Constitutive immune activity promotes JNK- and FoxO-dependent remodeling of Drosophila airways

Wagner, Christina; Uliczka, Karin; Bossen, Judith; Niu, Xiao; Fink, Christine; Thiedmann, Marcus; Knop, Mirjam; Vock, Christina; Abdelsadik, Ahmed; Zissler, Ulrich M.; Isermann, Kerstin; Garn, Holger; Pieper, Mario; Wegmann, Michael; Koczulla, Andreas Rembert; Vogelmeier, Claus; Schmidt‐Weber, Carsten B.; Fehrenbach, Heinz; König, Peter; Silverman, Neil; Renz, Harald; Pfefferle, Petra Ina; Heine, Holger; Roeder, Thomas

doi:10.1016/j.celrep.2021.108956

Cited by 22 publications

(14 citation statements)

References 74 publications

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“…Th2, Th9 and Th17 cell recruitment upon allergen challenge 39 was reduced in absence of TGFBR2 along with respective transcription factors PU.1 (Th9) and GATA3 (Th2). Moreover, the transcription factor FOXO1, which was recently described to be essential for IL-9 production and Th9 cell differentiation, thus promoting airway allergy 25,40,41 , was clearly reduced upon TGFBR2-ablation. This specific impact of TGFBR2depletion on T cell subsets during AAI was not limited to the respiratory system, but also extended to a systemic response measured in splenocytes.…”

Section: Discussionmentioning

confidence: 92%

TGF-β1 drives Th9 but not Treg cells upon allergen exposure

Musiol

Alessandrini

Jakwerth

et al. 2021

Preprint

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TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β acts in AAI by driving effector T cells into Th9 cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the TGFβ-receptor 2 (TGFBR2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of Th9 cell frequencies, but increased Treg cells. To translate these findings into a human clinically relevant context, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9 cell and reduced Tregs, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs.

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Section: Discussionmentioning

confidence: 92%

TGF-β1 drives Th9 but not Treg cells upon allergen exposure

Musiol

Alessandrini

Jakwerth

et al. 2021

Preprint

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“…NFAT5 is an osmosensitive transcription factor that negatively regulates IL-17 and IFN-g gene expression (71) and enhances Th2 response (72). Moreover, the transcription factor FOXO1, which was recently described to be essential for Th9 cell differentiation and IL-9 production, was clearly reduced upon Tgfbr2 ablation, correlating with reduced airway allergy (54,73,74). This specific impact of Tgfbr2 depletion on T cell subsets during AAI was not limited to the respiratory system, but also extended to a systemic response measured in splenocytes.…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Drives Inflammatory Th Cell But Not Treg Cell Compartment Upon Allergen Exposure

Musiol

Alessandrini²,

Jakwerth³

et al. 2022

Front. Immunol.

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TGF-β1 is known to have a pro-inflammatory impact by inducing Th9 and Th17 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β is a major player in AAI by driving effector T cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the gene encoding for TGFβ-receptor 2 (Tgfbr2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of pro-inflammatory T cell frequencies (Th2, Th9, Th17), but increased Treg cells. To translate these findings into a human clinically relevant context, Th2, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9, and reduced Tregs cells, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs cells.

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“…To understand the different outcomes of JNK signaling during aging, that is, its proapoptotic effects in young organisms and its cytoprotective effects in aging organisms, the upstream signaling is an important consideration. Numerous studies have revealed that JNK signaling during development and young adulthood can be activated by developmental cues as well as extrinsic or intrinsic stressors [103][104][105]. In contrast, the upstream signals that activate the JNK pathway in aging flies are less clear.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

JNK Signaling in Drosophila Aging and Longevity

Gan

Fan

Zhao

et al. 2021

IJMS

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The evolutionarily conserved c-Jun N-terminal kinase (JNK) signaling pathway is a critical genetic determinant in the control of longevity. In response to extrinsic and intrinsic stresses, JNK signaling is activated to protect cells from stress damage and promote survival. In Drosophila, global JNK upregulation can delay aging and extend lifespan, whereas tissue/organ-specific manipulation of JNK signaling impacts lifespan in a context-dependent manner. In this review, focusing on several tissues/organs that are highly associated with age-related diseases—including metabolic organs (intestine and fat body), neurons, and muscles—we summarize the distinct effects of tissue/organ-specific JNK signaling on aging and lifespan. We also highlight recent progress in elucidating the molecular mechanisms underlying the tissue-specific effects of JNK activity. Together, these studies highlight an important and comprehensive role for JNK signaling in the regulation of longevity in Drosophila.

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Constitutive immune activity promotes JNK- and FoxO-dependent remodeling of Drosophila airways

Cited by 22 publications

References 74 publications

TGF-β1 drives Th9 but not Treg cells upon allergen exposure

TGF-β1 drives Th9 but not Treg cells upon allergen exposure

TGF-β1 Drives Inflammatory Th Cell But Not Treg Cell Compartment Upon Allergen Exposure

JNK Signaling in Drosophila Aging and Longevity

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