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.
Highlights
Heligmosomoides polygyrus is a parasitic nematode that infects the intestines of mice
We previously showed that the parasite secretes the H. polygyrus Alarmin Release Inhibitor (HpARI), which blocks IL-33 responses [8]
HpARI CCP2 Binds IL-33, While HpARI CCP3 Is Required to Block IL-33-Suppression of Tumorigenicity 2 (ST2) Interaction
Summary
Heligmosomoides polygyrus is a parasitic nematode that infects the intestines of mice. It has a fecal/oral lifecycle, with infective L3 larvae being ingested, and rapidly penetrating the epithelium of the proximal duodenum. In order to negate this response, and allow persistence of the parasite in the host, H. polygyrus secretes multiple immunomodulatory factors, including Hp-TGM, a protein mimic of host TGF-β [5], and microRNA-containing extracellular vesicles [6] which modulate transcription of multiple host genes, including suppression of Suppression of Tumorigenicity 2 (ST2), the IL-33 receptor. Our recent work shows that H. polygyrus secretes HpBARI, a protein which binds and blocks ST2 [7]. We previously showed that the parasite secretes the H. polygyrus Alarmin Release Inhibitor (HpARI), which blocks IL-33 responses [8]
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