HRV Signaling in Airway Epithelial Cells Is Regulated by ITAM-Mediated Recruitment and Activation of Syk

Lau, Christine; Castellanos, Patricia; Ranev, Dimitre; Wang, Xiaomin; Chow, Chung‐Wai

doi:10.2174/092986611794927910

Cited by 15 publications

(10 citation statements)

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“…To better understand the role of Syk in mediating the pulmonary immune response to HDM, we analyzed inflammatory mediator gene expression using qPCR, focusing on those implicated in the pathogenesis of allergic asthma and/or previously reported to be regulated by Syk [21,32–34]. HDM sensitization significantly increased several chemokines and cytokines in Syk flox/flox and MC-treated BALB/c mice, including the neutrophil chemokine, CXCL-1, and the pro-inflammatory cytokine, IL-17, as well as eotaxin and IL13 (Fig 8, *p<0.05 HDM vs. Saline, n = 5-6/group).…”

Section: Resultsmentioning

confidence: 99%

Syk Regulates Neutrophilic Airway Hyper-Responsiveness in a Chronic Mouse Model of Allergic Airways Inflammation

et al. 2017

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BackgroundAsthma is a chronic inflammatory disease characterized by airways hyper-responsiveness (AHR), reversible airway obstruction, and airway inflammation and remodeling. We previously showed that Syk modulates methacholine-induced airways contractility in naïve mice and in mice with allergic airways inflammation. We hypothesize that Syk plays a role in the pathogenesis of AHR; this was evaluated in a chronic 8-week mouse model of house dust mite (HDM)-induced allergic airways inflammation.MethodsWe used the Sykflox/flox//rosa26CreERT2 conditional Syk knock-out mice to assess the role of Syk prior to HDM exposure, and treated HDM-sensitized mice with the Syk inhibitor, GSK143, to evaluate its role in established allergic airways inflammation. Respiratory mechanics and methacholine (MCh)-responsiveness were assessed using the flexiVent® system. Lungs underwent bronchoalveolar lavage to isolate inflammatory cells or were frozen for determination of gene expression in tissues.ResultsMCh-induced AHR was observed following HDM sensitization in the Syk-intact (Sykflox/flox) and vehicle-treated BALB/c mice. MCh responsiveness was reduced to control levels in HDM-sensitized Sykdel/del mice and in BALB/c and Sykflox/flox mice treated with GSK143. Both Sykdel/del and GSK143-treated mice mounted appropriate immune responses to HDM, with HDM-specific IgE levels that were comparable to Sykflox/flox and vehicle-treated BALB/c mice. HDM-induced increases in bronchoalveolar lavage cell counts were attenuated in both Sykdel/del and GSK143-treated mice, due primarily to decreased neutrophil recruitment. Gene expression analysis of lung tissues revealed that HDM-induced expression of IL-17 and CXCL-1 was significantly attenuated in both Sykdel/del and GSK143-treated mice.ConclusionSyk inhibitors may play a role in the management of neutrophilic asthma.

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Section: Resultsmentioning

confidence: 99%

Syk Regulates Neutrophilic Airway Hyper-Responsiveness in a Chronic Mouse Model of Allergic Airways Inflammation

et al. 2017

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“…Thus, it is apparent that HRV binding to its receptor and virus entry activate various signaling pathways leading to secretion of inflammatory mediators. The nonreceptor protein tyrosine kinase Syk has been identified as an early signaling molecule that ultimately leads to IL-8 expression [146, 147]. Upon binding of HRV16 to ICAM-1 in primary bronchial epithelial cells Syk is recruited to the plasma membrane together with ezrin that in turn can interact with filamentous actin.…”

