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

  1. Meera G. Naira,2
  1. aDivision of Biomedical Sciences, University of California, Riverside, CA 92521;
  2. bBiochemistry Department, University of California, Riverside, CA 92521;
  3. cInstitute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104;
  4. dDivision of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
  1. Edited by Genhong Cheng, University of California, Los Angeles, CA, and accepted by Editorial Board Member Tadatsugu Taniguchi October 20, 2017 (received for review September 12, 2017)

Significance

Gram-negative bacterial sepsis is a life-threatening disease that is exacerbated by an uncontrolled immune response to the endotoxin lipopolysaccharide (LPS). Human resistin is a highly expressed cytokine in sepsis, where it is hypothesized to exacerbate inflammation. We identify an unexpected protective role for resistin in endotoxic shock. We use human resistin-expressing transgenic mice and human immune cell assays to show that resistin prevents LPS-induced mortality by blocking LPS binding to its receptor Toll-like receptor 4 (TLR4) and by promoting anti-inflammatory signaling. Helminth infection-induced resistin and treatment with recombinant resistin or resistin N-terminal peptides also inhibited LPS function. These studies report a protective function for resistin and identify the therapeutic potential of resistin-mediated anti-inflammatory pathways or resistin-based reagents in sepsis.

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.

Footnotes

  • ?1J.C.J. and J.L. contributed equally to this work.

  • ?2To whom correspondence should be addressed. Email: meera.nair{at}ucr.edu.
  • Author contributions: J.C.J., J.L., H.M.B., M.P., and M.G.N. designed research; J.C.J., J.L., L.G., H.M.B., L.F., M.P., and M.G.N. performed research; J.C.J., J.L., L.G., S.S., M.A.L., L.F., M.P., and M.G.N. contributed new reagents/analytic tools; J.C.J., J.L., L.G., S.S., and M.G.N. analyzed data; and J.C.J., J.L., and M.G.N. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission. G.C. is a guest editor invited by the Editorial Board.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1716015114/-/DCSupplemental.

Published under the PNAS license.

Online Impact

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