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, S. E10399
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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 (h RETN 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 Nippostrongylus brasiliensis ( Nb )-infected h RETN Tg + mice after a fatal LPS dose compared with naive mice or Nb -infected h RETN Tg - mice. Employing immunoprecipitation assays, h RETN Tg + 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.
Competing Interests: The authors declare no conflict of interest.
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Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction.
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Autor/in / Beteiligte Person: | Jang, JC ; Li, J ; Gambini, L ; Batugedara, HM ; Sati, S ; Lazar, MA ; Fan, L ; Pellecchia, M ; Nair, MG |
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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, S. E10399 |
Veröffentlichung: | Washington, DC : National Academy of Sciences, 2017 |
Medientyp: | academicJournal |
ISSN: | 1091-6490 (electronic) |
DOI: | 10.1073/pnas.1716015114 |
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