Section: Hrv Entry Pathways and Intracellular Traffickingmentioning

confidence: 99%

Productive Entry Pathways of Human Rhinoviruses

Fuchs

Blaas

2012

Advances in Virology

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Currently, complete or partial genome sequences of more than 150 human rhinovirus (HRV) isolates are known. Twelve species A use members of the low-density lipoprotein receptor family for cell entry, whereas the remaining HRV-A and all HRV-B bind ICAM-1. HRV-Cs exploit an unknown receptor. At least all A and B type viruses depend on receptor-mediated endocytosis for infection. In HeLa cells, they are internalized mainly by a clathrin- and dynamin-dependent mechanism. Upon uptake into acidic compartments, the icosahedral HRV capsid expands by ~4% and holes open at the 2-fold axes, close to the pseudo-3-fold axes and at the base of the star-shaped dome protruding at the vertices. RNA-protein interactions are broken and new ones are established, the small internal myristoylated capsid protein VP4 is expelled, and amphipathic N-terminal sequences of VP1 become exposed. The now hydrophobic subviral particle attaches to the inner surface of endosomes and transfers its genomic (+) ssRNA into the cytosol. The RNA leaves the virus starting with the poly(A) tail at its 3′-end and passes through a membrane pore contiguous with one of the holes in the capsid wall. Alternatively, the endosome is disrupted and the RNA freely diffuses into the cytoplasm.

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“…Syk also has important functional roles in cells of nonhematopoietic origin, including vascular endothelial cells, different epithelial cell types and fibroblasts (20,22). In the lung, Syk is expressed in airway epithelia, in which it regulates cell proliferation and migration (23) and the inflammatory response to rhinovirus infection (24)(25)(26). Syk also regulates airway contractility and airway smooth muscle contraction; recent reports in animal models of chronic airway inflammation demonstrated a dual role for Syk in regulating immune cell and airway epithelial and smooth cell function (27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Spleen Tyrosine Kinase Modulates Fibrous Airway Obliteration and Associated Lymphoid Neogenesis After Transplantation

Matsuda

Wang

Oishi

et al. 2016

American Journal of Transplantation

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Chronic lung allograft dysfunction, the major cause of death following lung transplantation, usually manifests as irreversible airflow obstruction associated with obliterative bronchiolitis (OB), a lesion characterized by chronic inflammation, lymphoid neogenesis, fibroproliferation and small airway obliteration. Spleen tyrosine kinase (Syk), a tyrosine kinase that regulates B cell function and innate immunity, has been implicated in the pathogenesis of chronic inflammation and tissue repair. This study evaluated the role of Syk in development of OB, using an intrapulmonary tracheal transplant model of OB with the conditional Syk-knockout Syk flox/flox // rosa26-CreER T2 mice and a Syk-selective inhibitor, GSK2230413. BALB/c trachea allografts were transplanted into Syk-knockout (Syk del/del ) mice or wild-type C57BL/6 recipients treated with GSK2230413. At day 28, histological analysis revealed that in the Syk del/del and GSK2230413-treated C57BL/6 recipients, the graft lumen remained open compared with allografts transplanted into Syk-expressing (Syk flox/flox ) and placebo controltreated C57BL/6 recipients. Immunofluorescence showed lymphoid neogenesis with distinct B and T cell zones in control mice. In contrast, lymphoid neogenesis was absent and few B or T cells were found in Syk del/del and GSK2230413-treated mice. These observations suggest that inhibition of Syk may be a potential therapeutic strategy for the management of OB following lung transplantation.Abbreviations: BOS, bronchiolitis obliterans syndrome; CLAD, chronic lung allograft dysfunction; IPTT, intrapulmonary tracheal transplant; MC, methylcellulose; OB, obliterative bronchiolitis; PBS, phosphate-buffered saline; PNAd, peripheral node addressin; Syk, spleen tyrosine kinase

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HRV Signaling in Airway Epithelial Cells Is Regulated by ITAM-Mediated Recruitment and Activation of Syk

Cited by 15 publications

References 0 publications

Syk Regulates Neutrophilic Airway Hyper-Responsiveness in a Chronic Mouse Model of Allergic Airways Inflammation

Syk Regulates Neutrophilic Airway Hyper-Responsiveness in a Chronic Mouse Model of Allergic Airways Inflammation

Productive Entry Pathways of Human Rhinoviruses

Spleen Tyrosine Kinase Modulates Fibrous Airway Obliteration and Associated Lymphoid Neogenesis After Transplantation

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