Interesting because Montoya found low resistin levels in PWCFS. Which labs can test for resistin? Thanks.
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Human resistin protects against endotoxic shock by blocking LPS–TLR4 interaction
Jessica C. Janga,1,
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.
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Human resistin protects against endotoxic shock by blocking LPS–TLR4 interaction
Jessica C. Janga,1,
- Maurizio Pellecchiaa, and
- 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.
