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| Open AccessAutocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis
IPF is a progressive disease with few inflammatory pathology. Here, using alveolar organoid technology, the authors identified autocrine TGF-β-positive feedback in AT2-lineage cells as a core mechanism of inflammation-independent lung fibrogenesis.
- Yasunori Enomoto
- , Hiroaki Katsura
- & Mitsuru Morimoto
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Article
| Open AccessTGFβ1+CCR5+ neutrophil subset increases in bone marrow and causes age-related osteoporosis in male mice
Age-related osteoporosis is known to be dependent on TGFβ1 signalling. Here the authors show that a subset of neutrophils (identified by TGFβ1+CCR5+) increase during aging in mouse bone marrow resulting in bone loss, while a CCR5 antagonist can reduce the neutrophil numbers and increase bone mass in aged mice.
- Jinbo Li
- , Zhenqiang Yao
- & Brendan F. Boyce
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Article
| Open AccessTGF-β-dependent lymphoid tissue residency of stem-like T cells limits response to tumor vaccine
TGF-β has been shown to regulate stem-like CD8 + T cell differentiation into tissue resident memory T cells in chronic infection. Here authors show that in tumour-bearing mice, a similar TGF-βdependent CD8 + T cell differentiation program is carried out in the draining lymph nodes, which impedes generation of anti-tumor migratory effector T cells upon future vaccination.
- Guo Li
- , Saranya Srinivasan
- & Nu Zhang
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| Open AccessBreast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling
Understanding the factors that hamper immune therapy in breast cancer may increase the range of patients who benefit. Here authors show that breast cancer cells produce and subsequently transfer active TGF-β type II receptors to CD8 + T cells to render them exhausted, thus paralyzing the anti-tumor immune response.
- Feng Xie
- , Xiaoxue Zhou
- & Fangfang Zhou
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Article
| Open AccessUrsodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation
TGF-β can function to increase Treg cell function and reduce anti-tumour immunity. Here the authors show that UDCA is a potential mediator that can reduce TGF-β activity and promote anti-tumour immune responses in mice and can be additive to other checkpoint inhibitors.
- Yingying Shen
- , Chaojie Lu
- & Zhijian Cai
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Article
| Open AccessCrystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10
Mutations in BMPR2 is the major genetic cause for pulmonary arterial hypertension (PAH). Here by solving crystal structures of BMPRII in binary and ternary receptor complexes with BMP10, the authors report the molecular recognition between BMPRII and BMP10, and its implication in PAH.
- Jingxu Guo
- , Bin Liu
- & Wei Li
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Article
| Open AccessThe induction and function of the anti-inflammatory fate of TH17 cells
CD4+ T helper cells producing IL-17A (TH17 cells) can take on pathogenic or anti-inflammatory functions in context-specific manners. Here the authors show that the anti-inflammatory fate of TH17 cells contributes, via TGF-β signaling and induction of IL-10, to host immune tolerance, but also simultaneously dampens protective immunity against S. aureus.
- Hao Xu
- , Theodora Agalioti
- & Nicola Gagliani
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Article
| Open AccessMolecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms
The molecular basis of activin receptor-like kinase 1 (ALK1)-mediated endothelial bone morphogenetic protein (BMP) signalling is not fully understood. Here, the authors present crystal structures of the BMP10:ALK1 and prodomain-bound BMP9:ALK1 complexes, providing mechanistic insights into ALK1 signalling specificity.
- Richard M. Salmon
- , Jingxu Guo
- & Wei Li
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Article
| Open AccessRegulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing
Aberrant tissue repair may result in heterotopic ossification (HO), but how this process is regulated by local inflammatory responses is still unclear. Here the authors show, using a mouse burn/trauma model, that TGFβ-producing monocytes/macrophages at the injury site contribute to HO induction, while CD47 activation helps antagonize this process.
- Michael Sorkin
- , Amanda K. Huber
- & Benjamin Levi
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Article
| Open AccessTGF-β induces ST2 and programs ILC2 development
TGF-β is thought to be important for group 2 innate lymphoid cell (ILC2) function. Here the authors show that TGF-β drives expression of ST2 specifically in ILC2 progenitors and thereby is also important for the development of ILC2s in the bone marrow.
