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Inflammation

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Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction
Michio Nakaya, … , Shigekazu Nagata, Hitoshi Kurose
Michio Nakaya, … , Shigekazu Nagata, Hitoshi Kurose
Published December 5, 2016
Citation Information: J Clin Invest. 2016. https://doi.org/10.1172/JCI83822.
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Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction

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Abstract

Myocardial infarction (MI) results in the generation of dead cells in the infarcted area. These cells are swiftly removed by phagocytes to minimize inflammation and limit expansion of the damaged area. However, the types of cells and molecules responsible for the engulfment of dead cells in the infarcted area remain largely unknown. In this study, we demonstrated that cardiac myofibroblasts, which execute tissue fibrosis by producing extracellular matrix proteins, efficiently engulf dead cells. Furthermore, we identified a population of cardiac myofibroblasts that appears in the heart after MI in humans and mice. We found that these cardiac myofibroblasts secrete milk fat globule-epidermal growth factor 8 (MFG-E8), which promotes apoptotic engulfment, and determined that serum response factor is important for MFG-E8 production in myofibroblasts. Following MFG-E8–mediated engulfment of apoptotic cells, myofibroblasts acquired antiinflammatory properties. MFG-E8 deficiency in mice led to the accumulation of unengulfed dead cells after MI, resulting in exacerbated inflammatory responses and a substantial decrease in survival. Moreover, MFG-E8 administration into infarcted hearts restored cardiac function and morphology. MFG-E8–producing myofibroblasts mainly originated from resident cardiac fibroblasts and cells that underwent endothelial-mesenchymal transition in the heart. Together, our results reveal previously unrecognized roles of myofibroblasts in regulating apoptotic engulfment and a fundamental importance of these cells in recovery from MI.

Authors

Michio Nakaya, Kenji Watari, Mitsuru Tajima, Takeo Nakaya, Shoichi Matsuda, Hiroki Ohara, Hiroaki Nishihara, Hiroshi Yamaguchi, Akiko Hashimoto, Mitsuho Nishida, Akiomi Nagasaka, Yuma Horii, Hiroki Ono, Gentaro Iribe, Ryuji Inoue, Makoto Tsuda, Kazuhide Inoue, Akira Tanaka, Masahiko Kuroda, Shigekazu Nagata, Hitoshi Kurose

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TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage
Roslyn A. Taylor, … , J. Christopher Love, Lauren H. Sansing
Roslyn A. Taylor, … , J. Christopher Love, Lauren H. Sansing
Published November 28, 2016
Citation Information: J Clin Invest. 2016. https://doi.org/10.1172/JCI88647.
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TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage

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Abstract

Intracerebral hemorrhage (ICH) is a devastating form of stroke that results from the rupture of a blood vessel in the brain, leading to a mass of blood within the brain parenchyma. The injury causes a rapid inflammatory reaction that includes activation of the tissue-resident microglia and recruitment of blood-derived macrophages and other leukocytes. In this work, we investigated the specific responses of microglia following ICH with the aim of identifying pathways that may aid in recovery after brain injury. We used longitudinal transcriptional profiling of microglia in a murine model to determine the phenotype of microglia during the acute and resolution phases of ICH in vivo and found increases in TGF-β1 pathway activation during the resolution phase. We then confirmed that TGF-β1 treatment modulated inflammatory profiles of microglia in vitro. Moreover, TGF-β1 treatment following ICH decreased microglial Il6 gene expression in vivo and improved functional outcomes in the murine model. Finally, we observed that patients with early increases in plasma TGF-β1 concentrations had better outcomes 90 days after ICH, confirming the role of TGF-β1 in functional recovery from ICH. Taken together, our data show that TGF-β1 modulates microglia-mediated neuroinflammation after ICH and promotes functional recovery, suggesting that TGF-β1 may be a therapeutic target for acute brain injury.

