Notch signaling licenses allergic airway inflammation by promoting Th2 cell lymph node egress

Tindemans, Irma; Schoonhoven, Anne van; KleinJan, Alex; Bruijn, Marjolein J. W. de; Lukkes, Melanie; Nimwegen, Menno van; Branden, Anouk van den; Bergen, Ingrid M.; Corneth, Odilia B. J.; IJcken, Wilfred F. J. van; Stadhouders, Ralph; Hendriks, Rudolf W.

doi:10.1172/jci128310

Cited by 23 publications

(14 citation statements)

References 65 publications

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“…Other studies have also reported that pharmacologic inhibitors of Notch signaling can reduce allergic pulmonary inflammation by modulating Th1 and/or Th2 responses (203,207,208). These observations may be mechanistically explained by a critical requirement for Notch to license the Th2 response via promoting lymph node egress of effector Th2 cells (209). Moreover IL-17-producing T helper cells (Th17) are important players in asthma pathogenesis (203).…”

Section: Allergic Asthmamentioning

confidence: 97%

Targeting the Notch Signaling Pathway in Chronic Inflammatory Diseases

et al. 2021

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The Notch signaling pathway regulates developmental cell-fate decisions and has recently also been linked to inflammatory diseases. Although therapies targeting Notch signaling in inflammation in theory are attractive, their design and implementation have proven difficult, at least partly due to the broad involvement of Notch signaling in regenerative and homeostatic processes. In this review, we summarize the supporting role of Notch signaling in various inflammation-driven diseases, and highlight efforts to intervene with this pathway by targeting Notch ligands and/or receptors with distinct therapeutic strategies, including antibody designs. We discuss this in light of lessons learned from Notch targeting in cancer treatment. Finally, we elaborate on the impact of individual Notch members in inflammation, which may lay the foundation for development of therapeutic strategies in chronic inflammatory diseases.

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Section: Allergic Asthmamentioning

confidence: 97%

Targeting the Notch Signaling Pathway in Chronic Inflammatory Diseases

et al. 2021

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“…Recent work is expanding our understanding of Notch signaling in asthma, revealing new mechanisms and unexpected players. Tindemans et al (2020) used a house dust mite mouse model of allergic airway inflammation to document genetically a major pathogenic role of Notch1 and Notch2 in T cells. Interestingly, transgenic Gata3 expression in Notch1/2-deficient or Rbpj-deficient T cells only had a limited impact on their phenotype, suggesting Gata3-independent effects of canonical Notch signals.…”

Section: Asthma and Allergic Airway Inflammationmentioning

confidence: 99%

Therapeutic Targeting of Notch Signaling: From Cancer to Inflammatory Disorders

Allen

Maillard

2021

Front. Cell Dev. Biol.

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Over the past two decades, the Notch signaling pathway has been investigated as a therapeutic target for the treatment of cancers, and more recently in the context of immune and inflammatory disorders. Notch is an evolutionary conserved pathway found in all metazoans that is critical for proper embryonic development and for the postnatal maintenance of selected tissues. Through cell-to-cell contacts, Notch orchestrates cell fate decisions and differentiation in non-hematopoietic and hematopoietic cell types, regulates immune cell development, and is integral to shaping the amplitude as well as the quality of different types of immune responses. Depriving some cancer types of Notch signals has been shown in preclinical studies to stunt tumor growth, consistent with an oncogenic function of Notch signaling. In addition, therapeutically antagonizing Notch signals showed preclinical potential to prevent or reverse inflammatory disorders, including autoimmune diseases, allergic inflammation and immune complications of life-saving procedures such allogeneic bone marrow and solid organ transplantation (graft-versus-host disease and graft rejection). In this review, we discuss some of these unique approaches, along with the successes and challenges encountered so far to target Notch signaling in preclinical and early clinical studies. Our goal is to emphasize lessons learned to provide guidance about emerging strategies of Notch-based therapeutics that could be deployed safely and efficiently in patients with immune and inflammatory disorders.

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“…While Notch-deficient Th2 cells were prevented from invading the lung in a house dust mite driven, eosinophilic airway inflammation model, these Th2 cells could not leave the lymph node due to a lack of KLF2 and its downstream target S1PR1. They concluded, that in allergic airway inflammation, the Notch signaling pathway led to a KLF2-regulated, S1PR1-mediated egress of Th2 cells from the LN (Table A1) [79].…”

Section: Klf2 and T Cells In Diseasesmentioning

confidence: 99%

Krüppel-like Factor 2 (KLF2) in Immune Cell Migration

Wittner

Schuh

2021

Vaccines

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Krüppel-like factor 2 (KLF2), a transcription factor of the krüppel-like family, is a key regulator of activation, differentiation, and migration processes in various cell types. In this review, we focus on the functional relevance of KLF2 in immune cell migration and homing. We summarize the key functions of KLF2 in the regulation of chemokine receptors and adhesion molecules and discuss the relevance of the KLF2-mediated control of immune cell migration in the context of immune responses, infections, and diseases.

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Notch signaling licenses allergic airway inflammation by promoting Th2 cell lymph node egress

Cited by 23 publications

References 65 publications

Targeting the Notch Signaling Pathway in Chronic Inflammatory Diseases

Targeting the Notch Signaling Pathway in Chronic Inflammatory Diseases

Therapeutic Targeting of Notch Signaling: From Cancer to Inflammatory Disorders

Krüppel-like Factor 2 (KLF2) in Immune Cell Migration

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