Article (Scientific journals)
Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction.
Jang, Jessica C.; Li, Jiang; Gambini, Luca et al.
2017In Proceedings of the National Academy of Sciences of the United States of America, 114 (48), p. 10399-E10408
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Keywords :
Animals; Biological Therapy/methods; Disease Models, Animal; Female; Gram-Negative Bacteria/immunology/metabolism; Humans; Lipopolysaccharide Receptors/immunology/metabolism; Lipopolysaccharides/immunology/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nippostrongylus/immunology; Protective Agents; Protein-Serine-Threonine Kinases/metabolism; Recombinant Proteins/administration & dosage/immunology/metabolism; Resistin/immunology; STAT3 Transcription Factor/metabolism; Shock, Septic/immunology/microbiology/therapy; Signal Transduction/immunology; Toll-Like Receptor 4/immunology/metabolism; LPS; TLR4; inflammation; resistin; sepsis
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Jang, Jessica C.
Li, Jiang
Gambini, Luca
Batugedara, Hashini Maneesha ;  Université de Liège - ULiège > I3-Cellular and Molecular Immunology
Sati, Sandeep
Lazar, Mitchell A.
Fan, Li
Pellecchia, Maurizio
Nair, Meera G.
Language :
English
Title :
Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction.
Publication date :
2017
Journal title :
Proceedings of the National Academy of Sciences of the United States of America
ISSN :
0027-8424
eISSN :
1091-6490
Publisher :
National Academy of Sciences, Washington, United States - District of Columbia
Volume :
114
Issue :
48
Pages :
E10399-E10408
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 27 May 2019

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