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.
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
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.
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
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.
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
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
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
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-
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
Diabetic peripheral neuropathy (DPN) often leads to neurotrophic ulcerations in the cornea and skin; however, the underlying cellular mechanisms of this complication are poorly understood. Here, we used post-wound corneal sensory degeneration and regeneration as a model and tested the hypothesis that diabetes adversely affects DC populations and infiltration, resulting in disrupted DC-nerve communication and DPN. In streptozotocin-induced type 1 diabetic mice, there was a substantial reduction in sensory nerve density and the number of intraepithelial DCs in unwounded (UW) corneas. In wounded corneas, diabetes markedly delayed sensory nerve regeneration and reduced the number of infiltrating DCs, which were a major source of ciliary neurotrophic factor (CNTF) in the cornea. While CNTF neutralization retarded reinnervation in normal corneas, exogenous CNTF accelerated nerve regeneration in the wounded corneas of diabetic mice and healthy animals, in which DCs had been locally depleted. Moreover, blockade of the CNTF-specific receptor CNTFRα induced sensory nerve degeneration and retarded regeneration in normal corneas. Soluble CNTFRα also partially restored the branching of diabetes-suppressed sensory nerve endings and regeneration in the diabetic corneas. Collectively, our data show that DCs mediate sensory nerve innervation and regeneration through CNTF and that diabetes reduces DC populations in UW and wounded corneas, resulting in decreased CNTF and impaired sensory nerve innervation and regeneration.
Nan Gao, Chenxi Yan, Patrick Lee, Haijing Sun, Fu-Shin Yu
Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tgsm/p22phox mice, which overexpress the NADPH oxidase subunit p22
Jing Wu, Mohamed A. Saleh, Annet Kirabo, Hana A. Itani, Kim Ramil C. Montaniel, Liang Xiao, Wei Chen, Raymond L. Mernaugh, Hua Cai, Kenneth E. Bernstein, Jörg J. Goronzy, Cornelia M. Weyand, John A. Curci, Natalia R. Barbaro, Heitor Moreno, Sean S. Davies, L. Jackson Roberts II, Meena S. Madhur, David G. Harrison
Wound healing is a complex process that is characterized by an initial inflammatory phase followed by a proliferative phase. This transition is a critical regulatory point; however, the factors that mediate this process are not fully understood. Here, we evaluated microRNAs (miRs) in skin wound healing and characterized the dynamic change of the miRNome in human skin wounds. miR-132 was highly upregulated during the inflammatory phase of wound repair, predominantly expressed in epidermal keratinocytes, and peaked in the subsequent proliferative phase. TGF-β1 and TGF-β2 induced miR-132 expression in keratinocytes, and transcriptome analysis of these cells revealed that miR-132 regulates a large number of immune response– and cell cycle–related genes. In keratinocytes, miR-132 decreased the production of chemokines and the capability to attract leukocytes by suppressing the NF-κB pathway. Conversely, miR-132 increased activity of the STAT3 and ERK pathways, thereby promoting keratinocyte growth. Silencing of the miR-132 target heparin-binding EGF-like growth factor (HB-EGF) phenocopied miR-132 overexpression in keratinocytes. Using mouse and human ex vivo wound models, we found that miR-132 blockade delayed healing, which was accompanied by severe inflammation and deficient keratinocyte proliferation. Together, our results indicate that miR-132 is a critical regulator of skin wound healing that facilitates the transition from the inflammatory to the proliferative phase.
Dongqing Li, Aoxue Wang, Xi Liu, Florian Meisgen, Jacob Grünler, Ileana R. Botusan, Sampath Narayanan, Erdem Erikci, Xi Li, Lennart Blomqvist, Lei Du, Andor Pivarcsi, Enikö Sonkoly, Kamal Chowdhury, Sergiu-Bogdan Catrina, Mona Ståhle, Ning Xu Landén
The NF-κB signaling pathway is implicated in various inflammatory diseases, including rheumatoid arthritis (RA); therefore, inhibition of this pathway has the potential to ameliorate an array of inflammatory diseases. Given that NF-κB signaling is critical for many immune cell functions, systemic blockade of this pathway may lead to detrimental side effects. siRNAs coupled with a safe and effective delivery nanoplatform may afford the specificity lacking in systemic administration of small-molecule inhibitors. Here we demonstrated that a melittin-derived cationic amphipathic peptide combined with siRNA targeting the p65 subunit of NF-κB (p5RHH-p65) noncovalently self-assemble into stable nanocomplexes that home to the inflamed joints in a murine model of RA. Specifically, administration of p5RHH-p65 siRNA nanocomplexes abrogated inflammatory cytokine expression and cellular influx into the joints, protected against bone erosions, and preserved cartilage integrity. The p5RHH-p65 siRNA nanocomplexes potently suppressed early inflammatory arthritis without affecting p65 expression in off-target organs or eliciting a humoral response after serial injections. These data suggest that this self-assembling, largely nontoxic platform may have broad utility for the specific delivery of siRNA to target and limit inflammatory processes for the treatment of a variety of diseases.
Hui-fang Zhou, Huimin Yan, Hua Pan, Kirk K. Hou, Antonina Akk, Luke E. Springer, Ying Hu, J. Stacy Allen, Samuel A. Wickline, Christine T.N. Pham
Rheumatoid arthritis–associated (RA-associated) inflammation is mediated through the interaction between RA IgG immune complexes and IgG Fc receptors on immune cells. Polymorphisms within the gene encoding the human IgG Fc receptor IIA (hFcγRIIA) are associated with an increased risk of developing RA. Within the hFcγRIIA intracytoplasmic domain, there are 2 conserved tyrosine residues arranged in a noncanonical immunoreceptor tyrosine–based activation motif (ITAM). Here, we reveal that inhibitory engagement of the hFcγRIIA ITAM either with anti-hFcγRII F(ab′)2 fragments or intravenous hIgG (IVIg) ameliorates RA-associated inflammation, and this effect was characteristic of previously described inhibitory ITAM (ITAMi) signaling for hFcαRI and hFcγRIIIA, but only involves a single tyrosine. In hFcγRIIA-expressing mice, arthritis induction was inhibited following hFcγRIIA engagement. Moreover, hFcγRIIA ITAMi-signaling reduced ROS and inflammatory cytokine production through inhibition of guanine nucleotide exchange factor VAV-1 and IL-1 receptor–associated kinase 1 (IRAK-1), respectively. ITAMi signaling was mediated by tyrosine 304 (Y304) within the hFcγRIIA ITAM, which was required for recruitment of tyrosine kinase SYK and tyrosine phosphatase SHP-1. Anti-hFcγRII F(ab′)2 treatment of inflammatory synovial cells from RA patients inhibited ROS production through induction of ITAMi signaling. These data suggest that shifting constitutive hFcγRIIA-mediated activation to ITAMi signaling could ameliorate RA-associated inflammation.
Sanae Ben Mkaddem, Gilles Hayem, Friederike Jönsson, Elisabetta Rossato, Erwan Boedec, Tarek Boussetta, Jamel El Benna, Pierre Launay, Jean-Michel Goujon, Marc Benhamou, Pierre Bruhns, Renato C. Monteiro
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