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Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma

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Abstract
The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor a-chain (IL-7Ra) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Ra extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency.
Keywords
ACUTE LYMPHOBLASTIC-LEUKEMIA, STROMAL LYMPHOPOIETIN TSLP, EOSINOPHILIC, ESOPHAGITIS, AIRWAY INFLAMMATION, CYTOKINE RECEPTORS, MAMMALIAN-CELLS, FLT3 LIGAND, RESPONSES, VARIANTS, BIOLOGY

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Chicago
Verstraete, Kenneth, Frank Peelman, Harald Braun, Juan Lopez, Dries Van Rompaey, Ann Dansercoer, Isabel Vandenberghe, et al. 2017. “Structure and Antagonism of the Receptor Complex Mediated by Human TSLP in Allergy and Asthma.” Nature Communications 8.
APA
Verstraete, Kenneth, Peelman, F., Braun, H., Lopez, J., Van Rompaey, D., Dansercoer, A., Vandenberghe, I., et al. (2017). Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. NATURE COMMUNICATIONS, 8.
Vancouver
1.
Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, et al. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. NATURE COMMUNICATIONS. 2017;8.
MLA
Verstraete, Kenneth, Frank Peelman, Harald Braun, et al. “Structure and Antagonism of the Receptor Complex Mediated by Human TSLP in Allergy and Asthma.” NATURE COMMUNICATIONS 8 (2017): n. pag. Print.
@article{8521882,
  abstract     = {The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via structural and mechanistic considerations. Here we employ an integrative experimental approach focusing on productive and antagonized TSLP complexes and free cytokine. We reveal how cognate receptor TSLPR allosterically activates TSLP to potentiate the recruitment of the shared interleukin 7 receptor a-chain (IL-7Ra) by leveraging the flexibility, conformational heterogeneity and electrostatics of the cytokine. We further show that the monoclonal antibody Tezepelumab partly exploits these principles to neutralize TSLP activity. Finally, we introduce a fusion protein comprising a tandem of the TSLPR and IL-7Ra extracellular domains, which harnesses the mechanistic intricacies of the TSLP-driven receptor complex to manifest high antagonistic potency.},
  articleno    = {14937},
  author       = {Verstraete, Kenneth and Peelman, Frank and Braun, Harald and Lopez, Juan and Van Rompaey, Dries and Dansercoer, Ann and Vandenberghe, Isabel and Pauwels, Kris and Tavernier, Jan and Lambrecht, Bart and Hammad, Hamida and De Winter, Hans and Beyaert, Rudi and Lippens, Guy and Savvides, Savvas},
  issn         = {2041-1723},
  journal      = {NATURE COMMUNICATIONS},
  language     = {eng},
  pages        = {17},
  title        = {Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma},
  url          = {http://dx.doi.org/10.1038/ncomms14937},
  volume       = {8},
  year         = {2017},
}

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