Toll-like receptor 4 decoy, TOY, attenuates gram-negative bacterial sepsis.
Lipopolysaccharide (LPS), the Gram-negative bacterial outer membrane glycolipid, induces sepsis through its interaction with myeloid differentiation protein-2 (MD-2) and Toll-like receptor 4 (TLR4). To block interaction between LPS/MD-2 complex and TLR4, we designed and generated soluble fusion proteins capable of binding MD-2, dubbed TLR4 decoy receptor (TOY) using 'the Hybrid leucine-rich repeats (LRR) technique'. TOY contains the MD-2 binding ectodomain of TLR4, the LRR motif of hagfish variable lymphocyte receptor (VLR), and the Fc domain of IgG1 to make it soluble, productive, and functional. TOY exhibited strong binding to MD-2, but not to the extracellular matrix (ECM), resulting in a favorable pharmacokinetic profile in vivo. TOY significantly extended the lifespan, when administered in either preventive or therapeutic manners, in both the LPS- and cecal ligation/puncture-induced sepsis models in mice. TOY markedly attenuated LPS-triggered NF-kappaB activation, secretion of proinflammatory cytokines, and thrombus formation in multiple organs. Taken together, the targeting strategy for sequestration of LPS/MD-2 complex using the decoy receptor TOY is effective in treating LPS- and bacteria-induced sepsis; furthermore, the strategy used in TOY development can be applied to the generation of other novel decoy receptor proteins.
Jung
Keehoon
K
National Research Laboratory for Vascular Biology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Lee
Jung-Eun
JE
Kim
Hak-Zoo
HZ
Kim
Ho Min
HM
Park
Beom Seok
BS
Hwang
Seong-Ik
SI
Lee
Jie-Oh
JO
Kim
Sun Chang
SC
Koh
Gou Young
GY
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006090:Gram-Negative Bacteria / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry; D018805:Sepsis / Q000378:metabolism* / Q000382:microbiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C546114:TLR4 decoy; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4