A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils

Venkateshaiah, Sathisha Upparahalli; Mishra, Akanksha; Manohar, Murli; Verma, Alok; Rajavelu, Priya; Niranjan, Rituraj; Wild, Laurianne G.; Parada, Nereida A.; Blecker, Uwe; Lasky, Joseph A.; Mishra, Anil

doi:10.1016/j.jaci.2018.02.011

Cited by 27 publications

(59 citation statements)

References 11 publications

(19 reference statements)

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“…We recently reported that IL‐18 has a critical role in eosinophil differentiation and maturation of pathogenic CD274 + CD101 + ‐expressing eosinophils . This report also indicated that both CD101‐ and CD274‐expressing eosinophils exist in the blood of normal humans and mice, and accumulate in the tissue during allergic conditions in response to IL‐18 . The current study precisely establishes the role of IL‐18 in eosinophil‐associated intestinal disorder.…”

Section: Discussionsupporting

confidence: 80%

“…Induction of IL‐18 is reported in allergen‐induced gastrointestinal diseases, including food allergy, but the significance and mechanism of IL‐18 in EGID is not well understood. We recently reported that IL‐18 has a critical role in eosinophil differentiation and maturation of pathogenic CD274 + CD101 + ‐expressing eosinophils . This report also indicated that both CD101‐ and CD274‐expressing eosinophils exist in the blood of normal humans and mice, and accumulate in the tissue during allergic conditions in response to IL‐18 .…”

Section: Discussionmentioning

confidence: 80%

“…It has been reported that IL‐18‐derived eosinophils express CD101 + CD274 + and are detected in the tissues of allergic patients . Therefore, we next address whether local overexpression of IL‐18 promotes CD101 + CD274 + eosinophils in the jejunum.…”

Section: Resultsmentioning

confidence: 97%

“…Most recently we showed a critical role for IL‐18 in eosinophil differentiation and maturation, along with the role of nerve cells‐derived vasoactive intestinal peptide in the pathogenesis of EGID . We also reported that IL‐18 is involved in transforming IL‐5‐generated naïve eosinophils into a CD101 + CD274 + expressing pathogenic eosinophil subset . The pathogenic characteristics of CD101 + expressing eosinophils were previously established by adoptive transferring into mice .…”

Section: Introductionmentioning

confidence: 90%

“…In this report, we provide precise evidence on the important role of induced IL‐18 in promoting in vivo pathogenic eosinophils that have high levels of all four eosinophil‐associated toxic granular proteins, degranulated eosinophils in the mucosa, and the development of EGID‐like symptoms in response to food allergens. Notably, IL‐18 is implicated in differentiating and transforming CD101 + CD274 + ‐expressing pathogenic subsets of eosinophils, which are exclusively detected in allergic diseases and are different from the eosinophils present in CD2‐IL‐5 transgenic mice …”

Section: Introductionmentioning

confidence: 99%

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Intestinal overexpression of IL‐18 promotes eosinophils‐mediated allergic disorders

