Inhibition of 4-1BBL-regulated TLR response in macrophages ameliorates endotoxin-induced sepsis in mice

Abstract

Activation of Toll-like receptor (TLR) signaling rapidly induces the expression of inflammatory genes, which is persistent for a defined period of time. However, uncontrolled and excessive inflammation may lead to the development of diseases. 4-1BB ligand (4-1BBL) plays an essential role in sustaining the expression of inflammatory cytokines by interacting with TLRs during macrophage activation. Here, we show that inhibition of 4-1BBL signaling reduced the inflammatory responses in macrophages and ameliorated endotoxin-induced sepsis in mice. A 4-1BB-Fc fusion protein significantly reduced TNF production in macrophages by blocking the oligomerization of TLR4 and 4-1BBL. Administration of 4-1BB-Fc suppressed LPS-induced sepsis by reducing TNF production, and the coadministration of anti-TNF and 4-1BB-Fc provided better protection against LPS-induced sepsis. Taken together, these observations suggest that inhibition of the TLR/4-1BBL complex formation may be highly efficient in protecting against continued inflammation, and that 4-1BB-Fc could be a potential therapeutic target for the treatment of inflammatory diseases.

Keywords: 4-1BBL; Inflammation; Innate immunity; Sepsis; TNF; Toll-like receptor signaling.