Toll for water-insoluble molecules; gateway for inflammatory road

The water-insoluble damage-associated molecular patterns (DAMPs) may contribute to the initiation of inflammatory responses¹. Based on this model, we hypothesized that endogenous surfactant molecules might have co-evolved teleologically to regulate immune responses through the activation of various intrinsic anti-inflammatory pathways. To test this idea, we screened various endogenous surfactant molecules that are potentially associated with immune regulation². HY209 showed the most potent anti-sepsis activity in vitro and in mice model. HY209 is already known to enhance the intestinal uptake of dietary lipids by emulsification and to play a role in metabolic homeostasis via GPCR19³. HY209 expanded myeloid-derived suppressor cells, normalized blood pressure and inflammatory cytokine levels, protected against acute kidney damages in septic mice. Proteomic profiling of CD11b+Gr1+ cells revealed that the expression of various proteins responsible for inflammation, such as the acute phase response, signalling pathways of EIF2, LXR/RXR/FXR and protein kinase A, were controlled by HY209 treatment. HY209 also improved allergic dermatitis by reducing the amount of serum IgE, type 2 cytokines, TSLP and by increasing filaggrin expression of the skin. In mice model of Alzheimer’s disease, treatment of 5xFAD mice with HY209 decreased brain inflammation induced by beta-amyloid and increased ability in learning and memory. The effective pharmacological blood level was around 1/1,000 of critical micellar concentration of HY209, suggesting that HY209 interacts with GPCR19 at the concentration far below than toxic dose range. These findings suggest that an intrinsic surfactant molecule, HY209 synthesized in the liver, might has been coevolved as an immune regulator by activating GPCR19 pathway.