Externalized histones fuel pulmonary fibrosis via a platelet-macrophage circuit of TGFβ1 and IL-27

Significance Lung fibrosis is a progressive, lethal disease with limited treatment options available that do not provide cure. Hence, a better understanding of the inflammatory pathophysiology and molecular mechanisms of tissue remodeling is mandatory. In this study, we uncover that externalized histones from neutrophil extracellular traps act profibrotic by shifting the balance of critical cytokines. Externalized histones activate platelets to release TGFβ1, which subsequently antagonizes antifibrotic Interleukin-27 (IL-27) production from macrophages via multiple intracellular signaling pathways. The importance of these mechanisms is highlighted by the observation that blocking monoclonal antibodies against externalized histones protect from excessive collagen matrix deposition in injured lungs.

• Publication year

  2023

• Venue

  Proceedings of the National Academy of Sciences of the United States of America

• Publication date

  2023-09-27

• Fields of study

  Biology, Medicine, Environmental Science

• Identifiers
  DOI 10.1073/pnas.2215421120PMID 37756334PMCID 10556605
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Neutrophil extracellular traps and pulmonary fibrosis: an update

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• Neutrophil Extracellular Traps as an Exacerbating Factor in Bacterial Pneumonia

  2022influential reference
• IL-27 Enhances γδ T Cell–Mediated Innate Resistance to Primary Hookworm Infection in the Lungs

  2022cited by this paper
• IL-22 inhibits bleomycin-induced pulmonary fibrosis in association with inhibition of IL-17A in mice

  2022cited by this paper
• A proposed role of neutrophil extracellular traps and their interplay with fibroblasts in ANCA-associated vasculitis lung fibrosis.

  2021cited by this paper
• A novel murine model of pulmonary fibrosis: the role of platelets in chronic changes induced by bleomycin.

  2021cited by this paper
• Role of interleukins in the pathogenesis of pulmonary fibrosis

  2021cited by this paper
• Cangrelor alleviates bleomycin-induced pulmonary fibrosis by inhibiting platelet activation in mice.

  2020cited by this paper
• Extracellular histones stimulate collagen expression in vitro and promote liver fibrogenesis in a mouse model via the TLR4-MyD88 signaling pathway

  2020cited by this paper
• PAD4 Deficiency Improves Bleomycin-induced Neutrophil Extracellular Traps and Fibrosis in Mouse Lung.

  2020cited by this paper
• Neutrophil Extracellular Traps Induce the Epithelial-Mesenchymal Transition: Implications in Post-COVID-19 Fibrosis

  2020cited by this paper
• Activated Endothelial TGFβ1 Signaling Promotes Venous Thrombus Non-Resolution in Mice Via Endothelin-1: Potential Role for Chronic Thromboembolic Pulmonary Hypertension.

  2019cited by this paper
• Update in Pulmonary Fibrosis 2018.

  2019cited by this paper
• Blockade of platelet-derived growth factor receptor-β, not receptor-α ameliorates bleomycin-induced pulmonary fibrosis in mice

  2018cited by this paper
• Macrophages, Wound Healing, and Fibrosis: Recent Insights

  2018cited by this paper
• Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging

  2018cited by this paper
• Neutrophil extracellular traps in immunity and disease

  2017cited by this paper
• Validation of an enzyme-linked immunosorbent assay for the quantification of citrullinated histone H3 as a marker for neutrophil extracellular traps in human plasma

  2017cited by this paper
• Peptidylarginine deiminase 4 promotes age-related organ fibrosis

  2017cited by this paper
• IL‐17A deficiency mitigates bleomycin‐induced complement activation during lung fibrosis

  2017cited by this paper
• Neuroendocrine Modulation of IL-27 in Macrophages

  2017cited by this paper
• IL-27 attenuates the TGF-β1-induced proliferation, differentiation and collagen synthesis in lung fibroblasts.

  2016cited by this paper
• Neutrophil Extracellular Traps in Pulmonary Diseases: Too Much of a Good Thing?

  2016cited by this paper
• Extracellular traps and macrophages: new roles for the versatile phagocyte

  2015cited by this paper
• IL-27 alleviates the bleomycin-induced pulmonary fibrosis by regulating the Th17 cell differentiation

  2015cited by this paper
• Neutrophil extracellular traps promote differentiation and function of fibroblasts

  2014cited by this paper
• Citrullination regulates pluripotency and histone H1 binding to chromatin

  2014cited by this paper
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  2014cited by this paper
• Epithelial–mesenchymal transition in lung development and disease: does it exist and is it important?