- Li Wang
- , Jun Tang
- & WanJun Chen
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Article
| Open AccessMetformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis
Idiopathic pulmonary fibrosis is associated with myofibroblast activation in the lungs and metabolic alterations. Here, the authors show that the antidiabetic drug metformin has antifibrotic effects in human-derived samples and mouse models, by modulating a number of metabolic pathways to induce lipogenic transdifferentiation of myofibroblasts.
- Vahid Kheirollahi
- , Roxana M. Wasnick
- & Elie El Agha
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| Open AccessThe mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis
The PI3K/Akt/mTOR pathway has been previously implicated in fibrosis and a pan-PI3K/mTOR inhibitor is currently under clinical evaluation for the treatment of IPF. Here the authors show that the mTORC1/4E-BP1 axis is critical for TGF-β1-induced fibrogenesis in in vitro and ex vivo models and that canonical PI3K/Akt signalling is dispensable.
- Hannah V. Woodcock
- , Jessica D. Eley
- & Rachel C. Chambers
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Article
| Open AccessMolecular definition of group 1 innate lymphoid cells in the mouse uterus
Studying the uterine lymphocyte pool is difficult due to its dynamic nature induced by various pregnancy-related factors. Here the authors provide, using transcriptome data from sorted mouse group 1 innate lymphoid cells (ILC), a molecular atlas of these cells, which implicates tissue-resident natural killer cells as a hub for uterine immune crosstalk.
- Iva Filipovic
- , Laura Chiossone
- & Francesco Colucci
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| Open AccessThe tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis
Hyperactivation of TGFβ signaling is a common feature of fibrotic diseases. Here the authors show that genetic or pharmacologic inactivation of the tyrosine phosphatase SHP2 prevents TGFβ-induced JAK2/STAT3 signaling, inhibits fibroblast activation and exerts potent anti-fibrotic effects.
- Ariella Zehender
- , Jingang Huang
- & Jörg H. W. Distler
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Article
| Open AccessDistinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models
Feingold syndrome is a skeletal dysplasia caused by mutations in MYCN or MIR17HG, but it is not clear if these mutations lead to pathology via a common molecular mechanism. Here, the authors show that mutations in MIR17HG lead to upregulated TGF-β signaling in limb mesenchymal cells, while mutations in MYCN downregulate PI3K signaling.
- Fatemeh Mirzamohammadi
- , Anastasia Kozlova
- & Tatsuya Kobayashi
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| Open AccessInhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice
Heterotopic ossification (HO) is a painful disease of unknown etiology characterized by extraskeletal bone formation after injury. Here the authors show that TGF-β is increased in HO lesions, where it promotes the early stages of HO pathology, and demonstrate that TGF-β inhibition ameliorates HO in mice.
- Xiao Wang
- , Fengfeng Li
- & Xu Cao
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Article
| Open AccessA structurally distinct TGF-β mimic from an intestinal helminth parasite potently induces regulatory T cells
Heligmosomoides polygyrus can activate mammalian TGF-β signalling pathways, but how it does so is not known. Here the authors identify and isolate a H. polygyrus TFG-β mimic that can bind both mammalian TGF-β receptor subunits, activate Smad signalling and generate inducible regulatory T cells.
- Chris J. C. Johnston
- , Danielle J. Smyth
- & Rick M. Maizels
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| Open Accessαv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis
The mechanisms underlying tissue fibrosis are unclear. The authors show that mesenchymal cells expressing PDGFRβ mediate fibrosis in skeletal muscle and heart via a mechanism involving αv integrin, and that inhibitors of αv integrins attenuate fibrotic responses in mice.
- I. R. Murray
- , Z. N. Gonzalez
- & N. C. Henderson
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| Open AccessActivation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis
STAT3 is a transcription factor that is activated in fibrotic diseases such as systemic sclerosis. Here the authors show that STAT3 is the converging point for multiple pro-fibrotic signalling pathways, and that its genetic ablation or inhibition ameliorate skin fibrosis in mouse models.
- Debomita Chakraborty
- , Barbora Šumová
- & Jörg H. W. Distler
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Article
| Open AccessPTP4A1 promotes TGFβ signaling and fibrosis in systemic sclerosis
Although protein tyrosine kinases are being explored as antifibrotic agents for the treatment of systemic sclerosis, little is known about the function of counteractive protein tyrosine phosphatases in this context. Here, the authors show that PTP4A1 is highly expressed by fibroblasts from patients with systemic sclerosis and promotes TGFβ activity via SRC–ERK–SMAD3 signaling.
