Decreased sphingolipid synthesis in children with 17q21 asthma–risk genotypes

Ono, Jennie G.; Kim, Benjamin I.; Zhao, Yize; Christos, Paul J.; Tesfaigzi, Yohannes; Worgall, Tilla S.; Worgall, Stefan

doi:10.1172/jci130860

Cited by 53 publications

(66 citation statements)

References 32 publications

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“…Unlike the previous report, however, ICAM1 was not reduced following ORMDL3 knockdown which may suggest the influence of ORMDL3 occurs after viral binding [34,35]. ORMDL3 is also important in the regulation of endoplasmic reticulum stress and the unfolded protein response, and the regulation of levels of ceramide and sphingosine 1-sulfate [36,37]. GSDMB is highly expressed in bronchial epithelial cells from subjects with asthma and expression is correlated with disease severity.…”

Section: Geneticscontrasting

confidence: 69%

Decoding Susceptibility to Respiratory Viral Infections and Asthma Inception in Children

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Bosco

2020

IJMS

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Human Respiratory Syncytial Virus and Human Rhinovirus are the most frequent cause of respiratory tract infections in infants and children and are major triggers of acute viral bronchiolitis, wheezing and asthma exacerbations. Here, we will discuss the application of the powerful tools of systems biology to decode the molecular mechanisms that determine risk for infection and subsequent asthma. An important conceptual advance is the understanding that the innate immune system is governed by a Bow-tie architecture, where diverse input signals converge onto a few core pathways (e.g., IRF7), which in turn generate diverse outputs that orchestrate effector and regulatory functions. Molecular profiling studies in children with severe exacerbations of asthma/wheeze have identified two major immunological phenotypes. The IRF7hi phenotype is characterised by robust upregulation of antiviral response networks, and the IRF7lo phenotype is characterised by upregulation of markers of TGFβ signalling and type 2 inflammation. Similar phenotypes have been identified in infants and children with severe viral bronchiolitis. Notably, genome-wide association studies supported by experimental validation have identified key pathways that increase susceptibility to HRV infection (ORMDL3 and CHDR3) and modulate TGFβ signalling (GSDMB, TGFBR1, and SMAD3). Moreover, functional deficiencies in the activation of type I and III interferon responses are already evident at birth in children at risk of developing febrile lower respiratory tract infections and persistent asthma/wheeze, suggesting that the trajectory to asthma begins at birth or in utero. Finally, exposure to microbes and their products reprograms innate immunity and provides protection from the development of allergies and asthma in children, and therefore microbial products are logical candidates for the primary prevention of asthma.

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Section: Geneticscontrasting

confidence: 69%

Decoding Susceptibility to Respiratory Viral Infections and Asthma Inception in Children

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Bosco

2020

IJMS

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“…As ORMDL3 is a major regulator of SPT, the rate limiting enzyme that catalyzes all sphingolipid biosynthesis, we posit that increased ORMDL3 expression and dysregulation of sphingolipid levels likely exacerbates asthma through effects in multiple cell types, including T cells. Ample evidence indicates that variations in ORMDL3 expression directly affect levels of S1P and ceramides in various cells and tissues (25,58,(65)(66)(67), sometimes in unpredictable ways. Changes in membrane sphingolipids may also simply disrupt TCR signaling via alterations in lipid raft composition.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a recent study from the Worgall group quantified sphingolipids in plasma and whole blood samples in children with or without asthma, linking 17q21 SNPs associated with elevated ORMDL3 expression to lower circulating sphingolipid species (e.g. ceramides) (66). Moreover, in vitro experiments demonstrated lower de novo sphingolipid synthesis in peripheral blood cells from children with asthma compared to controls.…”

Section: Discussionmentioning

confidence: 99%

ORMDL3 and Asthma: Linking Sphingolipid Regulation to Altered T Cell Function

2020

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Orosomucoid like 3 (ORMDL3) encodes an ER-resident transmembrane protein that regulates the activity of serine palmitoyltransferase (SPT), the first and rate-limiting enzyme for sphingolipid biosynthesis in cells. A decade ago, several genome wide association studies revealed single nucleotide polymorphisms associated with increased ORMDL3 protein expression and susceptibility to allergic asthma. Since that time, numerous studies have investigated how altered ORMDL3 expression might predispose to asthma and other autoimmune/inflammatory diseases. In this brief review, we focus on growing evidence suggesting that heightened ORMDL3 expression specifically in CD4+ T lymphocytes, the central orchestrators of adaptive immunity, constitutes a major underlying mechanism of asthma pathogenesis by skewing their differentiation and function. Furthermore, we explore how sphingolipid modulation in T cells might be responsible for these effects, and how further studies may interrogate this intriguing hypothesis.

