Toll-like receptor ligands and atopy: A coin with at least two sides

Horner, Anthony A.

doi:10.1016/j.jaci.2006.02.035

Cited by 44 publications

(51 citation statements)

References 78 publications

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Section: Introductionmentioning

confidence: 99%

“…The different signaling pathways employ different protein kinase complexes and show distinct cytokine profiles, but all activate NF-κB [4]. In addition to their role in pathogen defense, TLRs also play a dominant role in innate responses to noninfectious immunostimulatory components present in our environment [2,[5][6][7], making them important mediators in atopic reactions. Glucocorticoid-induced leucine zipper (GILZ) was first described in 1997 as a glucocorticoid-inducible gene [8].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, noninfectious diseases such as chronic obstructive pulmonary disCorrespondence: Prof. Alexandra K. Kiemer e-mail: pharm.bio.kiemer@mx.uni-saarland.de ease (COPD) are characterized by chronic inflammatory processes. Asthma and allergic diseases are other examples of chronic inflammatory lung diseases with major clinical relevance [1,2].Toll-like receptors (TLRs) represent an important family of innate immune receptors, which act as a first line of defense of host immunity against various pathogens. Presently, ten human TLRs are known, which recognize pathogen-associated molecular patterns including bacterial cell wall components, such as lipoproteins (TLR1/2 or TLR1/6 dimers) or lipopolysaccharide (LPS, TLR4), C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur.…”

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Glucocorticoid‐induced leucine zipper is downregulated in human alveolar macrophages upon Toll‐like receptor activation

et al. 2012

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Induction of the glucocorticoid-induced leucine zipper (GILZ) by glucocorticoids plays a role in their antiinflammatory action, whereas GILZ expression is reduced under inflammatory conditions. The mechanisms regulating GILZ expression during inflammation, however, have not yet been characterized. Here, we investigated GILZ expression in human alveolar macrophages (AMs) following Toll-like receptor (TLR) activation. Macrophages were shown to predominantly express GILZ transcript variant 2. Lipopolysaccharide-treated AMs, THP-1 cells, and lungs of lipopolysaccharide-exposed mice displayed decreased GILZ protein and mRNA levels. The effect was strictly dependent on the adapter molecule MyD88, as shown by using specific ligands or a knockdown strategy. Investigations on the functional significance of GILZ downregulation performed by GILZ knockdown revealed a proinflammatory response, as indicated by increased cytokine expression and NF-κB activity. We found that TLR activation reduced GILZ mRNA stability, which was mediated via the GILZ 3 -untranslated region. Finally, involvement of the mRNA-binding protein tristetraprolin (TTP) is suggested, since TTP overexpression or knockdown modulated GILZ expression and TTP was induced in a MyD88-dependent fashion. Taken together, our data show a MyD88-and TTP-dependent GILZ downregulation in human macrophages upon TLR activation. Suppression of GILZ is mediated by mRNA destabilization, which might represent a regulatory mechanism in macrophage activation.Keywords: GILZ transcript variants · Inflammation · Innate immunity · mRNA stability · Pulmonary macrophages IntroductionInflammatory processes in the lung play an important role in different diseases, such as viral and bacterial infections. Moreover, noninfectious diseases such as chronic obstructive pulmonary disCorrespondence: Prof. Alexandra K. Kiemer e-mail: pharm.bio.kiemer@mx.uni-saarland.de ease (COPD) are characterized by chronic inflammatory processes. Asthma and allergic diseases are other examples of chronic inflammatory lung diseases with major clinical relevance [1,2].Toll-like receptors (TLRs) represent an important family of innate immune receptors, which act as a first line of defense of host immunity against various pathogens. Presently, ten human TLRs are known, which recognize pathogen-associated molecular patterns including bacterial cell wall components, such as lipoproteins (TLR1/2 or TLR1/6 dimers) or lipopolysaccharide (LPS, TLR4), C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1282-1293 Innate immunity 1283 bacterial flagellin (TLR5), viral RNA (TLR3, 7 and 8), as well as bacterial DNA (TLR9) [3]. Except for TLR3, all TLRs signal via the adapter molecule MyD88. The MyD88-independent pathway used by TLR3 can also be utilized by TLR4. The different signaling pathways employ different protein kinase complexes and show distinct cytokine profiles, but all activate NF-κB [4]. In addition to their role in pathogen defense, TLRs also play a dominant role in ...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Glucocorticoid‐induced leucine zipper is downregulated in human alveolar macrophages upon Toll‐like receptor activation

