Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons

Gielen, Vera; Sykes, Annemarie; Zhu, Jie; Chan, Brian H. K.; Macintyre, Jonathan; Regamey, Nicolas; Kieninger, Elisabeth; Gupta, Atul; Shoemark, Amelia; Bossley, Cara; Davies, Jane C.; Saglani, Sejal; Walker, Patrick; Nicholson, Sandra E.; Dalpke, Alexander H.; Kon, Onn Min; Bush, Andrew; Johnston, Sebastian L.; Edwards, Michael R.

doi:10.1016/j.jaci.2014.11.039

Cited by 86 publications

(85 citation statements)

References 48 publications

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“…[35] Another study has recently shown that increased nuclear SOCS1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate IFNs. [36] However, our data in severe asthmatics would suggest that reduced SOCS1 in the epithelium is associated with persistent eosinophilia, which is a major risk factor for exacerbations in this population. [37] In summary, we have investigated the expression of SOCS1, SOCS2 and SOCS3 within the airways of healthy controls, mild/moderate asthmatics, and severe asthmatics.…”

Section: Discussionmentioning

confidence: 63%

Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic asthma

Doran

Choy²,

Shikotra³

et al. 2016

Eur Respir J

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Take home message:Persistent airway eosinophilia/Th2 inflammation in severe asthma is associated with reduced epithelial SOCS1 expression. ABSTRACTSevere asthma represents a major unmet clinical need. Eosinophilic inflammation persists in the airways of many patients with uncontrolled asthma, despite high dose inhaled corticosteroid therapy. Suppressors of cytokine signalling (SOCS) are a family of molecules involved in the regulation of cytokine signalling via inhibition of the JAK-STAT pathway.We examined SOCS expression in the airways of asthma patients and investigated whether this is associated with persistent eosinophilia.Healthy controls, mild/moderate asthmatics and severe asthmatics were studied. Whole genome expression profiling, qPCR and immunohistochemical analysis were used to examine expression of SOCS1, SOCS2 and SOCS3 in bronchial biopsies. Bronchial epithelial cells were utilised to examine the role of SOCS1 in regulating IL-13 signalling in vitro.

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Section: Discussionmentioning

confidence: 63%

Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic asthma

Doran

Choy²,

Shikotra³

et al. 2016

Eur Respir J

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“…This is highlighted by the altered function of the epithelium in patients with asthma compared with those without [60]. Epithelial cells actively secrete immune mediators in response to environmental stimuli [61], which are different in patients with asthma compared with controls [62].…”

Section: Bronchial Epitheliummentioning

confidence: 99%

Novel concepts in airway inflammation and remodelling in asthma

2015

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The hallmark pathological features of asthma include airway eosinophilic inflammation and structural changes (remodelling) which are associated with an irreversible loss in lung function that tracks from childhood to adulthood. In parallel with changes in function, pathological abnormalities occur early, during the pre-school years, are established by school age and subsequently remain (even though symptoms may remit for periods during adulthood). Given the equal importance of inflammation and remodelling in asthma pathogenesis, there is a significant disparity in studies undertaken to investigate the contribution of each. The majority focus on the role of inflammation, and although novel therapeutics such as those targeted against T-helper cell type 2 (Th2) mediators have arisen, it is apparent that targeting inflammation alone has not allowed disease modification. Therefore, unless airway remodelling is addressed for future therapeutic strategies, it is unlikely that we will progress towards a cure for asthma. Having acknowledged these limitations, the focus of this review is to highlight the gaps in our current knowledge about the mechanisms underlying airway remodelling, the relationships between remodelling, inflammation and function, remodelling and clinical phenotypes, and the importance of utilising innovative and realistic pre-clinical models to uncover effective, disease-modifying therapeutic strategies. @ERSpublications We discuss mechanisms of airway inflammation and remodelling in asthma to uncover effective therapeutic strategies http://ow.ly/SsXiO

