Human resistin protects against endotoxic shock by blocking LPS–TLR4 interaction
In: Proceedings of the National Academy of Sciences of the United States of America, Jg. 114 (2017-11-28), Heft 48
academicJournal
- e10399 - e10408
Zugriff:
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
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Autor/in / Beteiligte Person: | Jang, Jessica C ; Li, Jiang ; Gambini, Luca ; Batugedara, Hashini M ; Sati, Sandeep ; Lazar, Mitchell A ; Fan, Li ; Pellecchia, Maurizio ; Nair, Meera G |
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Zeitschrift: | Proceedings of the National Academy of Sciences of the United States of America, Jg. 114 (2017-11-28), Heft 48 |
Veröffentlichung: | eScholarship, University of California, 2017 |
Medientyp: | academicJournal |
Umfang: | e10399 - e10408 |
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