  2013cited by this paper
• Extracellular histones are essential effectors of C5aR‐ and C5L2‐mediated tissue damage and inflammation in acute lung injury

  2013cited by this paper
• PAD4 regulates proliferation of multipotent haematopoietic cells by controlling c-myc expression

  2013cited by this paper
• Modulation of inflammation by interleukin‐27

  2013cited by this paper
• Epidemiology of idiopathic pulmonary fibrosis

  2013cited by this paper
• Suppression of IL-12 Production by Tristetraprolin through Blocking NF-кB Nuclear Translocation

  2013cited by this paper
• Crosstalk between p38 and Smad3 through TGF-β1 in JEG-3 choriocarcinoma cells.

  2013cited by this paper
• Host responses in tissue repair and fibrosis.

  2013cited by this paper
• Circulating histones are mediators of trauma-associated lung injury.

  2013cited by this paper
• CD11c+ Alveolar Macrophages are a Source of IL-23 During Lipopolysaccharide-Induced Acute Lung Injury

  2013cited by this paper
• Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury.

  2012cited by this paper
• Secretory leukocyte protease inhibitor (SLPI) might contaminate murine monoclonal antibodies after purification on protein G.

  2012cited by this paper
• Cellular and Molecular Mechanisms of Chronic Inflammation-Associated Organ Fibrosis

  2012cited by this paper
• TGFβ signalling in context

  2012cited by this paper
• Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4.

  2012cited by this paper
• Complement Activation Product C5a Is a Selective Suppressor of TLR4-Induced, but Not TLR3-Induced, Production of IL-27(p28) from Macrophages

  2012cited by this paper
• Platelet TGF-β1 contributions to plasma TGF-β1, cardiac fibrosis, and systolic dysfunction in a mouse model of pressure overload.

  2012cited by this paper
• Integrating mechanisms of pulmonary fibrosis

  2011cited by this paper
• Lipopolysaccharide inhibits transforming growth factor‐beta1‐stimulated Smad6 expression by inducing phosphorylation of the linker region of Smad3 through a TLR4–IRAK1–ERK1/2 pathway

  2011cited by this paper
• TLR2-Mediated Production of IL-27 and Chemokines by Respiratory Epithelial Cells Promotes Bleomycin-Induced Pulmonary Fibrosis in Mice

  2011cited by this paper
• Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4.

  2011cited by this paper
• Extracellular Histones Are Mediators of Death through TLR2 and TLR4 in Mouse Fatal Liver Injury

  2011cited by this paper
• The Outcome of Polymicrobial Sepsis Is Independent of T and B CellS

  2011cited by this paper
• An essential role for resident fibroblasts in experimental lung fibrosis is defined by lineage-specific deletion of high-affinity type II transforming growth factor β receptor.

  2011cited by this paper
• Extracellular DNA traps promote thrombosis

  2010cited by this paper
• PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps

  2010cited by this paper
• Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent

  2010cited by this paper
• IL-27 Is a Key Regulator of IL-10 and IL-17 Production by Human CD4+ T Cells1

  2009cited by this paper
• Netting neutrophils in autoimmune small-vessel vasculitis

  2009cited by this paper
• Extracellular histones are major mediators of death in sepsis

  2009cited by this paper
• COMPARISON OF CONDITIONING REGIMENS FOR ALVEOLAR MACROPHAGE RECONSTITUTION AND INNATE IMMUNE FUNCTION POST BONE MARROW TRANSPLANT

  2008cited by this paper
• Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood

  2007cited by this paper
• Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17–producing T cells

  2006cited by this paper
• Neutrophil Extracellular Traps Kill Bacteria

  2004cited by this paper
• TGF‐β signaling and the fibrotic response

  2004cited by this paper
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  2003cited by this paper
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  2003cited by this paper
• The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection.

  2003cited by this paper
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  2001cited by this paper
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  2001cited by this paper
• Plasmin regulates the activation of cell-associated latent TGF-beta 1 secreted by rat alveolar macrophages after in vivo bleomycin injury.

  1996cited by this paper
• A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency.

  1996cited by this paper
• Pulmonary platelet trapping induced by bleomycin: correlation with fibrosis and involvement of the beta 2 integrins.

  1994cited by this paper
• Structure and binding properties of monoclonal antibodies to core histones from autoimmune mice.

  1993cited by this paper
• The measurement of transforming growth factor type beta (TGF beta) levels produced by peripheral blood mononuclear cells requires the efficient elimination of contaminating platelets.

  1992cited by this paper

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  2025cites this paper
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  2025cites this paper
• PAD4 inhibition impacts immune responses in SARS-CoV-2 infection.

  2025cites this paper
• "Capture and kill" circulating fibrocytes by cisplatin prodrug loaded albumin disrupt the progress of pulmonary fibrosis in mice.

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• Immunobiology of pulmonary fibrosis

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  2025cites this paper
• Emerging therapeutic strategies targeting extracellular histones for critical and inflammatory diseases: an updated narrative review

  2024cites this paper
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  2024cites this paper
• Dissecting the role of platelet-derived transforming growth factor-β1 in pulmonary fibrosis

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• Reply to Chong et al.: Investigating TGFβ1 biological activities using genetically engineered mouse strains

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