NOD-like receptors mediated activation of eosinophils interacting with bronchial epithelial cells: a link between innate immunity and allergic asthma

Wong, Chun Kwok; Hu, Shuiqing; Leung, Karen Ming Lam; Dong, Jie; Chu, Y. J.; Chu, Ida Miu-Ting; Qiu, Huai Na; Liu, Kelly Yan Ping; Lam, Christopher Wai Kei

doi:10.1038/cmi.2012.77

Cited by 43 publications

(59 citation statements)

References 57 publications

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“…NOD2 and TLR2 are the pivotal PRRs responsible for the immune recognition of S. aureus and are prevalently expressed on innate immune cells, including basophils and eosinophils. [20][21][22][23] Moreover, our results provide the first evidence showing that IL-3C-expanded basophils and eosinophils further deteriorate AD-like inflammation in mice treated with epicutaneous S. aureus components and that the targeted experimental depletion of these innate immune cells protects mice from IL-3C-exacerbated skin inflammation (Figure 2 and Supplementary Figure S4). …”

Section: Discussionmentioning

confidence: 66%

“…22,23 In the present study, both the p38 MAPK and NFkB pathways were found to be essential for the NOD2/TLR2 ligand-mediated activation of basophils and eosinophils by interacting with dermal fibroblasts. However, the ERK pathway was indispensable for the activation of eosinophils (but not basophils) co-cultured with dermal fibroblasts (Figure 7).…”

Section: Discussionmentioning

confidence: 91%

“…Regarding the intracellular signaling mechanisms, previous reports characterized the signal transduction pathways involved in the NOD2/TLR2-mediated activation of basophils and eosinophils co-cultured with bronchial epithelial cells and highlighted an important role for the MAPK and NF-kB pathways in the pathogenesis of allergic asthma. [21][22][23]40 Using optimal concentrations of the small molecule inhibitors SB203580 (7.5 mM), BAY11-7082 (1 mM), U0126 (10 mM), LY294002 (5 mM), and SP600125 (3 mM) that had maximum inhibitory effects but no observable toxicity in the cells, 33 we demonstrated the involvement of the NF-kB, p38 MAPK, and ERK pathways in the NOD2/TLR2-mediated activation of basophils, eosinophils, and dermal fibroblasts ( Figure 7). Moreover, the phosphorylation of pivotal cell signaling molecules necessary for the activation of these pathways was confirmed using high-throughput bead-based multiplex assays (Figure 8).…”

Section: Discussionmentioning

confidence: 99%

“…[21][22][23] Briefly, human basophils or eosinophils (3 3 10 5 cells) co-cultured with confluent dermal fibroblasts (1 3 10 5 cells) were pretreated with 7.5 mM SB203580, 1 mM BAY11-7082, 10 mM U0126, 5 mM LY294002, or 3 mM SP600125 (Calbiochem, Merck Millipore, Darmstadt, Germany) for 1 h, followed by incubation with or without the NOD2/TLR2 ligands in the presence of these inhibitors for an additional 20 h. Then, cytokine/chemokine release and ICAM-1 expression were determined.…”

Section: Selective Inhibition Of Cell Signaling Pathwaysmentioning

confidence: 99%

“…19 Interestingly, both basophils and eosinophils have been shown to express NOD2 and TLR2, which facilitate the detection of S. aureus by these innate immune cells. [20][21][22][23] Although NOD2 and TLR2 have been reported to be crucial for the inflammatory response in S. aureus infection, whether these PRRs are involved in the pathophysiology of AD remains unclear. Therefore, in the present study, we aimed to reveal the underlying relationship between concurrent S. aureus infection and AD by demonstrating that the NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

