IL-11 disrupts alveolar epithelial progenitor function

Kortekaas, Rosa K.; K, Geillinger-Kaestle; Borghuis, Theo; Belharch, Kaoutar; Webster, Megan; Timens, Wim; Burgess, Janette K.; Gosens, Reinoud

doi:10.1101/2022.11.11.516088

Cited by 3 publications

(13 citation statements)

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“…Similar as observed for iAT2 co-cultures with different seeding densities of ILD fibroblasts (Figure 1), direct treatment of alveolosphere monocultures with IL11 caused a dose dependent increase in their metabolic activity (Figure 4) associated with elevated mesenchymal markers and decreases in AT2 stemness and identity (Figure 2). High levels of IL11 (20 ng/mL) even induced apoptotic cell death (data not shown) supporting the strong induction of senescence and disturbance of stem cell function in alveolar organoids (Kortekaas et al, 2022). These results are in line with modeling Hermansky-Pudlak syndrome-associated interstitial pneumonia (HPSIP), a disease with high similarity to IPF, in iPSC-derived lung organoids shown by Strikoudis et al 2019.…”

Section: Discussionsupporting

confidence: 75%

“…IL11 alone induced fibrotic changes in healthy alveolar organoids and knock-out of IL11 expression in diseases organoids reversed organoid fibrosis (Strikoudis et al, 2019). Moreover, IL11 exposure impacts on the progenitor function that characterizes AT2s, thereby likely suppressing the formation of mature AT2s as described by Kortekaas and colleagues (Kortekaas et al, 2022; Kortekaas et al, 2021).…”

Section: Discussionmentioning

confidence: 88%

“…The top 15 differentially regulated proteins are listed in Supplementary Table 1 and 2. Upregulated proteins widely belong to the C-X-C motif chemokine family (CXCL1, CXCL3, and CXCL8) indicating pro-inflammatory signaling, leucocyte attraction and tissue remodeling (Kortekaas et al, 2022; Mukaida, 2003; Ng et al, 2020; Strikoudis et al, 2019). Furthermore, significantly regulated proteins support a pro-inflammation response indicating pro-fibrotic signaling, IL13-related responses (IL13RA) and IL11 at the center of the signaling circuit.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, the significant increase in metabolic activity was provoked by diseased human fibroblasts in high-seeding ratios, indicating their potential to impact on the metabolic program of the epithelial cell, potentially indicating epithelial dedifferentiation or EMT (Kalluri, 2009;Kalluri & Weinberg, 2009;Wang et al, 2020). These considerations are supported by the expression signature characterizing the co-cultures: The decrease in SFTPC expression (Adams et al, 2020;Katzen & Beers, 2020;Kortekaas et al, 2022;Kortekaas et al, 2021) we observed in the ILD co-cultures points towards the loss of epithelial stem cell characteristics, as SFTPC expression is sensitive to epithelial inflammation and injury, lately supported by studies in Sars-CoV-2 infected alveolar organoids (Mou, 2021). Differentiation of AT2s is key for regeneration in injured alveoli marked by their expression of transient basaloid features such as Keratin 5 (KRT5) and the amount of alveolar KRT5 + basaloid cells directly correlates with disease progression in pulmonary fibrosis (Kathiriya et al, 2022;Khan et al, 2022;Ng et al, 2022), mirrored by the decreased expression observed in our study.…”

Section: Discussionmentioning

confidence: 96%

“…Cytokines that belong to the C-X-C motif family dominated the protein signature in the secretome, demonstrating their increased abundance in ILD. These signaling molecules act on the CXCR1 and CXCR2 receptor, as well as regulate the expression of cytokines from the interleukin family, central to the pathogenesis of fibrotic and inflammatory lung diseases such as IPF and acute respiratory distress syndrome (Kortekaas et al, 2022; Mukaida, 2003; Ng et al, 2020; Strikoudis et al, 2019). The majority of the differentially abundant proteins are proinflammatory cytokines that primarily act on neutrophil, monocyte or lymphocyte recruitment ( CXCL1, CXCL3, CXCL5, CXCL8 ).…”

Section: Discussionmentioning

confidence: 99%

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Cytokine signaling converging onIL11in ILD fibroblasts provokes aberrant epithelial differentiation signatures

Kastlmeier

Rodriguez

Cabanis

et al. 2022

Preprint

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Fibrotic interstitial lung disease (ILD) is a group of lung disorders characterized by the accumulation of extracellular matrix, ultimately resulting in the destruction of the pulmonary scaffold. Continuous mesenchyme-derived profibrotic signaling perpetuates the remodeling process, specifically targeting the epithelial cell compartment, thereby destroying the gas exchange area. Studies that address this detrimental crosstalk between lung epithelial cells and fibroblasts are key to understanding ILD.With the aim of identifying functionally relevant targets that drive lung mesenchymal-epithelial crosstalk and their potential as new avenues to therapeutic strategies, we developed a 3D organoid co-culture system based on human induced pluripotent stem cell (hiPSC)-derived alveolar epithelial type 2 cells (iAT2s) and lung fibroblasts from ILD patients as well as IMR-90 controls. While organoid formation capacity and organoid size was comparable in the presence of ILD or control lung fibroblasts, metabolic activity was significantly increased in ILD co-cultures. Alveolar organoids cultured with ILD fibroblasts further demonstrated reduced stem cell function supported by reducedSurfactant Protein C (SFTPC)gene expression together with an aberrant basaloid-prone differentiation program indicated by elevatedCadherin 2 (CDH2), Bone Morphogenic Protein 4 (BMP4)andVimentin (VIM)transcription.In order to identify key mediators of the misguided mesenchymal-to-epithelial crosstalk with a focus on disease-relevant inflammatory processes, we used secretome mass spectrometry to identify key signals secreted by end stage ILD lung fibroblasts. Over 2000 proteins were detected in a single-shot experiment with 47 differentially upregulated proteins when comparing ILD and non-Chronic Lung Disease (CLD) control fibroblasts.The secretome profile was dominated by chemokines of the C-X-C motif family, including CXCL1, CXCL-3, and -8, all interfering with (epithelial) growth factor signaling orchestrated by Interleukin 11 (IL11), steering fibrogenic cell-cell communication, and proteins regulating extracellular matrix remodeling including epithelial-to-mesenchymal transition (EMT). When in turn treating 3D monocultures of iAT2s with IL11 we recapitulated the co-culture results obtained with primary ILD fibroblasts including changes in metabolic activity as well as organoid formation capacity and size.In summary, our analysis identified mesenchyme-derived mediators likely contributing to the disease-perpetuating mesenchymal-to-epithelial crosstalk in ILD by using sophisticated alveolar organoid co-cultures indicating the importance of cytokine-driven aberrant epithelial differentiation and confirmed IL11 as a key player in ILD using an unbiased approach.Abstract Figure