Authors

Roslyn A. Taylor, Che-Feng Chang, Brittany A. Goods, Matthew D. Hammond, Brian Mac Grory, Youxi Ai, Arthur F. Steinschneider, Stephen C. Renfroe, Michael H. Askenase, Louise D. McCullough, Scott E. Kasner, Michael T. Mullen, David A. Hafler, J. Christopher Love, Lauren H. Sansing

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Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury
Irina A. Leaf, … , William A. Altemeier, Jeremy S. Duffield
Irina A. Leaf, … , William A. Altemeier, Jeremy S. Duffield
Published November 21, 2016
Citation Information: J Clin Invest. 2016. https://doi.org/10.1172/JCI87532.
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Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury

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Abstract

Fibrotic disease is associated with matrix deposition that results in the loss of organ function. Pericytes, the precursors of myofibroblasts, are a source of pathological matrix collagens and may be promising targets for treating fibrogenesis. Here, we have shown that pericytes activate a TLR2/4- and MyD88-dependent proinflammatory program in response to tissue injury. Similarly to classic immune cells, pericytes activate the NLRP3 inflammasome, leading to IL-1β and IL-18 secretion. Released IL-1β signals through pericyte MyD88 to amplify this response. Unexpectedly, we found that MyD88 and its downstream effector kinase IRAK4 intrinsically control pericyte migration and conversion to myofibroblasts. Specific ablation of MyD88 in pericytes or pharmacological inhibition of MyD88 signaling by an IRAK4 inhibitor in vivo protected against kidney injury by profoundly attenuating tissue injury, activation, and differentiation of myofibroblasts. Our data show that in pericytes, MyD88 and IRAK4 are key regulators of 2 major injury responses: inflammatory and fibrogenic. Moreover, these findings suggest that disruption of this MyD88-dependent pathway in pericytes might be a potential therapeutic approach to inhibit fibrogenesis and promote regeneration.

Authors

Irina A. Leaf, Shunsaku Nakagawa, Bryce G. Johnson, Jin Joo Cha, Kristen Mittelsteadt, Kevin M. Guckian, Ivan G. Gomez, William A. Altemeier, Jeremy S. Duffield

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Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer
Mingzhu Yin, … , Ge Lou, Wang Min
Mingzhu Yin, … , Ge Lou, Wang Min
Published October 10, 2016
Citation Information: J Clin Invest. 2016. https://doi.org/10.1172/JCI87252.
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Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer

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Abstract

Tumor-associated macrophages (TAMs) can influence ovarian cancer growth, migration, and metastasis, but the detailed mechanisms underlying ovarian cancer metastasis remain unclear. Here, we have shown a strong correlation between TAM-associated spheroids and the clinical pathology of ovarian cancer. Further, we have determined that TAMs promote spheroid formation and tumor growth at early stages of transcoelomic metastasis in an established mouse model for epithelial ovarian cancer. M2 macrophage–like TAMs were localized in the center of spheroids and secreted EGF, which upregulated αMβ2 integrin on TAMs and ICAM-1 on tumor cells to promote association between tumor cells and TAM. Moreover, EGF secreted by TAMs activated EGFR on tumor cells, which in turn upregulated VEGF/VEGFR signaling in surrounding tumor cells to support tumor cell proliferation and migration. Pharmacological blockade of EGFR or antibody neutralization of ICAM-1 in TAMs blunted spheroid formation and ovarian cancer progression in mouse models. These findings suggest that EGF secreted from TAMs plays a critical role in promoting early transcoelomic metastasis of ovarian cancer. As transcoelomic metastasis is also associated with many other cancers, such as pancreatic and colon cancers, our findings uncover a mechanism for TAM-mediated spheroid formation and provide a potential target for the treatment of ovarian cancer and other transcoelomic metastatic cancers.

