Intestinal overexpression of <scp>IL</scp>‐18 promotes eosinophils‐mediated allergic disorders

Verma, Alok; Kandikattu, Hemanth Kumar; Manohar, Murli; Shukla, Anshi; Venkateshaiah, Sathisha Upparahalli; Zhu, Xin‐Guang; Mishra, Anil

doi:10.1111/imm.13051

Cited by 16 publications

(9 citation statements)

References 48 publications

(144 reference statements)

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“…More recently, studies reported that CD101 + CD274 + eosinophils were induced in the blood of patients with eosinophilic esophagitis and allergic asthma, and their levels were positively associated with disease severity [21,40]. In addition, CD101 + CD274 + eosinophils were responsible for IL-18-induced allergic intestine inflammation in mice, demonstrating that CD101 and CD274 are markers of pathogenic eosinophils [28]. Consistent with these studies, our study also found that the majority of eosinophils expressed CD101.…”

Section: Discussionsupporting

confidence: 91%

“…Recent studies have revealed that CD101 and CD274 are markers of mature and activated pathogenic eosinophils in asthmatics and eosinophilic esophagitis [ 21 , 27 , 28 ]; we hence examined the CD101 + and CD274 + eosinophils in allergic rhinitis. In line with other allergic diseases [ 21 ], most eosinophils in the peripheral blood and in nasal brushes were CD101 + (Figure S2A-B ).…”

Section: Resultsmentioning

confidence: 99%

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Elevated Levels of Activated and Pathogenic Eosinophils Characterize Moderate-Severe House Dust Mite Allergic Rhinitis

Yang

Wang

et al. 2020

Journal of Immunology Research

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Eosinophils play a critical role in the pathogenesis of allergic airway inflammation. However, the relative importance of eosinophil activation and pathogenicity in driving the progression of disease severity of allergic rhinitis (AR) remains to be defined. We aimed to assess the relation of activated and pathogenic eosinophils with disease severity of patients with AR. Peripheral blood and nasal samples were collected from patients with mild (n=10) and moderate-severe (n=21) house dust mite AR and healthy control subjects (n=10) recruited prospectively. Expressions of activation and pathogenic markers on eosinophils in the blood and nose were analyzed by flow cytometry. The eosinophilic cation protein- (ECP-) releasing potential and the pro-Th2 function of blood eosinophils were compared between the mild and moderate-severe patients and healthy controls. Our results showed that the numbers of activated (CD44+ and CD69+) and pathogenic (CD101+CD274+) eosinophils in the blood and nose as well as blood eosinophil progenitors were increased in moderate-severe AR compared with the mild patients and healthy controls. In addition, the levels of activated and pathogenic eosinophils in the blood were positively correlated with the total nasal symptom score and serum ECP and eosinophil peroxidase (EPX) levels in patients with AR. Furthermore, the blood eosinophils obtained from the moderate-severe patients exhibited a higher potential of releasing ECP and EPX induced by CCL11 and of promoting Th2 responses than those from the mild patients and healthy controls. In conclusion, patients with moderate-severe AR are characterized by elevated levels of activated and pathogenic eosinophils, which are associated with higher production of ECP, EPX, and IL-4 in the peripheral blood.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Elevated Levels of Activated and Pathogenic Eosinophils Characterize Moderate-Severe House Dust Mite Allergic Rhinitis

Yang

Wang

et al. 2020

Journal of Immunology Research

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“…The immunoregulatory role of IL-18 does not exclude a potential inflammatory function. In agreement, it was recently demonstrated that enterocyte-specific IL-18 transgenic mice accumulate pathogenic eosinophils in the intestine and have a worse outcome in a model of food allergy (Verma et al, 2019). Similarly, it has been shown that IECspecific deletion of IL-18 resulted in protection from DSS-induced colitis (Nowarski et al, 2015).…”

Section: Il-18: Inflammatory or Immunoregulatory?mentioning

confidence: 69%

Canonical and noncanonical inflammasomes in intestinal epithelial cells

Winsor

Krustev

Bruce

et al. 2019

Cellular Microbiology

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Inflammasomes are cytosolic, multimeric protein complexes capable of activating pro‐inflammatory cytokines such as IL‐1β and IL‐18, which play a key role in host defence. Inflammasome components are highly expressed in the intestinal epithelium. In recent years, studies have begun to demonstrate that epithelial‐intrinsic inflammasomes play a critical role in regulating epithelial homeostasis, both by defending the epithelium from pathogenic insult and through the regulation of the mucosal environment. However, the majority of research regarding inflammasome activation has focused on professional immune cells, such as macrophages. Here, we present an overview of the current understanding of inflammasome function in epithelial cells and at mucosal surfaces and, in particular, in the intestine.

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“…Recently, basic and clinical studies provided sufficient progress in our understanding to the mechanism operational in eosinophil recruitment to the epithelial, subepithelial and muscular mucosa, [32][33][34][35] and associated tissue remodelling, including fibrosis. 36 However, there remains a great need for a better mechanistic and therapeutic understanding of the pathobiology of eosinophil-associated allergic diseases such as asthma, EoE and EG.…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus (FK506) treatment protects allergen‐, IL‐5‐ and IL‐13‐induced mucosal eosinophilia

et al. 2021

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Eosinophils are a common clinical feature associated with chronic allergic diseases, and elemental diets, systemic steroids, anti-IL-5 and anti-IL-13 treatment have shown some therapeutic promise. Herein, we present evidence that pre-and post-intraperitoneal administration of tacrolimus (FK506) is very effective in reducing CCR3/Siglec-F + eosinophils in Aspergillus-challenged asthma and EoE, CD2-IL-5 induced global eosinophilia, and DOX regulated IL-13-induced asthma. We used flow cytometry and anti-major basic protein (MBP) immunostaining to examine eosinophils in the spleen, bone marrow, BALF, lung, oesophagus and intestine. Additionally, we also performed ELISA and Western blot analyses to show that tacrolimus treatment also reduces the levels of eosinophil-specific cytokines IL-4, IL-5, IL-13 and TGF-b, eosinophil-specific chemokines Eotaxin-1 and Eotaxin-2, and progenitors of target RCAN1 mRNA and protein levels. Additionally, the current investigations also show that the TGF-bmediated oesophageal and lung fibrosis is also reduced in Aspergilluschallenged, CD2-IL-5 transgenic and DOX-responsive IL-13 mice. Mechanistically, we show that tacrolimus in vitro treatment inhibited bone marrow-derived eosinophil proliferation and viability by promoting eosinophil apoptosis that may be associated with downregulation of RCAN1. Taken together, we provide in vivo and in vitro evidence that tacrolimus ameliorates eosinophil levels and associated pathogenesis in allergen-, IL-5-and IL-13-induced EoE, EG and asthma pathogenesis. Considering tacrolimus side-effects and reactivity to several other drugs, we propose the topical use of tacrolimus for paediatric and low-dose oral for adult patients as a novel therapeutic strategy for the clinical trial to reduce mucosal eosinophilia first in steroid-refractory or elemental diet non-responsive adult EoE, EG and asthma patients.

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

Cited by 16 publications

References 48 publications

Elevated Levels of Activated and Pathogenic Eosinophils Characterize Moderate-Severe House Dust Mite Allergic Rhinitis

Elevated Levels of Activated and Pathogenic Eosinophils Characterize Moderate-Severe House Dust Mite Allergic Rhinitis

Canonical and noncanonical inflammasomes in intestinal epithelial cells

Tacrolimus (FK506) treatment protects allergen‐, IL‐5‐ and IL‐13‐induced mucosal eosinophilia

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