- Cristiano Sacchetti
- , Yunpeng Bai
- & Nunzio Bottini
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| Open AccessTGFβR signalling controls CD103+CD11b+ dendritic cell development in the intestine
Developmental cues for the different dendritic cell (DC) subsets in the intestine are yet to be defined. Here the authors show that TGFβR1 signalling is needed for development of CD103+CD11b+ intestinal DCs from CD103−CD11b+ cells and that they contribute to the generation of Th17 and regulatory T cells
- C. C. Bain
- , J. Montgomery
- & A. McI. Mowat
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Article
| Open AccessActivin A more prominently regulates muscle mass in primates than does GDF8
Inhibition of GDF8 increases muscle mass in mice, but is less effective in monkeys and humans. Here the authors show that activin A also inhibits muscle hypertrophy and that concomitant inhibition of activin A and GDF8 synergistically increases muscle mass in mice and non-human primates.
- Esther Latres
- , Jason Mastaitis
- & Jesper Gromada
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| Open AccessStructure and activation of pro-activin A
Activins are members of the TGF-β family of growth factors that are processed from precursors into the mature proteins. Here, the authors use structural biology and biochemistry to examine the protein domain organisation and gain insights into the activation of pro-activin A.
- Xuelu Wang
- , Gerhard Fischer
- & Marko Hyvönen
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Article
| Open AccessId1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation
Tumour progression is promoted by the generation of an immunosuppressive macroenvironment. Here, the authors demonstrate that the Inhibitor of Differentiation 1 promotes the switch from dendritic cell differentiation towards myeloid-derived suppressor cell expansion during tumour progression.
- Marianna Papaspyridonos
- , Irina Matei
- & David Lyden
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Article |
miR-1269 promotes metastasis and forms a positive feedback loop with TGF-β
Colorectal cancer (CRC), like many solid tumours, progresses from adenomas to carcinomas in a sequence that leads to metastasis. Here the authors show that miR1269 plays a role in CRC relapse and metastasis by regulating TGF-β activity.
- Pengcheng Bu
- , Lihua Wang
- & Xiling Shen
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Article |
IL-10 inhibits neuraminidase-activated TGF-β and facilitates Th1 phenotype during early phase of infection
The role of IL-10 in influenza infection is controversial. Here the authors show that early during infection, IL-10 promotes Th1 immunity by inhibiting viral neuraminidase-mediated release of TGF-β, but later acts as an immunosuppressive cytokine to inhibit immunopathology and promote recovery.
- Avijit Dutta
- , Ching-Tai Huang
- & Yueh-Chia He
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| Open AccessTGF-β3-expressing CD4+CD25−LAG3+ regulatory T cells control humoral immune responses
B cells reactive against self antigens can cause autoimmune disease, but are normally suppressed by regulatory T cells (Tregs). Here the authors show that a subset of Tregs can suppress lupus in a mouse model by making TGF-β3 cytokine and by engaging an inhibitory PD-1 receptor on B cells.
- Tomohisa Okamura
- , Shuji Sumitomo
- & Kazuhiko Yamamoto
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TGFβ induces the formation of tumour-initiating cells in claudinlow breast cancer
TGF-β signalling suppresses tumorigenesis in breast cancer cells but its effects on breast cancer initiating cells have not been reported. Using cells in culture, Brunaet al. show that TGF-β increases breast cancer initiating cell numbers in cells that have low levels of the tight junction protein claudin.
- Alejandra Bruna
- , Wendy Greenwood
- & Carlos Caldas
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| Open AccessActivation of canonical Wnt signalling is required for TGF-β-mediated fibrosis
Aberrant activation of the TGF-β pathway leads to fibrotic disease. Distler and colleagues show that TGF-β-mediated fibrosis requires the decrease of Dickkopf-1, an antagonist of canonical Wnt signalling, suggesting that the two pathways interact for the manifestation of this disease.
- Alfiya Akhmetshina
- , Katrin Palumbo
- & Jörg H.W. Distler