et al. 2019

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Summary Baseline eosinophils reside in the gastrointestinal tract; however, in several allergic disorders, excessive eosinophils accumulate in the blood as well in the tissues. Recently, we showed in vitro that interleukin (IL)‐18 matures and transforms IL‐5‐generated eosinophils into the pathogenic eosinophils that are detected in human allergic diseases. To examine the role of local induction of IL‐18 in promoting eosinophil‐associated intestinal disorders, we generated enterocyte IL‐18‐overexpressing mice using the rat intestinal fatty acid‐binding promoter (Fabpi) and analysed tissue IL‐18 overexpression and eosinophilia by performing real‐time polymerase chain reaction, Enzyme‐Linked Immunosorbent Assay and anti‐major basic protein immunostaining. Herein we show that Fabpi‐IL‐18 mice display highly induced IL‐18 mRNA and protein in the jejunum. IL‐18 overexpression in enterocytes promotes marked increases of eosinophils in the blood and jejunum. Our analysis shows IL‐18 overexpression in the jejunum induces a specific population of CD101+ CD274+ tissue eosinophils. Additionally, we observed comparable tissue eosinophilia in IL‐13‐deficient‐Fabpi‐IL‐18 mice, and reduced numbers of tissue eosinophils in eotaxin‐deficient‐Fabpi‐IL‐18 and IL‐5‐deficient‐Fabpi‐IL‐18 mice compared with Fabpi‐IL‐18 transgenic mice. Notably, jejunum eosinophilia in IL‐5‐deficient‐Fabpi‐IL‐18 mice is significantly induced compared with wild‐type mice, which indicates the direct role of induced IL‐18 in the tissue accumulation of eosinophils and mast cells. Furthermore, we also found that overexpression of IL‐18 in the intestine promotes eosinophil‐associated peanut‐induced allergic responses in mice. Taken together, we provide direct in vivo evidence that induced expression of IL‐18 in the enterocytes promotes eotaxin‐1, IL‐5 and IL‐13 independent intestinal eosinophilia, which signifies the clinical relevance of induced IL‐18 in eosinophil‐associated gastrointestinal disorders (EGIDs) to food allergens.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Intestinal overexpression of IL‐18 promotes eosinophils‐mediated allergic disorders

et al. 2019

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Association of asthma genetic variants with asthma‐associated traits reveals molecular pathways of eosinophilic asthma

El‐Husseini

Vonk

Berge

et al. 2023

Clinical & Translational All

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IntroductionAsthma is a complex, polygenic, heterogenous inflammatory disease. Recently, we generated a list of 128 independent single nucleotide polymorphisms (SNPs) associated with asthma in genome‐wide association studies. However, it is unknown if asthma SNPs are associated with specific asthma‐associated traits such as high eosinophil counts, atopy, and airway obstruction, revealing molecular endotypes of this disease. Here, we aim to identify the association between asthma SNPs and asthma‐associated traits and assess expression quantitative trait locus (e‐QTLs) to reveal their downstream functional effects and find drug targets.MethodsAssociation analyses between 128 asthma SNPs and associated traits (blood eosinophil numbers, atopy, airway obstruction, airway hyperresponsiveness) were conducted using regression modelling in population‐based studies (Lifelines N = 32,817/Vlagtwedde‐Vlaardingen N = 1554) and an asthma cohort (Dutch Asthma genome‐wide association study N = 917). Functional enrichment and pathway analysis were performed with genes linked to the significant SNPs by e‐QTL analysis. Genes were investigated to generate novel drug targets.ResultsWe identified 69 asthma SNPs that were associated with at least one trait, with 20 SNPs being associated with multiple traits. The SNP annotated to SMAD3 was the most pleiotropic. In total, 42 SNPs were associated with eosinophil counts, 18 SNPs with airway obstruction, and 21 SNPs with atopy. We identified genetically driven pathways regulating eosinophilia. The largest network of eosinophilia contained two genes (IL4R, TSLP) targeted by drugs currently available for eosinophilic asthma. Several novel targets were identified such as IL‐18, CCR4, and calcineurin.ConclusionMany asthma SNPs are associated with blood eosinophil counts and genetically driven molecular pathways of asthma‐associated traits were identified.

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Experimental Modeling of Eosinophil-Associated Diseases

Venkateshaiah

Manohar

Kandikattu

et al. 2021

Methods in Molecular Biology

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A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils

Abstract: Capsule Summary The current studies demonstrate a critical role of IL-18 in transforming IL-5 generated naïve eosinophils into the distinct inflammatory CD101+CD274+ expressing mature and activated tissue eosinophils that promote disease pathogenesis.

Cited by 27 publications

References 11 publications

Intestinal overexpression of IL‐18 promotes eosinophils‐mediated allergic disorders

Intestinal overexpression of IL‐18 promotes eosinophils‐mediated allergic disorders

Association of asthma genetic variants with asthma‐associated traits reveals molecular pathways of eosinophilic asthma

Experimental Modeling of Eosinophil-Associated Diseases

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