A Truncated Form of HpARI Stabilizes IL-33, Amplifying Responses to the Cytokine

Caroline Chauché, Francesco Vacca, Shin Li Chia, Josh Richards, William F. Gregory, Adefunke Ogunkanbi, Martin A. Wear, Henry J. McSorley (Lead / Corresponding author)

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Abstract

The murine intestinal nematode Heligmosomoides polygyrus releases the H. polygyrus Alarmin Release Inhibitor (HpARI) - a protein which binds to IL-33 and to DNA, effectively tethering the cytokine in the nucleus of necrotic cells. Previous work showed that a non-natural truncation consisting of the first 2 domains of HpARI (HpARI_CCP1/2) retains binding to both DNA and IL-33, and inhibited IL-33 release in vivo. Here, we show that the affinity of HpARI_CCP1/2 for IL-33 is significantly lower than that of the full-length protein, and that HpARI_CCP1/2 lacks the ability to prevent interaction of IL-33 with its receptor. When HpARI_CCP1/2 was applied in vivo it potently amplified IL-33-dependent immune responses to Alternaria alternata allergen, Nippostrongylus brasiliensis infection and recombinant IL-33 injection, in direct contrast to the IL-33-suppressive effects of full-length HpARI. Mechanistically, we found that HpARI_CCP1/2 is able to bind to and stabilize IL-33, preventing its degradation and maintaining the cytokine in its active form. This study highlights the importance of IL-33 inactivation, the potential for IL-33 stabilization in vivo, and describes a new tool for IL-33 research.
Original languageEnglish
Article number1363
Number of pages10
JournalFrontiers in Immunology
Volume11
DOIs
Publication statusPublished - 30 Jun 2020

Keywords

  • Heligmosomoides polygyrus
  • IL-33
  • ILC2
  • allergy
  • cytokine

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