et al. 2012

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“…While the exact mechanisms dictating this immune modulation are not known, it is generally accepted that the role LPS plays in asthma severity depends on the dose and timing of exposure [4]. This is further highlighted by the hygiene hypothesis, which asserts that early exposure to high levels of innate immune activating compounds can protect against the onset of atopy, while lack of exposure can increase the risk of developing allergic diseases [5,6]. This has been postulated as an underlying cause for increased asthma incidence and severity in developed countries.…”

Section: Introductionmentioning

confidence: 99%

Pulmonary Endotoxin Tolerance Protects against Cockroach Allergen-Induced Asthma-Like Inflammation in a Mouse Model

Natarajan

Kim²,

Bouchard³

et al. 2012

Int Arch Allergy Immunol

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Background: Compounds which activate the innate immune system, such as lipopolysaccharide, are significant components of ambient air, and extremely difficult to remove from the environment. It is currently unclear how prior inhalation of endotoxin affects allergen sensitization. We examined whether lung-specific endotoxin tolerance induction prior to sensitization can modulate the response to allergen. Methods: Endotoxin tolerance was induced by repeated intratracheal exposure to endotoxin. All mice were then sensitized and challenged by direct intratracheal instillation of cockroach allergen. Results: After allergen sensitization and challenge, endotoxin tolerant mice had significantly decreased airways hyperresponsiveness to methacholine challenge, which was confirmed by invasive lung function tests. Decreased goblet cell hyperplasia and mucus production were also found by histological assessment. Tolerant mice were protected from airway eosinophilia through the mechanism of reduced CCL11 and CCL24. Interestingly, endotoxin tolerant mice had only a modest reduction in cockroach-specific IgE; however, total IgE was significantly reduced. Conclusions: These data show that induction of endotoxin tolerance prior to sensitization protects against the hallmark features of asthma-like inflammation, and that transient modulation of innate immunity can have long-lasting effects on adaptive responses.

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IntroductionAsthma and other allergic diseases have become far more common in industrialized countries in recent decades, while atopy rates remain low in less developed countries [1][2][3] . Although reasons for these trends remain speculative, the rapidity with which allergic disease prevalence has increased in affected countries strongly suggests environmental factors are responsible.

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confidence: 99%

Regulation of Aeroallergen Immunity by the Innate Immune System: Laboratory Evidence for a New Paradigm

Horner

2009

J Innate Immun

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Over the last decade, it has become increasingly clear that innate responses to microbes are mediated largely by toll-like receptors (TLRs), which recognize a diverse family of molecules produced by viruses, bacteria and fungi. This article will present evidence that TLRs also play a dominant role in innate responses to non-infectious immunostimulatory materials present in house dust extracts (HDEs) and the living environments they represent. However, our investigations challenge the commonly held view that microbial products in ambient air protect against the allergic march by promoting protective Th1 biased responses to inspired aeroallergens. Instead, all HDEs studied to date have preferentially promoted the development of Th2 biased airway hypersensitivities when used as adjuvants for intranasal (i.n.) vaccination. In contrast, daily low dose i.n. HDE delivery was found to promote the development of aeroallergen tolerance. This article will review these experimental findings as evidence to propose a new paradigm by which airborne TLR ligands and other stimulants of innate immunity may influence aeroallergen specific immunity and the genesis of allergic respiratory diseases.

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Toll-like receptor ligands and atopy: A coin with at least two sides

Cited by 44 publications

References 78 publications

Glucocorticoid‐induced leucine zipper is downregulated in human alveolar macrophages upon Toll‐like receptor activation

Glucocorticoid‐induced leucine zipper is downregulated in human alveolar macrophages upon Toll‐like receptor activation

Pulmonary Endotoxin Tolerance Protects against Cockroach Allergen-Induced Asthma-Like Inflammation in a Mouse Model

Regulation of Aeroallergen Immunity by the Innate Immune System: Laboratory Evidence for a New Paradigm

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