TSLP Inhibitors for Asthma: Current Status and Future Prospects

Matera, Maria Gabriella; Rogliani, Paola; Calzetta, Luigino; Cazzola, Mario

doi:10.1007/s40265-020-01273-4

Cited by 61 publications

(40 citation statements)

References 58 publications

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“…Hence, these studies suggest the role of TSLP as a crucial mediator of AD pathogenesis [ 31 ] and a potential drug target [ 32 ]. Various therapeutic agents that prevent TSLP function can effectively relieve clinical symptoms [ 33 ]. TSLP expression is regulated by various cytokines, including pro-inflammatory cytokines, such as TNFα and IL-1, and Th2-related cytokines, such as IL-4, IL-13, and IL-33 [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes

Yeo

Lee

Ahn

et al. 2021

IJMS

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Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that acts as a critical mediator in the pathogenesis of atopic dermatitis (AD). Various therapeutic agents that prevent TSLP function can efficiently relieve the clinical symptoms of AD. However, the downregulation of TSLP expression by therapeutic agents remains poorly understood. In this study, we investigated the mode of action of chrysin in TSLP suppression in an AD-like inflammatory environment. We observed that the transcription factor early growth response (EGR1) contributed to the tumor necrosis factor alpha (TNFα)-induced transcription of TSLP. Chrysin attenuated TNFα-induced TSLP expression by downregulating EGR1 expression in HaCaT keratinocytes. We also showed that the oral administration of chrysin improved AD-like skin lesions in the ear and neck of BALB/c mice challenged with 2,4-dinitrochlorobenzene. We also showed that chrysin suppressed the expression of EGR1 and TSLP by inhibiting the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 mitogen-activated protein kinase pathways. Collectively, the findings of this study suggest that chrysin improves AD-like skin lesions, at least in part, through the downregulation of the ERK1/2 or JNK1/2-EGR1-TSLP signaling axis in keratinocytes.

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Section: Introductionmentioning

confidence: 99%

Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes

Yeo

Lee

Ahn

et al. 2021

IJMS

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“…Originally identified in thymic stromal cells, TSLP is an innate pleiotropic cytokine belonging to the four-helix-bundle cytokine family and is distantly related to interleukin-7 (IL-7) [ 29 ]. Two TSLP variants exist, including a long isoform (159 amino acids) and a short one (60 amino acids), whose expressions are respectively regulated by different gene promoters, which are responsive to distinct patterns of environmental agents [ 30 , 31 ]. Short TSLP is constitutively present in many tissues where it plays a homeostatic role, whilst the production of the long isoform can be induced by proinflammatory stimuli and is increased in asthmatic patients [ 31 ].…”

Section: Pathogenic Role Of Tslp In Asthmamentioning

confidence: 99%

Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma

Pelaia

Crimi

et al. 2021

IJMS

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Thymic stromal lymphopoietin (TSLP) is an innate cytokine, belonging to the group of alarmins, which plays a key pathogenic role in asthma by acting as an upstream activator of cellular and molecular pathways leading to type 2 (T2-high) airway inflammation. Released from airway epithelial cells upon tissue damage induced by several noxious agents including allergens, viruses, bacteria, and airborne pollutants, TSLP activates dendritic cells and group 2 innate lymphoid cells involved in the pathobiology of T2-high asthma. Tezepelumab is a fully human monoclonal antibody that binds to TSLP, thereby preventing its interaction with the TSLP receptor complex. Preliminary results of randomized clinical trials suggest that tezepelumab is characterized by a good safety and efficacy profile in patients with severe, uncontrolled asthma.

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“…Within this context, a key role is played by the innate cytokines known as alarmins, including TSLP, IL-33, and IL-25 (142). So far, the most extensively studied alarmin as suitable target for novel biological therapies of asthma has been TSLP (13,143).…”

Section: Targets Of Emerging Biological Therapies In Clinical Developmentioning

confidence: 99%

Molecular Targets for Biological Therapies of Severe Asthma

et al. 2020

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Asthma is a heterogeneous respiratory disease characterized by usually reversible bronchial obstruction, which is clinically expressed by different phenotypes driven by complex pathobiological mechanisms (endotypes). Within this context, during the last years several molecular effectors and signalling pathways have emerged as suitable targets for biological therapies of severe asthma, refractory to standard treatments. Indeed, various therapeutic antibodies currently allow to intercept at different levels the chain of pathogenic events leading to type 2 (T2) airway inflammation. In addition to pro-allergic immunoglobulin E (IgE), that chronologically represents the first molecule against which an anti-asthma monoclonal antibody (omalizumab) was developed, today other targets are successfully exploited by biological treatments of severe asthma. In particular, pro-eosinophilic interleukin 5 (IL-5) can be targeted by mepolizumab or reslizumab, whereas benralizumab is a selective blocker of IL-5 receptor. Moreover, dupilumab behaves as a dual receptor antagonist of pleiotropic interleukins 4 (IL-4) and 13 (IL-13). Besides these drugs that are already available in medical practice, other biologics are under clinical development such as those targeting innate cytokines, also including the alarmin thymic stromal lymphopoietin (TSLP), which plays a key role in the pathogenesis of type 2 asthma. Therefore, ongoing and future biological therapies are significantly changing the global scenario of severe asthma management. These new therapeutic options make it possible to implement phenotype/endotype-specific treatments, that are delineating personalized approaches precisely addressing the individual traits of asthma pathobiology. Such tailored strategies are thus allowing to successfully target the immune-inflammatory responses underlying uncontrolled T2-high asthma.

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TSLP Inhibitors for Asthma: Current Status and Future Prospects

Cited by 61 publications

References 58 publications

Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes

Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes

Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma

Molecular Targets for Biological Therapies of Severe Asthma

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