Authors

Mingzhu Yin, Xia Li, Shu Tan, Huanjiao Jenny Zhou, Weidong Ji, Stefania Bellone, Xiaocao Xu, Haifeng Zhang, Alessandro D. Santin, Ge Lou, Wang Min

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MST1-dependent vesicle trafficking regulates neutrophil transmigration through the vascular basement membrane
Angela R.M. Kurz, … , Sergio D. Catz, Markus Sperandio
Angela R.M. Kurz, … , Sergio D. Catz, Markus Sperandio
Published October 4, 2016
Citation Information: J Clin Invest. 2016. https://doi.org/10.1172/JCI87043.
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MST1-dependent vesicle trafficking regulates neutrophil transmigration through the vascular basement membrane

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Abstract

Neutrophils need to penetrate the perivascular basement membrane for successful extravasation into inflamed tissue, but this process is incompletely understood. Recent findings have associated mammalian sterile 20–like kinase 1 (MST1) loss of function with a human primary immunodeficiency disorder, suggesting that MST1 may be involved in immune cell migration. Here, we have shown that MST1 is a critical regulator of neutrophil extravasation during inflammation. Mst1-deficient (Mst1–/–) neutrophils were unable to migrate into inflamed murine cremaster muscle venules, instead persisting between the endothelium and the basement membrane. Mst1–/– neutrophils also failed to extravasate from gastric submucosal vessels in a murine model of Helicobacter pylori infection. Mechanistically, we observed defective translocation of VLA-3, VLA-6, and neutrophil elastase from intracellular vesicles to the surface of Mst1–/– neutrophils, indicating that MST1 is required for this crucial step in neutrophil transmigration. Furthermore, we found that MST1 associates with the Rab27 effector protein synaptotagmin-like protein 1 (JFC1, encoded by Sytl1 in mice), but not Munc13-4, thereby regulating the trafficking of Rab27-positive vesicles to the cellular membrane. Together, these findings highlight a role for MST1 in vesicle trafficking and extravasation in neutrophils, providing an additional mechanistic explanation for the severe immune defect observed in patients with MST1 deficiency.

Authors

Angela R.M. Kurz, Monika Pruenster, Ina Rohwedder, Mahalakshmi Ramadass, Kerstin Schäfer, Ute Harrison, Gabriel Gouveia, Claudia Nussbaum, Roland Immler, Johannes R. Wiessner, Andreas Margraf, Dae-Sik Lim, Barbara Walzog, Steffen Dietzel, Markus Moser, Christoph Klein, Dietmar Vestweber, Rainer Haas, Sergio D. Catz, Markus Sperandio

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Different activation signals induce distinct mast cell degranulation strategies
Nicolas Gaudenzio, … , Eric Espinosa, Stephen J. Galli
Nicolas Gaudenzio, … , Eric Espinosa, Stephen J. Galli
Published September 19, 2016
Citation Information: J Clin Invest. 2016. https://doi.org/10.1172/JCI85538.
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Different activation signals induce distinct mast cell degranulation strategies

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Abstract

Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-β during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P–dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation.

Authors

Nicolas Gaudenzio, Riccardo Sibilano, Thomas Marichal, Philipp Starkl, Laurent L. Reber, Nicolas Cenac, Benjamin D. McNeil, Xinzhong Dong, Joseph D. Hernandez, Ronit Sagi-Eisenberg, Ilan Hammel, Axel Roers, Salvatore Valitutti, Mindy Tsai, Eric Espinosa, Stephen J. Galli

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Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation
Christian C. Yost, … , Andrew S. Weyrich, Guy A. Zimmerman
Christian C. Yost, … , Andrew S. Weyrich, Guy A. Zimmerman
Published September 6, 2016
Citation Information: J Clin Invest. 2016. https://doi.org/10.1172/JCI83873.
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Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation