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“…Moreover, they demonstrated that SOCS1 mRNA was significantly decreased in the airways of severe asthma patients when compared to mild/moderate asthma patients but that no difference was found when compared to healthy subjects. However, a recent study investigating SOCS1 and SOCS3 proteins in endobronchial biopsies showed that SOCS1, but not SOCS3, protein staining intensity was significantly increased in the bronchial epithelium of patients with asthma, as compared to healthy volunteers [20]. These observed differences could be partially explained by the fact that the data from DORAN et al [19] were obtained from whole endobronchial biopsy mRNA and, therefore, integrated several cell types, not exclusively epithelial cells.…”

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confidence: 97%

“…The severity of the population studied is different (mild/moderate versus severe asthma), with a potential specific regulation of SOCS family proteins in severe asthma. Additionally, GIELEN et al [20] found that SOCS1, but not SOCS3, mRNA expression levels are increased in primary human bronchial epithelial cells from children with severe asthma. This last finding points to the age of patients as a confounding factor, which may be crucial to understanding the biology of the SOCS proteins.…”

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confidence: 99%

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New sociology for better understanding severe eosinophilic asthma: introducing the SOCS family

Gras

Chanez

2016

Eur Respir J

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@ERSpublications SOCS proteins' involvement in severe eosinophilic asthma http://ow.ly/lG943023yxZSevere asthma is a heterogeneous condition characterised by a persistent uncontrolled situation with an inadequate response to current therapy [1]. This definition points the serious unmet needs of the patients and an urgent research effort to understand better the mechanisms sustaining this clinical condition for our community. However, severe asthma is still not identified as a distinct entity and is very heterogeneous. At present, several endotypes have been described based on the presence of upregulated cytokines leading to the recruitment, activation and increased survival of inflammatory cells such as eosinophils. One major endotype is related to T2 lymphocyte (T-helper cell type 2 and innate lymphoid cell type 2) activation, which is observed in most severe asthma patients. Fortunately, several new drugs are or have been developed to interfere with this endotype, but there are still important gaps of knowledge to be filled and clearly, other targets should be identified to develop innovative treatments [2].The SOCS (suppressors of cytokine signalling) family is composed of eight proteins, i.e. SOCS1-7 and SH2 cytokine-inducible protein (CIS) [3,4], each of which has a central SH2 domain, an amino-terminal domain of varying length and sequence, and a carboxy-terminal 40-amino-acid-long module known as the SOCS box [5]. SOCS proteins act as a substrate-recruiting component of E3-ubiquitin ligase complexes and target interacting proteins for degradation. The regulation exerted by SOCS proteins is critical to the normal functioning and cessation of the primary cytokine signal, and is achieved at many levels in the intracellular biochemical cascade [6]. Aberrant regulation of SOCS proteins has been linked to a variety of inflammatory diseases [7]. The most studied family members, CIS, SOCS1, SOCS2 and SOCS3, are important regulators of the Janus kinase ( JAK)-signal transducer and activator of transcription (STAT) pathway, and SOCS1-3 have been studied in detail, including the development of knockout mice [8][9][10]. SOCS1 is a member of this cytokine signalling pathway inhibitor family and is induced by a variety of cytokines, including interferons (IFNs). It inhibits signalling by suppression of JAK kinase activity [11] and by a promotion of the degradation of the activated cytokine-receptor complex [12]. T2-associated cytokines, such as interleukin (IL)4 or IL13, are major factors of the ongoing inflammation, including airway eosinophilia, found in severe asthma. Interestingly, they mediate their actions via the JAK-STAT pathway and are regulated by several proteins including the SOCS family.Little information is available concerning the potential role of SOCS proteins in human asthma. A polymorphism in the SOCS1 promoter has been identified by HARADA et al. [13] in a Japanese population of adult asthma patients. This polymorphism correlates with asthma severity and with increased SOCS1 expression in nasal epit...

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Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons

Cited by 86 publications

References 48 publications

Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic asthma

Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic asthma

Novel concepts in airway inflammation and remodelling in asthma

New sociology for better understanding severe eosinophilic asthma: introducing the SOCS family

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