The fifth epidermal growth factor like region of thrombomodulin alleviates LPS-induced sepsis through interacting with GPR15.

Thrombomodulin (TM) exerts cytoprotection via the fifth region of epidermal growth factor (EGF)-like domain of TM (TME5) by interacting with G-protein coupled receptor 15 (GPR15) expressed on cell surface of vascular endothelial cells. TM is also implied to mediate anti-inflammatory functions by unknown mechanism. By applying a lipopolysaccharide (LPS)-induced murine sepsis model, we assessed the role of TME5 in septic inflammation and coagulation. We found that TME5 treatment protected mice in association with ameliorating inflammation and coagulopathy in LPS-induced sepsis. Further study confirmed that TME5 bound GPR15 in vitro. Knock out of GPR15 abolished protective role of TME5 in sepsis model. GPR15 mediated anti-inflammatory function of TME5 through suppression of phosphorylation of IκBα, nuclear translocation of NF-κB and release of pro-inflammatory cytokines in macrophages (Macs). Knock out of GPR15 resulted in dysregulated immune response of Macs, characterised by excessive expression of pro-inflammatory genes and failing to limit immune response. This study indicates that TME5 exerts anti-inflammatory function through inhibition of NF-κB in a GPR15-dependent manner. The use of TME5 may be a potential therapeutic option for treatment of sepsis.