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Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma

Abstract

Severe asthma is associated with the production of interleukin 17A (IL-17A). The exact role of IL-17A in severe asthma and the factors that drive its production are unknown. Here we demonstrate that IL-17A mediated severe airway hyperresponsiveness (AHR) in susceptible strains of mice by enhancing IL-13-driven responses. Mechanistically, we demonstrate that IL-17A and AHR were regulated by allergen-driven production of anaphylatoxins, as mouse strains deficient in complement factor 5 (C5) or the complement receptor C5aR mounted robust IL-17A responses, whereas mice deficient in C3aR had fewer IL-17-producing helper T cells (TH17 cells) and less AHR after allergen challenge. The opposing effects of C3a and C5a were mediated through their reciprocal regulation of IL-23 production. These data demonstrate a critical role for complement-mediated regulation of the IL-23–TH17 axis in severe asthma.

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Figure 1: Susceptibility to allergen-driven AHR is associated a mixed TH17-TH2 immune response.
Figure 2: IL-17A blockade protects against allergen-induced AHR.
Figure 3: IL-17A and IL-13 synergistically induce AHR.
Figure 4: Enhanced responsiveness to IL-17A in susceptible A/J mice.
Figure 5: Link between C5 deficiency the production of IL-17A and IL-23.
Figure 6: C3 signaling promotes DC IL-23 production.
Figure 7: Positive feedback regulation of C3-C3aR by IL-17A.
Figure 8: C5a-induced IL-10 regulates IL-23 production by engaging Jnk and AP-1.

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Acknowledgements

We thank C. Gerard (Harvard University) for C3ar1-deficient and C5ar1-deficient mice; F. Finkelman (Cincinnati Children's Hospital Medical Center) for IgG2a (GL117); M. Adcock (Imperial College London) for AS602868; and C. Karp for discussions. Supported by the US National Institutes of Health (HL67736, AI083315, U19A1070235 and P50ES015903 to M.W.-K., and AR47363 to the flow cytometry core of Cincinnati Children's Hospital Medical Center) and the Parker B. Francis Fellowship Program (I.P.L.).

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S.L. and I.P.L. initiated, designed and did experiments, analyzed data and wrote the manuscript; K.D., A.A.S., J.R.C. and Y.S. did experiments; A.L.B. provided critical materials; and M.W.-K. directed the research, designed experiments and wrote the manuscript.

Corresponding author

Correspondence to Marsha Wills-Karp.

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Competing interests

A.L.B. is an employee of Amgen.

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Lajoie, S., Lewkowich, I., Suzuki, Y. et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol 11, 928–935 (2010). https://doi.org/10.1038/ni.1926

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