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NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

et al. 2015

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The skin of patients with atopic dermatitis (AD) has a unique predisposition for colonization by Staphylococcus aureus (S. aureus), which contributes to the inflammation and grim prognosis of AD. Although the mechanism underlying the S. aureus-induced exacerbation of AD remains unclear, recent studies have found a pivotal role for pattern recognition receptors in regulating the inflammatory responses in S. aureus infection. In the present study, we used a typical mouse model of AD-like skin inflammation and found that S. aureus-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and toll-like receptor 2 (TLR2) ligands exacerbated AD-like symptoms, which were further deteriorated by the in vivo expansion of basophils and eosinophils. Subsequent histological analyses revealed that dermal fibroblasts were pervasive in the AD-like skin lesions. Co-culture of human dermal fibroblasts with basophils and eosinophils resulted in a vigorous cytokine/chemokine response to the NOD2/TLR2 ligands and the enhanced expression of intercellular adhesion molecule-1 on the dermal fibroblasts. Basophils and eosinophils were primarily responsible for the AD-related cytokine/chemokine expression in the co-cultures. Direct intercellular contact was necessary for the crosstalk between basophils and dermal fibroblasts, while soluble mediators were sufficient to mediate the eosinophil-fibroblast interactions. Moreover, the intracellular p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and nuclear factor-kappa B signaling pathways were essential for NOD2/TLR2 ligand-mediated activation of basophils, eosinophils, and dermal fibroblasts in AD-related inflammation. This study provides the evidence of NOD2/TLR2-mediated exacerbation of AD through activation of innate immune cells and therefore sheds light on a novel mechanistic pathway by which S. aureus contributes to the pathophysiology of AD. Cellular & Molecular Immunology

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Selective Inhibition Of Cell Signaling Pathwaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

et al. 2015

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Impact of eosinophil-peroxidase (EPX) deficiency on eosinophil structure and function in mouse airways

Percopo¹,

Krumholz²,

Fischer³

et al. 2018

Journal of Leukocyte Biology

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Eosinophil-peroxidase (EPX) is a major constituent of the large cytoplasmic granules of both human and mouse eosinophilic leukocytes. Human EPX-deficiency is a rare, autosomal-recessive disorder limited to the eosinophil lineage. Our intent was to explore the impact of EPX gene-deletion on eosinophil content, structure and function. In response to repetitive intranasal challenge with a filtrate of the allergen, Alternaria alternata, we found significantly fewer eosinophils peripherally and in the respiratory tracts of EPX-/- mice compared to wild-type controls; furthermore, both the major population (Gr1-/lo) and the smaller population of Gr1hi eosinophils from EPX-/- mice displayed lower MFIs for Siglec F. Quantitative evaluation of transmission electron micrographs of lung eosinophils confirmed the relative reduction in granule outer matrix volume in cells from the EPX-/- mice, a finding analogous to that observed in human EPX deficiency. Despite the reduced size of the granule matrix, the cytokine content of eosinophils isolated from allergen-challenged EPX-/- and wild-type mice were largely comparable to one another, although the EPX-/- eosinophils contained reduced concentrations of IL-3. Other distinguishing features of lung eosinophils from allergen-challenged EPX-/- mice included a reduced fraction of surface TLR4-positive cells and reduced MFI for NOD1. Interestingly, the EPX gene-deletion had no impact on eosinophil-mediated clearance of gram-negative Hemophilius influenzae from the airways. As such, although no clinical findings have been associated with human EPX-deficiency, our findings suggest that further evaluation for alterations in eosinophil structure and function may be warranted.

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Gene Variants, mRNA and NOD1/2 Protein Levels in Tunisian Childhood Asthma

Belhaj

Kaabachi

Khalfallah

et al. 2019

Lung

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NOD-like receptors mediated activation of eosinophils interacting with bronchial epithelial cells: a link between innate immunity and allergic asthma

Cited by 43 publications

References 57 publications

NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation

Impact of eosinophil-peroxidase (EPX) deficiency on eosinophil structure and function in mouse airways

Gene Variants, mRNA and NOD1/2 Protein Levels in Tunisian Childhood Asthma

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