Regulatory T Cells Limit Pneumococcus-Induced Exacerbation of Lung Fibrosis in Mice

Moyé, Steffi; Bormann, Tina; Maus, Regina; Sparwasser, Tim; Sandrock, Inga; Prinz, Immo; Warnecke, G.; Welte, Tobias; Gauldie, Jack; Kolb, Martin; Maus, Ulrich A.

doi:10.4049/jimmunol.1900980

Cited by 23 publications

(13 citation statements)

References 43 publications

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“…Moreover, depletion of Tregs by anti-CD25 antibodies at a late stage increased fibrotic scores and hydroxyproline content in the lungs of bleomycin-treated mice, suggesting a protective role of Tregs in pulmonary fibrosis [ 98 ]. Similarly, Tregs played a protective role against pneumococcus-induced lung fibrosis in mice [ 99 ]. Depletion of Tregs by diphtheria toxin resulted in increased lung collagen deposition, elevated Th1/Th2 cytokine levels and exacerbated infection-induced pulmonary fibrosis [ 99 ].…”

Section: Adaptive Immune Cells In the Pathogenesis Of Fibrosismentioning

confidence: 99%

“…Similarly, Tregs played a protective role against pneumococcus-induced lung fibrosis in mice [ 99 ]. Depletion of Tregs by diphtheria toxin resulted in increased lung collagen deposition, elevated Th1/Th2 cytokine levels and exacerbated infection-induced pulmonary fibrosis [ 99 ]. However, Tregs expansion markedly attenuated pneumococcus-induced fibrosis in mice [ 99 ].…”

Section: Adaptive Immune Cells In the Pathogenesis Of Fibrosismentioning

confidence: 99%

“…Depletion of Tregs by diphtheria toxin resulted in increased lung collagen deposition, elevated Th1/Th2 cytokine levels and exacerbated infection-induced pulmonary fibrosis [ 99 ]. However, Tregs expansion markedly attenuated pneumococcus-induced fibrosis in mice [ 99 ]. Tregs suppressed TGF-β-induced pulmonary fibrosis through decreasing fibroblast growth factor 9 (FGF-9) expression by parenchymal cells and alveolar macrophages [ 100 ].…”

Section: Adaptive Immune Cells In the Pathogenesis Of Fibrosismentioning

confidence: 99%

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The Roles of Immune Cells in the Pathogenesis of Fibrosis

Huang

Peng

Xiao

et al. 2020

IJMS

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Tissue injury and inflammatory response trigger the development of fibrosis in various diseases. It has been recognized that both innate and adaptive immune cells are important players with multifaceted functions in fibrogenesis. The activated immune cells produce various cytokines, modulate the differentiation and functions of myofibroblasts via diverse molecular mechanisms, and regulate fibrotic development. The immune cells exhibit differential functions during different stages of fibrotic diseases. In this review, we summarized recent advances in understanding the roles of immune cells in regulating fibrotic development and immune-based therapies in different disorders and discuss the underlying molecular mechanisms with a focus on mTOR and JAK-STAT signaling pathways.

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Section: Adaptive Immune Cells In the Pathogenesis Of Fibrosismentioning

confidence: 99%

Section: Adaptive Immune Cells In the Pathogenesis Of Fibrosismentioning

confidence: 99%

Section: Adaptive Immune Cells In the Pathogenesis Of Fibrosismentioning

confidence: 99%

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The Roles of Immune Cells in the Pathogenesis of Fibrosis

Huang

Peng

Xiao

et al. 2020

IJMS

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“…Male C57BL6 mice aged between 8 and 12 weeks at the time point of the first infection were infected once or twice with an intranasal inoculum containing 1–1.5×10 6 CFU S. pneumoniae isolate 89/17 tested for a high macrolide resistance (MIC 256 μg/ml) under ketamine/xylazine anesthesia. S. pneumoniae was grown, as recently described [ 47 ], and CFU contained in the inoculum was determined as described before [ 48 ]. To allow the inoculum to reach the lungs, mice were kept in a vertical position for around 1 min.…”