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Abstract

Neutrophil granulocytes, also called polymorphonuclear leukocytes (PMNs), extrude molecular lattices of decondensed chromatin studded with histones, granule enzymes, and antimicrobial peptides that are referred to as neutrophil extracellular traps (NETs). NETs capture and contain bacteria, viruses, and other pathogens. Nevertheless, experimental evidence indicates that NETs also cause inflammatory vascular and tissue damage, suggesting that identifying pathways that inhibit NET formation may have therapeutic implications. Here, we determined that neonatal NET-inhibitory factor (nNIF) is an inhibitor of NET formation in umbilical cord blood. In human neonatal and adult neutrophils, nNIF inhibits key terminal events in NET formation, including peptidyl arginine deiminase 4 (PAD4) activity, neutrophil nuclear histone citrullination, and nuclear decondensation. We also identified additional nNIF-related peptides (NRPs) that inhibit NET formation. nNIFs and NRPs blocked NET formation induced by pathogens, microbial toxins, and pharmacologic agonists in vitro and in mouse models of infection and systemic inflammation, and they improved mortality in murine models of systemic inflammation, which are associated with NET-induced collateral tissue injury. The identification of NRPs as neutrophil modulators that selectively interrupt NET generation at critical steps suggests their potential as therapeutic agents. Furthermore, our results indicate that nNIF may be an important regulator of NET formation in fetal and neonatal inflammation.

Authors

Christian C. Yost, Hansjörg Schwertz, Mark J. Cody, Jared A. Wallace, Robert A. Campbell, Adriana Vieira-de-Abreu, Claudia V. Araujo, Sebastian Schubert, Estelle S. Harris, Jesse W. Rowley, Matthew T. Rondina, James M. Fulcher, Curry L. Koening, Andrew S. Weyrich, Guy A. Zimmerman

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Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation
Adrian Achuthan, … , Stephen J. Turner, John A. Hamilton
Adrian Achuthan, … , Stephen J. Turner, John A. Hamilton
Published August 15, 2016
Citation Information: J Clin Invest. 2016. https://doi.org/10.1172/JCI87828.
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Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation

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Abstract

Data from preclinical and clinical studies have demonstrated that granulocyte macrophage colony-stimulating factor (GM-CSF) can function as a key proinflammatory cytokine. However, therapies that directly target GM-CSF function could lead to undesirable side effects, creating a need to delineate downstream pathways and mediators. In this work, we provide evidence that GM-CSF drives CCL17 production by acting through an IFN regulatory factor 4–dependent (IRF4-dependent) pathway in human monocytes, murine macrophages, and mice in vivo. In murine models of arthritis and pain, IRF4 regulated the formation of CCL17, which mediated the proinflammatory and algesic actions of GM-CSF. Mechanistically, GM-CSF upregulated IRF4 expression by enhancing JMJD3 demethylase activity. We also determined that CCL17 has chemokine-independent functions in inflammatory arthritis and pain. These findings indicate that GM-CSF can mediate inflammation and pain by regulating IRF4-induced CCL17 production, providing insights into a pathway with potential therapeutic avenues for the treatment of inflammatory diseases and their associated pain.

Authors

Adrian Achuthan, Andrew D. Cook, Ming-Chin Lee, Reem Saleh, Hsu-Wei Khiew, Melody W.N. Chang, Cynthia Louis, Andrew J. Fleetwood, Derek C. Lacey, Anne D. Christensen, Ashlee T. Frye, Pui Yeng Lam, Hitoshi Kusano, Koji Nomura, Nancy Steiner, Irmgard Förster, Stephen L. Nutt, Moshe Olshansky, Stephen J. Turner, John A. Hamilton

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Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis
Hsin-Yuan Cheng, … , Mary Sorci-Thomas, Catherine C. Hedrick
Hsin-Yuan Cheng, … , Mary Sorci-Thomas, Catherine C. Hedrick
Published August 2, 2016
Citation Information: J Clin Invest. 2016. https://doi.org/10.1172/JCI83136.
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Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis