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Cytokine signaling converging onIL11in ILD fibroblasts provokes aberrant epithelial differentiation signatures

Kastlmeier

Rodriguez

Cabanis

et al. 2022

Preprint

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Precision cut lung slices: an integrated ex vivo model for studying lung physiology, pharmacology, disease pathogenesis and drug discovery

Koziol-White,

Gebski,

Cao

et al. 2024

Respir Res

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Precision Cut Lung Slices (PCLS) have emerged as a sophisticated and physiologically relevant ex vivo model for studying the intricacies of lung diseases, including fibrosis, injury, repair, and host defense mechanisms. This innovative methodology presents a unique opportunity to bridge the gap between traditional in vitro cell cultures and in vivo animal models, offering researchers a more accurate representation of the intricate microenvironment of the lung. PCLS require the precise sectioning of lung tissue to maintain its structural and functional integrity. These thin slices serve as invaluable tools for various research endeavors, particularly in the realm of airway diseases. By providing a controlled microenvironment, precision-cut lung slices empower researchers to dissect and comprehend the multifaceted interactions and responses within lung tissue, thereby advancing our understanding of pulmonary pathophysiology.

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Cytokine signaling converging on IL11 in ILD fibroblasts provokes aberrant epithelial differentiation signatures

et al. 2023

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IntroductionInterstitial lung disease (ILD) is a heterogenous group of lung disorders where destruction and incomplete regeneration of the lung parenchyma often results in persistent architectural distortion of the pulmonary scaffold. Continuous mesenchyme-centered, disease-relevant signaling likely initiates and perpetuates the fibrotic remodeling process, specifically targeting the epithelial cell compartment, thereby destroying the gas exchange area.MethodsWith the aim of identifying functional mediators of the lung mesenchymal-epithelial crosstalk with potential as new targets for therapeutic strategies, we developed a 3D organoid co-culture model based on human induced pluripotent stem cell-derived alveolar epithelial type 2 cells that form alveolar organoids in presence of lung fibroblasts from fibrotic-ILD patients, in our study referring to cases of pulmonary fibrosis, as well as control cell line (IMR-90).ResultsWhile organoid formation capacity and size was comparable in the presence of fibrotic-ILD or control lung fibroblasts, metabolic activity was significantly increased in fibrotic-ILD co-cultures. Alveolar organoids cultured with fibrotic-ILD fibroblasts further demonstrated reduced stem cell function as reflected by reduced Surfactant Protein C gene expression together with an aberrant basaloid-prone differentiation program indicated by elevated Cadherin 2, Bone Morphogenic Protein 4 and Vimentin transcription. To screen for key mediators of the misguided mesenchymal-to-epithelial crosstalk with a focus on disease-relevant inflammatory processes, we used mass spectrometry and characterized the secretome of end stage fibrotic-ILD lung fibroblasts in comparison to non-chronic lung disease (CLD) patient fibroblasts. Out of the over 2000 proteins detected by this experimental approach, 47 proteins were differentially abundant comparing fibrotic-ILD and non-CLD fibroblast secretome. The fibrotic-ILD secretome profile was dominated by chemokines, including CXCL1, CXCL3, and CXCL8, interfering with growth factor signaling orchestrated by Interleukin 11 (IL11), steering fibrogenic cell-cell communication, and proteins regulating extracellular matrix remodeling including epithelial-to-mesenchymal transition. When in turn treating alveolar organoids with IL11, we recapitulated the co-culture results obtained with primary fibrotic-ILD fibroblasts including changes in metabolic activity.ConclusionWe identified mediators likely contributing to the disease-perpetuating mesenchymal-to-epithelial crosstalk in ILD. In our alveolar organoid co-cultures, we were able to highlight the importance of fibroblast-initiated aberrant epithelial differentiation and confirmed IL11 as a key player in fibrotic-ILD pathogenesis by unbiased fibroblast secretome analysis.

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IL-11 disrupts alveolar epithelial progenitor function

Cited by 3 publications

References 67 publications

Cytokine signaling converging onIL11in ILD fibroblasts provokes aberrant epithelial differentiation signatures

Cytokine signaling converging onIL11in ILD fibroblasts provokes aberrant epithelial differentiation signatures

Precision cut lung slices: an integrated ex vivo model for studying lung physiology, pharmacology, disease pathogenesis and drug discovery

Cytokine signaling converging on IL11 in ILD fibroblasts provokes aberrant epithelial differentiation signatures

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