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“…A few human studies corroborate preclinical evidence of a link between sphingolipids and asthma. In a sample of pediatric asthmatics, sphingolipids were reduced in those with high-risk variants in the 17q21 locus that promotes expression of ORMDL3 and in those with non-allergic asthma in comparison to those with allergic asthma or healthy controls [99]. De novo sphingolipid synthesis was also lower in children with asthma than controls [99].…”

Section: Sphingolipidsmentioning

confidence: 93%

“…In a sample of pediatric asthmatics, sphingolipids were reduced in those with high-risk variants in the 17q21 locus that promotes expression of ORMDL3 and in those with non-allergic asthma in comparison to those with allergic asthma or healthy controls [99]. De novo sphingolipid synthesis was also lower in children with asthma than controls [99]. In another human study, circulating sphingolipids were inversely associated with childhood asthma and recurrent wheeze, and those with high-risk ORMDL3 expression-promoting genetic variants exhibited limited benefit from vitamin D supplementation in comparison to those with low-risk variants [100].…”

Section: Sphingolipidsmentioning

confidence: 96%

Gut Microbial-Derived Metabolomics of Asthma

et al. 2020

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In this review, we discuss gut microbial-derived metabolites involved with the origins and pathophysiology of asthma, a chronic respiratory disease that is influenced by the microbiome. Although both gut and airway microbiomes may be important in asthma development, we focus here on the gut microbiome and metabolomic pathways involved in immune system ontogeny. Metabolite classes with existing evidence that microbial-derived products influence asthma risk include short chain fatty acids, polyunsaturated fatty acids and bile acids. While tryptophan metabolites and sphingolipids have known associations with asthma, additional research is needed to clarify the extent to which the microbiome contributes to the effects of these metabolites on asthma. These metabolite classes can influence immune function in one of two ways: (i) promoting growth or maturity of certain immune cell populations or (ii) influencing antigenic load by enhancing the number or species of specific bacteria. A more comprehensive understanding of how gut microbes and metabolites interact to modify asthma risk and morbidity will pave the way for targeted diagnostics and treatments. Introduction: Microbiome-Metabolome Associations in AsthmaAsthma and other allergic diseases have well known associations with early life environmental exposures that modify the gut microbiota, such as living on a farm, mode of delivery, breastfeeding status and having a dog in the home [1]. As mounting animal and human data point to a prominent role of the gut microbiome in asthma development [2], relevant metabolomic mechanisms behind this association are beginning to be elucidated [3]. Integration of metabolomic data with gut microbiome data has been particularly fruitful in understanding the gut-lung axis as it pertains to asthma. Here, we review a set of metabolites and metabolite groups that appear to link the gut microbiota with asthma development and pathophysiology and immune system ontology. Some of these classes, such as short chain fatty acids, are relatively well-studied and understood, while others, including the sphingolipids, include more numerous metabolites with less straightforward relationships to asthma and allergy. While we focus here on the metabolite classes most prominently discussed in today's literature, future unbiased studies of asthma metabolomics are likely to identify additional important pathways.

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Decreased sphingolipid synthesis in children with 17q21 asthma–risk genotypes

Cited by 53 publications

References 32 publications

Decoding Susceptibility to Respiratory Viral Infections and Asthma Inception in Children

Decoding Susceptibility to Respiratory Viral Infections and Asthma Inception in Children

ORMDL3 and Asthma: Linking Sphingolipid Regulation to Altered T Cell Function

Gut Microbial-Derived Metabolomics of Asthma

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