Section: Methodsmentioning

confidence: 99%

Clarithromycin impairs tissue-resident memory and Th17 responses to macrolide-resistant Streptococcus pneumoniae infections

et al. 2021

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The increasing prevalence of antimicrobial resistance in pathogens is a growing public health concern, with the potential to compromise the success of infectious disease treatments in the future. Particularly, the number of infections by macrolide antibiotics-resistant Streptococcus pneumoniae is increasing. We show here that Clarithromycin impairs both the frequencies and number of interleukin (IL)-17 producing T helper (Th) 17 cells within the lungs of mice infected with a macrolide-resistant S. pneumoniae serotype 15A strain. Subsequently, the tissue-resident memory CD4+ T cell (Trm) response to a consecutive S. pneumoniae infection was impaired. The number of lung resident IL-17+ CD69+ Trm was diminished upon Clarithromycin treatment during reinfection. Mechanistically, Clarithromycin attenuated phosphorylation of the p90-S6-kinase as part of the ERK pathway in Th17 cells. Moreover, a strong increase in the mitochondrial-mediated maximal respiratory capacity was observed, while mitochondrial protein translation and mTOR sisgnaling were unimpaired. Therefore, treatment with macrolide antibiotics may favor the spread of antimicrobial-resistant pathogens not only by applying a selection pressure but also by decreasing the natural T cell immune response. Clinical administration of macrolide antibiotics as standard therapy procedure during initial hospitalization should be reconsidered accordingly and possibly be withheld until microbial resistance is determined. Key messages • Macrolide-resistant S. pneumoniae infection undergoes immunomodulation by Clarithromycin • Clarithromycin treatment hinders Th17 and tissue-resident memory responses • Macrolide antibiotics impair Th17 differentiation in vitro by ERK-pathway inhibition

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“…Moyé and collaborators, in a mice model of IPF, studied the potential role of Tregs in the modulation of infection-driven AE-IPF. They observed that Treg depletion worsened the severity of AE-IPF, whereas IL-2 complex-induced expansion of Tregs leads to an attenuation, suggesting that Tregs could act as a regulator of the immune response during AE-IPF through downregulation of lung inflammatory cytokines, including TNF-α, IL-6, and TGF-β [107]. Finally, AE-ILDs result in acute respiratory failure and severe hypoxemia due to an increased intrapulmonary shunt, with consequent strong activation of the respiratory drive.…”

Section: Severe Exacerbations Of Ildmentioning

confidence: 99%

COPD, Pulmonary Fibrosis and ILAs in Aging Smokers: The Paradox of Striking Different Responses to the Major Risk Factors

Beghè

Cerri

Fabbri

et al. 2021

IJMS

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Aging and smoking are associated with the progressive development of three main pulmonary diseases: chronic obstructive pulmonary disease (COPD), interstitial lung abnormalities (ILAs), and idiopathic pulmonary fibrosis (IPF). All three manifest mainly after the age of 60 years, but with different natural histories and prevalence: COPD prevalence increases with age to >40%, ILA prevalence is 8%, and IPF, a rare disease, is 0.0005–0.002%. While COPD and ILAs may be associated with gradual progression and mortality, the natural history of IPF remains obscure, with a worse prognosis and life expectancy of 2–5 years from diagnosis. Acute exacerbations are significant events in both COPD and IPF, with a much worse prognosis in IPF. This perspective discusses the paradox of the striking pathological and pathophysiologic responses on the background of the same main risk factors, aging and smoking, suggesting two distinct pathophysiologic processes for COPD and ILAs on one side and IPF on the other side. Pathologically, COPD is characterized by small airways fibrosis and remodeling, with the destruction of the lung parenchyma. By contrast, IPF almost exclusively affects the lung parenchyma and interstitium. ILAs are a heterogenous group of diseases, a minority of which present with the alveolar and interstitial abnormalities of interstitial lung disease.

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Regulatory T Cells Limit Pneumococcus-Induced Exacerbation of Lung Fibrosis in Mice

Abstract: The current study has been funded by the Bundesministerium für Bildung und Forschung supporting the German Center for Lung Research (Deutsches Zentrum für Lungenforschung).

Cited by 23 publications

References 43 publications

The Roles of Immune Cells in the Pathogenesis of Fibrosis

The Roles of Immune Cells in the Pathogenesis of Fibrosis

Clarithromycin impairs tissue-resident memory and Th17 responses to macrolide-resistant Streptococcus pneumoniae infections

COPD, Pulmonary Fibrosis and ILAs in Aging Smokers: The Paradox of Striking Different Responses to the Major Risk Factors

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