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

Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):E10399-E10408. doi: 10.1073/pnas.1716015114. Epub 2017 Nov 13.

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 (hRETNTg+) 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 Nippostrongylus brasiliensis (Nb)-infected hRETNTg+ mice after a fatal LPS dose compared with naive mice or Nb-infected hRETNTg- mice. Employing immunoprecipitation assays, hRETNTg+Tlr4-/- 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.

Keywords: LPS; TLR4; inflammation; resistin; sepsis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Therapy / methods
  • Disease Models, Animal
  • Female
  • Gram-Negative Bacteria / immunology
  • Gram-Negative Bacteria / metabolism
  • Humans
  • Lipopolysaccharide Receptors / immunology
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nippostrongylus / immunology
  • Protective Agents
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / immunology
  • Recombinant Proteins / metabolism
  • Resistin / immunology*
  • STAT3 Transcription Factor / metabolism
  • Shock, Septic / immunology*
  • Shock, Septic / microbiology
  • Shock, Septic / therapy
  • Signal Transduction / immunology
  • Toll-Like Receptor 4 / immunology*
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Protective Agents
  • RETN protein, human
  • Recombinant Proteins
  • Resistin
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human