerS6 蛋白表达和 LPS 诱导的致死率显著降低。总之，我们的研究结果表明，CerS6 衍生的 C16-神经酰胺在内毒素诱导的炎症中发挥关键作用，并表明 CerS6 及其调节剂 CD36 可能成为危及生命的炎症（如败血症休克）治疗的潜在靶点。
