IL-33trap is a novel IL-33–neutralizing biologic that inhibits allergic airway inflammation

Holgado, Aurora; Braun, Harald; Nuffel, Elien Van; Detry, Sammy; Schuijs, Martijn J.; Deswarte, Kim; Vergote, Karl; Haegman, Mira; Baudelet, Griet; Haustraete, Jurgen; Hammad, Hamida; Lambrecht, Bart N.; Savvides, Savvas N.; Afonina, Inna S.; Beyaert, Rudi

doi:10.1016/j.jaci.2019.02.028

Cited by 52 publications

(48 citation statements)

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“…In pathologies such as asthma and COPD, IL‐33 plays a central role in disease pathology, those pathologies were shown to be exacerbated by respiratory virus infection that mediates the release of type 1 cytokines such as IL‐12 40–43 . Thus, we speculate that NK cells derived from the blood or tissues of patients exhibiting elevated levels of IL‐33 would be more sensitive to ex vivo IL‐12 stimulation.…”

Section: Discussionmentioning

confidence: 92%

“…Each line or dot represents 1 of 2 biological replicates for 1 of 3 different subjects. Multiple comparisons of ordinary 1way ANOVA were used to compare cell treatments cytokines such as IL-12 [40][41][42][43]. Thus, we speculate that NK cells derived from the blood or tissues of patients exhibiting elevated levels of IL-33 would be more sensitive to ex vivo IL-12 stimulation.…”

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confidence: 99%

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IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

Ochayon

Ali

Alarcon

et al. 2020

Journal of Leukocyte Biology

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This study tests the hypothesis that activation of MAPK by physiologically relevant concentrations of IL‐33 contributes to enhanced cytokine expression by IL‐12 stimulated human NK cells. While IL‐33 canonically triggers type 2 cytokine responses, this cytokine can also synergize with type 1 cytokines like IL‐12 to provoke IFN‐γ. We show that picogram concentrations of IL‐12 and IL‐33 are sufficient to promote robust secretion of IFN‐γ by human NK cells that greatly exceeds resposes to either cytokine alone. Nanogram doses of IL‐33, potentially consistent with levels in tissue microenvironments, synergize with IL‐12 to induce secretion of additional cytokines, including TNF and GM‐CSF. IL‐33‐induced activation of the p38 MAPK pathway in human NK cells is crucial for enhanced release of IFN‐γ and TNF in response to IL‐12. Mechanistically, IL‐33‐induced p38 MAPK signaling enhances stability of IFNG transcripts and triggers A disintegrin and metalloproteinase domain 17 (ADAM17) mediated cleavage of TNF from the cell surface. These data support our hypothesis and suggest that altered sensitivity of NK cells to IL‐12 in the presence of IL‐33 may have important consequences in diseases associated with mixed cytokine milieus, like asthma and chronic obstructive pulmonary disease.

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Section: Discussionmentioning

confidence: 92%

mentioning

confidence: 99%

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

Ochayon

Ali

Alarcon

et al. 2020

Journal of Leukocyte Biology

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“…However, several limitations remain in therapeutically targeting the IL-33/ST2 pathway for cancer treatment using the fusion protein IL-33trap (extracellular parts of ST2 and IL-1RAcP fused by a flexible linker). Even though, IL-33trap is superior to soluble ST2 (sST2) in sequestering IL-33, its half-life requires daily treatment (21). Other than IL-33, IL-4 and IL-13 are also capable of regulating ST2 expression on macrophages (37,38).…”

Section: Discussionmentioning

confidence: 99%

“…Exposure to IL-33 enhanced ST2 expression in a dose-dependent manner ( Figure 5, E and F, and Supplemental Figure 9B). We then tested whether we could alter the ST2 + TAM population in vivo by targeting the IL-33/ST2 pathway using the IL-33trap fusion protein, which consists of the extracellular parts of ST2 and its coreceptor IL-1 receptor accessory protein (IL-1RAcP) -fused by a flexible linker -and is able to capture free IL-33 with high affinity (Figure 5G) (21). Administration of IL-33trap from the onset of tumor development resulted in significantly reduced tumor growth as compared with vehicle treatment ( Figure 5H).…”

Section: St2 Expression On Macrophages Is Associated With Low Cd8 + Tmentioning

confidence: 99%

ST2 as checkpoint target for colorectal cancer immunotherapy

Jeught¹,

Sun²,

Fang³

et al. 2020

JCI Insight

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“…A recent publication describes a rare loss-of-function mutation in IL-33, protecting from asthma [ 74 ]. Recently, a biologic recombinant protein called IL-33trap was shown to neutralize IL-33 and inhibit acute allergic airway inflammation in a mouse model [ 75 ]. Clinical trials are ongoing with several monoclonal antibodies targeting IL-33/ST2 signaling [ 76 ].…”

Section: Literature Reviewmentioning

confidence: 99%

Genomics of asthma, allergy and chronic rhinosinusitis: novel concepts and relevance in airway mucosa

Laulajainen‐Hongisto

Lyly

Hanif

et al. 2020

Clin Transl Allergy

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Genome wide association studies (GWASs) have revealed several airway disease-associated risk loci. Their role in the onset of asthma, allergic rhinitis (AR) or chronic rhinosinusitis (CRS), however, is not yet fully understood. The aim of this review is to evaluate the airway relevance of loci and genes identified in GWAS studies. GWASs were searched from databases, and a list of loci associating significantly (p < 10–8) with asthma, AR and CRS was created. This yielded a total of 267 significantly asthma/AR–associated loci from 31 GWASs. No significant CRS -associated loci were found in this search. A total of 170 protein coding genes were connected to these loci. Of these, 76/170 (44%) showed bronchial epithelial protein expression in stained microscopic figures of Human Protein Atlas (HPA), and 61/170 (36%) had a literature report of having airway epithelial function. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation analyses were performed, and 19 functional protein categories were found as significantly (p < 0.05) enriched among these genes. These were related to cytokine production, cell activation and adaptive immune response, and all were strongly connected in network analysis. We also identified 15 protein pathways that were significantly (p < 0.05) enriched in these genes, related to T-helper cell differentiation, virus infection, JAK-STAT signaling pathway, and asthma. A third of GWAS-level risk loci genes of asthma or AR seemed to have airway epithelial functions according to our database and literature searches. In addition, many of the risk loci genes were immunity related. Some risk loci genes also related to metabolism, neuro-musculoskeletal or other functions. Functions overlapped and formed a strong network in our pathway analyses and are worth future studies of biomarker and therapeutics.

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IL-33trap is a novel IL-33–neutralizing biologic that inhibits allergic airway inflammation

Cited by 52 publications

References 50 publications

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

IL-33 promotes type 1 cytokine expression via p38 MAPK in human NK cells

ST2 as checkpoint target for colorectal cancer immunotherapy

Genomics of asthma, allergy and chronic rhinosinusitis: novel concepts and relevance in airway mucosa

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