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Exploiting a novel conformational switch to control innate immunity mediated by complement protein C3a

Author

Listed:
  • Rink-Jan Lohman

    (The University of Queensland
    The University of Queensland
    The University of Queensland)

  • Johan K. Hamidon

    (The University of Queensland
    The University of Queensland)

  • Robert C. Reid

    (The University of Queensland
    The University of Queensland
    The University of Queensland)

  • Jessica A. Rowley

    (The University of Queensland
    The University of Queensland
    The University of Queensland)

  • Mei-Kwan Yau

    (The University of Queensland
    The University of Queensland)

  • Maria A. Halili

    (The University of Queensland
    The University of Queensland)

  • Daniel S. Nielsen

    (The University of Queensland
    The University of Queensland)

  • Junxian Lim

    (The University of Queensland
    The University of Queensland
    The University of Queensland)

  • Kai-Chen Wu

    (The University of Queensland
    The University of Queensland
    The University of Queensland)

  • Zhixuan Loh

    (The University of Queensland
    The University of Queensland
    The University of Queensland)

  • Anh Do

    (The University of Queensland
    The University of Queensland
    The University of Queensland)

  • Jacky Y. Suen

    (The University of Queensland
    The University of Queensland
    The University of Queensland)

  • Abishek Iyer

    (The University of Queensland
    The University of Queensland
    The University of Queensland)

  • David P. Fairlie

    (The University of Queensland
    The University of Queensland
    The University of Queensland)

Abstract

Complement C3a is an important protein in innate and adaptive immunity, but its specific roles in vivo remain uncertain because C3a degrades rapidly to form the C3a-desArg protein, which does not bind to the C3a receptor and is indistinguishable from C3a using antibodies. Here we develop the most potent, stable and highly selective small molecule modulators of C3a receptor, using a heterocyclic hinge to switch between agonist and antagonist ligand conformations. This enables characterization of C3 areceptor-selective pro- vs. anti-inflammatory actions in human mast cells and macrophages, and in rats. A C3a receptor-selective agonist induces acute rat paw inflammation by first degranulating mast cells before activating macrophages and neutrophils. An orally administered C3a receptor-selective antagonist inhibits mast cell degranulation, thereby blocking recruitment and activation of macrophages and neutrophils, expression of inflammatory mediators and inflammation in a rat paw edema model. These novel tools reveal the mechanism of C3a-induced inflammation and provide new insights to complement-based medicines.

Suggested Citation

  • Rink-Jan Lohman & Johan K. Hamidon & Robert C. Reid & Jessica A. Rowley & Mei-Kwan Yau & Maria A. Halili & Daniel S. Nielsen & Junxian Lim & Kai-Chen Wu & Zhixuan Loh & Anh Do & Jacky Y. Suen & Abishe, 2017. "Exploiting a novel conformational switch to control innate immunity mediated by complement protein C3a," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00414-w
    DOI: 10.1038/s41467-017-00414-w
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