Oxidized CaMKII promotes asthma through the activation of mast cells

Qu, Jingjing; Danh, C.; Zhou, Yufeng; Luczak, Elizabeth D.; Mitzner, Wayne; Anderson, Mark E.; Gao, Peisong

doi:10.1172/jci.insight.90139

Cited by 39 publications

(65 citation statements)

References 62 publications

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“…21,33 BMMCs were isolated and identified by flow cytometry with antibodies against both c-Kit and FcεRI (Fig 3, B ). The mRNA expression of AhR , cyp1a1 , and cyp1b1 was significantly increased in the OVA-activated BMMCs, which could be further enhanced by KYN (Fig 3, C–E ).…”

Section: Resultsmentioning

confidence: 99%

“…33 To test whether ox-CaMKII is also involved in KYN/AhR signaling–mediated mast cell activation in CRSwNP, we first measured ox-CaMKII expression in the polyp tissues (Fig 6, A ). Immunohistochemical staining showed that ox-CaMKII was mainly expressed in airway epithelial cells and infiltrating cells in sinonasal mucosa.…”

Section: Resultsmentioning

confidence: 99%

“…38 Degranulation was also quantified by measuring β-hexosaminidase release in the culture supernatants as previously described. 33 Histamine release was assessed by using automated fluorimetry as previously described. 39 …”

Section: Methodsmentioning

confidence: 99%

“…21,33 In brief, BMMCs sensitized with anti-OVA IgE in the presence or absence of 50 μM of KYN were loaded with 2.5 μM of Fluo-4-acetomethoxy ester (ThermoFisher) for 1 hour in the dark at 37°C and then challenged with 10 μg/mL of OVA. Fluoresecent signals at 488 nm excitation were imaged continuously for 90 to 120 seconds to detect intracellular free calcium.…”

Section: Methodsmentioning

confidence: 99%

“…30–32 We have recently demonstrated that ox-CaMKII in mast cells play a critical role in regulating mast cell activation and the exacerbation of cockroach allergen–induced lung inflammation. 33 However, it remains unknown whether ox-CaMKII regulates chronic inflammation in CRSwNP.…”

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confidence: 99%

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Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps

Wang

Danh

Liu

et al. 2018

Journal of Allergy and Clinical Immunology

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Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with mast cell–mediated inflammation and heightened oxidant stress. Kynurenine (KYN), an endogenous tryptophan metabolite, can promote allergen-induced mast cell activation through the aryl hydrocarbon receptor (AhR). Objectives We sought to determine the role of the KYN/AhR axis and oxidant stress in mast cell activation and the development of CRSwNP. Methods We measured the expression of indoleamine 2,3-dioxygenase 1, tryptophan 2,3-dioxygenase, KYN, and oxidized calmodulin-dependent protein kinase II (ox-CaMKII) in nasal polyps and controls. KYN-potentiated ovalbumin (OVA)-induced ROS generation, cell activation, and ox-CaMKII expression were investigated in wild-type and AhR-deficient (AhR−/−) mast cells. The role of ox-CaMKII in mast cell activation was further investigated. Results Nasal polyps in CRSwNP showed an increased expression of indoleamine 2,3-dioxygenase 1, tryptophan2,3-dioxygenase, and KYN compared with controls. AhR was predominantly expressed in mast cells in nasal polyps. Activated mast cells and local IgE levels were substantially increased in eosinophilic polyps compared with noneosinophilic polyps and controls. Furthermore, KYN potentiated OVA-induced ROS generation, intracellular Ca2+ levels, cell activation, and expression of ox-CaMKII in wild-type, but not in AhR−/− mast cells. Compared with noneosinophilic polyps and controls, eosinophilic polyps showed increased expression of ox-CaMKII in mast cells. Mast cells from ROS-resistant CaMKII MMVVδ mice or pretreated with CaMKII inhibitor showed protection against KYN-promoted OVA-induced mast cell activation. Conclusions These studies support a potentially critical but previously unidentified function of the KYN/AhR axis in regulating IgE-mediated mast cell activation through ROS and ox-CaMKII in CRSwNP.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps

Wang

Danh

Liu

et al. 2018

Journal of Allergy and Clinical Immunology

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RhoA/Rho‐kinases in asthma: from pathogenesis to therapeutic targets

et al. 2020

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Asthma is a chronic and heterogeneous disease characterised by airway inflammation and intermittent airway narrowing. The key obstacle in the prevention and treatment of asthma has been our incomplete understanding of its aetiology and biological mechanisms. The ras homolog family member A (RhoA) of the Rho family GTPases has been considered to be one of the most promising and novel therapeutic targets for asthma. It is well known that RhoA/Rho-kinases play an important role in the pathophysiology of asthma, including airway smooth muscle contraction, airway hyper-responsiveness, b-adrenergic desensitisation and airway remodelling. However, recent advances have suggested novel roles for RhoA in regulating allergic airway inflammation. Specifically, RhoA has been shown to regulate allergic airway inflammation through controlling Th2 or Th17 cell differentiation and to regulate airway remodelling through regulating mesenchymal stem cell (MSC) differentiation. In this review, we evaluate the literature regarding the recent advances in the activation of RhoA/Rho-kinase, cytokine and epigenetic regulation of RhoA/Rho-kinase, and the role of RhoA/Rho-kinase in regulating major features of asthma, such as airway hyperresponsiveness, remodelling and inflammation. We also discuss the importance of the newly identified role of RhoA/Rho-kinase signalling in MSC differentiation and bronchial epithelial barrier dysfunction. These findings indicate the functional significance of the RhoA/Rho-kinase pathway in the pathophysiology of asthma and suggest that RhoA/Rho-kinase signalling may be a promising therapeutic target for the treatment of asthma.

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5-Hydroxymethylfurfural Ameliorates Allergic Inflammation in HMC-1 Cells by Inactivating NF-κB and MAPK Signaling Pathways

Hu,

Zhang,

et al. 2023

Biochem Genet

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Oxidized CaMKII promotes asthma through the activation of mast cells

Cited by 39 publications

References 62 publications

Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps

Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps

RhoA/Rho‐kinases in asthma: from pathogenesis to therapeutic targets

5-Hydroxymethylfurfural Ameliorates Allergic Inflammation in HMC-1 Cells by Inactivating NF-κB and MAPK Signaling Pathways

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