CD36 deficiency protects lipopolysaccharide-induced sepsis via inhibiting CerS6-mediated endoplasmic reticulum stress

Abstract

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.

Keywords: Acyl chain length; CD36; Ceramide synthase 6; Endoplasmic reticulum stress; Inflammasome.