Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction.

Abstract

Helminths trigger multiple immunomodulatory pathways that can protect from sepsis. Human resistin (hRetn) is an immune cell-derived protein that is highly elevated in helminth infection and sepsis. However, the function of hRetn in sepsis, or whether hRetn influences helminth protection against sepsis, is unknown. Employing hRetn-expressing transgenic mice (h<i>RETN</i>Tg⁺) and recombinant hRetn, we identify a therapeutic function for hRetn in lipopolysaccharide (LPS)-induced septic shock. hRetn promoted helminth-induced immunomodulation, with increased survival of <i>Nippostrongylus brasiliensis</i> (<i>Nb</i>)-infected h<i>RETN</i>Tg⁺ mice after a fatal LPS dose compared with naive mice or <i>Nb</i>-infected h<i>RETN</i>Tg^- mice. Employing immunoprecipitation assays, h<i>RETN</i>Tg⁺<i>Tlr4</i>^-/- mice, and human immune cell culture, we demonstrate that hRetn binds the LPS receptor Toll-like receptor 4 (TLR4) through its N terminal and modulates STAT3 and TBK1 signaling, triggering a switch from proinflammatory to anti-inflammatory responses. Further, we generate hRetn N-terminal peptides that are able to block LPS proinflammatory function. Together, our studies identify a critical role for hRetn in blocking LPS function with important clinical significance in helminth-induced immunomodulation and sepsis.