IL-17 in Severe Asthma. Where Do We Stand?

Chesné, Julie; Braza, Faouzi; Mahay, Guillaume; Brouard, Sophie; Aronica, Marc; Magnan, A.

doi:10.1164/rccm.201405-0859pp

Cited by 295 publications

(215 citation statements)

References 89 publications

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“…ERK5 has been identified to be part of an IL-17-mediated signaling cascade that drives keratinocyte proliferation and tumorigenesis (39). IL-17A is also overexpressed in conditions of chronic inflammation such as asthma and is thought to mediate airway neutrophilia through the induction of additional cytokines from target cells (40)(41)(42). After preincubation with compound, BEAS-2B cells were stimulated with the proinflammatory cytokine IL-17A.…”

Section: Resultsmentioning

confidence: 99%

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Lin¹,

Amantea²,

Nomanbhoy³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal, and tissue-restricted deletions have profound effects on erythroid development, cardiac function, and neurogenesis. In addition, depletion of ERK5 is antiinflammatory and antitumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no antiinflammatory or antiproliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains, conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a noncatalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity and delineate which can be pharmacologically targeted.) is a member of the mitogen-activated protein kinase (MAPK) family, which includes ERK1/2, JNK1/2/3, and p38α/β/δ/γ (1). However, unlike the other MAPK members, ERK5 contains a unique 400-amino-acid C-terminal domain in addition to the kinase domain. Through the MAPK signaling cascade, mitogenactivated protein kinase kinase 5 (MEK5) activates ERK5 by phosphorylating the TEY motif in the N-terminal activation loop (2). This event unlocks the N-and C-terminal halves, allowing ERK5 to auto-phosphorylate multiple sites in its C-terminal region, which can then regulate nuclear shuttling and gene transcription (3, 4). Noncanonical pathways (including cyclin-dependent kinases during mitosis and ERK1/2 during growth factor stimulation) also exist for phosphorylation of sites in the ERK5 tail (5-7). Although ERK5 has been demonstrated to directly phosphorylate transcription factors (8-10), the noncatalytic C-terminal tail of ERK5 can also interact with transcription factors and influence gene expression (4,11,12).ERK5 can be activated in response to a range of mitogenic stimuli [e.g., growth factors, G protein-coupled receptor (GPCR) agonists, cytokines] and cellular stresses (e.g., hypoxia, shear stress) (13). Like most kinases including MAPK members, ERK5 function is assumed to be driven by its kinase activity. ERK5 deletion is embryonic lethal in mice and a variety of tissue-or development-stage restricted KOs have shown clear phenotypes, suggesting that the catalytic function and/or an aspect of the nonkinase domain(s) have key roles in development and mature organ function (14-18). The availability of the first ERK5 inhibitor ...

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Section: Resultsmentioning

confidence: 99%

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Lin¹,

Amantea²,

Nomanbhoy³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…It is typically well controlled with b2-receptor agonists and corticosteroids. However, 5-10% of asthmatics have particularly poorly controlled severe disease that is frequently associated with a neutrophilic infiltrate alongside elevated levels of IL-17A, the prototypical cytokine of T helper 17 (Th17) cells, throughout the airways (1). Chronic obstructive pulmonary disease (COPD), another respiratory disease that is predicted to be the third leading cause of mortality by 2020, is also characterized by elevated levels of IL-17A in the bronchial submucosa and peripheral blood (2).…”

Section: Clinical Relevancementioning

confidence: 99%

Vitamin D Counteracts an IL-23–Dependent IL-17A⁺IFN-γ⁺ Response Driven by Urban Particulate Matter

Mann

Pfeffer

et al. 2017

Am J Respir Cell Mol Biol

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Urban particulate matter (UPM) air pollution and vitamin D deficiency are detrimentally associated with respiratory health. This is hypothesized to be due in part to regulation of IL-17A, which UPM is reported to promote. Here, we used a myeloid dendritic cell (DC)-memory CD41 T cell co-culture system to characterize UPM-driven IL-17A 1 cells, investigate the mechanism by which UPM-primed DCs promote this phenotype, and address evidence for crossregulation by vitamin D. Clinical RelevanceUrban particulate matter air pollution and vitamin D deficiency are both detrimentally associated with airway function. This research describes an IL-23-dependent pathway by which urban particulate matter promotes a proinflammatory T helper 17 cell response, which is predicted to exacerbate respiratory diseases, and the capacity of vitamin D to oppose this effect. This supports the concept that restoring vitamin D sufficiency will help to counteract the detrimental properties of air pollution to maintain immune homeostasis.

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“…They are increased during infection induced exacerbations, yet use of the anti-inflammatory macrolide azithromycin has proved disappointing [49,50]. Neutrophilic inflammation is particularly associated with Th17 responses and disease severity in asthma [51]. However, much of these data come from murine models that have used ovalbumin and therefore translation to patients is questionable.…”

Section: The Role Of Neutrophils In Asthma and Relationships With Remmentioning

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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IL-17 in Severe Asthma. Where Do We Stand?

Cited by 295 publications

References 89 publications

ERK5 kinase activity is dispensable for cellular immune response and proliferation

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Vitamin D Counteracts an IL-23–Dependent IL-17A⁺IFN-γ⁺ Response Driven by Urban Particulate Matter

Novel concepts in airway inflammation and remodelling in asthma

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IL-17 in Severe Asthma. Where Do We Stand?

Cited by 295 publications

References 89 publications

ERK5 kinase activity is dispensable for cellular immune response and proliferation

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Vitamin D Counteracts an IL-23–Dependent IL-17A+IFN-γ+ Response Driven by Urban Particulate Matter

Novel concepts in airway inflammation and remodelling in asthma

Contact Info

Product

Resources

About

Vitamin D Counteracts an IL-23–Dependent IL-17A⁺IFN-γ⁺ Response Driven by Urban Particulate Matter