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Abstract

ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol accumulation and alters T cell homeostasis, which may contribute to progression of atherosclerosis. Here, we investigated how the selective loss of ABCG1 in T cells impacts atherosclerosis in LDL receptor–deficient (LDLR-deficient) mice, a model of the disease. In LDLR-deficient mice fed a high-cholesterol diet, T cell–specific ABCG1 deficiency protected against atherosclerotic lesions. Furthermore, T cell–specific ABCG1 deficiency led to a 30% increase in Treg percentages in aorta and aorta-draining lymph nodes (LNs) of these mice compared with animals with only LDLR deficiency. When Abcg1 was selectively deleted in Tregs of LDLR-deficient mice, we observed a 30% increase in Treg percentages in aorta and aorta-draining LNs and reduced atherosclerosis. In the absence of ABCG1, intracellular cholesterol accumulation led to downregulation of the mTOR pathway, which increased the differentiation of naive CD4 T cells into Tregs. The increase in Tregs resulted in reduced T cell activation and increased IL-10 production by T cells. Last, we found that higher ABCG1 expression in Tregs was associated with a higher frequency of these cells in human blood samples. Our study indicates that ABCG1 regulates T cell differentiation into Tregs, highlighting a pathway by which cholesterol accumulation can influence T cell homeostasis in atherosclerosis.

Authors

Hsin-Yuan Cheng, Dalia E. Gaddis, Runpei Wu, Chantel McSkimming, LaTeira D. Haynes, Angela M. Taylor, Coleen A. McNamara, Mary Sorci-Thomas, Catherine C. Hedrick

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Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury
Christopher E. Pedigo, … , Sandra Merscher, Alessia Fornoni
Christopher E. Pedigo, … , Sandra Merscher, Alessia Fornoni
Published August 2, 2016
Citation Information: J Clin Invest. 2016. https://doi.org/10.1172/JCI85939.
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Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury

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Abstract

High levels of circulating TNF and its receptors, TNFR1 and TNFR2, predict the progression of diabetic kidney disease (DKD), but their contribution to organ damage in DKD remains largely unknown. Here, we investigated the function of local and systemic TNF in podocyte injury. We cultured human podocytes with sera collected from DKD patients, who displayed elevated TNF levels, and focal segmental glomerulosclerosis (FSGS) patients, whose TNF levels resembled those of healthy patients. Exogenous TNF administration or local TNF expression was equally sufficient to cause free cholesterol–dependent apoptosis in podocytes by acting through a dual mechanism that required a reduction in ATP-binding cassette transporter A1–mediated (ABCA1-mediated) cholesterol efflux and reduced cholesterol esterification by sterol-O-acyltransferase 1 (SOAT1). TNF-induced albuminuria was aggravated in mice with podocyte-specific ABCA1 deficiency and was partially prevented by cholesterol depletion with cyclodextrin. TNF-stimulated free cholesterol–dependent apoptosis in podocytes was mediated by nuclear factor of activated T cells 1 (NFATc1). ABCA1 overexpression or cholesterol depletion was sufficient to reduce albuminuria in mice with podocyte-specific NFATc1 activation. Our data implicate an NFATc1/ABCA1-dependent mechanism in which local TNF is sufficient to cause free cholesterol–dependent podocyte injury irrespective of TNF, TNFR1, or TNFR2 serum levels.

Authors

Christopher E. Pedigo, Gloria Michelle Ducasa, Farah Leclercq, Alexis Sloan, Alla Mitrofanova, Tahreem Hashmi, Judith Molina-David, Mengyuan Ge, Mariann I. Lassenius, Carol Forsblom, Markku Lehto, Per-Henrik Groop, Matthias Kretzler, Sean Eddy, Sebastian Martini, Heather Reich, Patricia Wahl, GianMarco Ghiggeri, Christian Faul, George W. Burke III, Oliver Kretz, Tobias Huber, Armando J. Mendez, Sandra Merscher, Alessia Fornoni

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