16 research outputs found

    Mechanisms and disease relevance of neutrophil extracellular trap formation

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    While the microscopic appearance of neutrophil extracellular traps (NETs) has fascinated basic researchers since its discovery, the (patho)physiological mechanisms triggering NET release, the disease relevance and clinical translatability of this unconventional cellular mechanism remained poorly understood. Here, we summarize and discuss current concepts of the mechanisms and disease relevance of NET formation

    Mechanisms of haemolysis-induced kidney injury

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    Intravascular haemolysis is a fundamental feature of chronic hereditary and acquired haemolytic anaemias, including those associated with haemoglobinopathies, complement disorders and infectious diseases such as malaria. Destabilization of red blood cells (RBCs) within the vasculature results in systemic inflammation, vasomotor dysfunction, thrombophilia and proliferative vasculopathy. The haemoprotein scavengers haptoglobin and haemopexin act to limit circulating levels of free haemoglobin, haem and iron — potentially toxic species that are released from injured RBCs. However, these adaptive defence systems can fail owing to ongoing intravascular disintegration of RBCs. Induction of the haem-degrading enzyme haem oxygenase 1 (HO1) — and potentially HO2 — represents a response to, and endogenous defence against, large amounts of cellular haem; however, this system can also become saturated. A frequent adverse consequence of massive and/or chronic haemolysis is kidney injury, which contributes to the morbidity and mortality of chronic haemolytic diseases. Intravascular destruction of RBCs and the resulting accumulation of haemoproteins can induce kidney injury via a number of mechanisms, including oxidative stress and cytotoxicity pathways, through the formation of intratubular casts and through direct as well as indirect proinflammatory effects, the latter via the activation of neutrophils and monocytes. Understanding of the detailed pathophysiology of haemolysis-induced kidney injury offers opportunities for the design and implementation of new therapeutic strategies to counteract the unfavourable and potentially fatal effects of haemolysis on the kidney

    Bacterial Immune Evasion through Manipulation of Host Inhibitory Immune Signaling

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    An innate immune response is essential for survival of the host upon infection, yet excessive inflammation can result in harmful complications [1]. Inhibitory signaling evolved to limit host responses and prevent inflammatory pathology [2,3]. Given the significance of inhibitory pathways for immunity and homeostasis, they provide ideal targets for manipulation by bacterial pathogens. Recent evidence highlights that bacteria have developed diverse strategies to exploit these inhibitory pathways to avoid host defense for their own benefit. In this review, we cover these different immune evasion strategies for the first time. The recent literature discussed emphasizes that bacteria subvert host immune responses not only by direct engagement of inhibitory receptors (i.e., often through "molecular mimicry" of host ligands [4,5]) but also through virulence factors that resemble intermediates of host inhibitory signaling and interfere with defense functions [6-8]. Understanding how bacteria manipulate inhibitory signaling affords promising opportunities to counteract these escape strategies and tip the balance in favor of the host. In addition, these understandings may provide useful insights on the functional roles of inhibitory pathways in limiting host responses and preventing pathology

    Mechanisms of haemolysis-induced kidney injury.

    No full text
    Intravascular haemolysis is a fundamental feature of chronic hereditary and acquired haemolytic anaemias, including those associated with haemoglobinopathies, complement disorders and infectious diseases such as malaria. Destabilization of red blood cells (RBCs) within the vasculature results in systemic inflammation, vasomotor dysfunction, thrombophilia and proliferative vasculopathy. The haemoprotein scavengers haptoglobin and haemopexin act to limit circulating levels of free haemoglobin, haem and iron - potentially toxic species that are released from injured RBCs. However, these adaptive defence systems can fail owing to ongoing intravascular disintegration of RBCs. Induction of the haem-degrading enzyme haem oxygenase 1 (HO1) - and potentially HO2 - represents a response to, and endogenous defence against, large amounts of cellular haem; however, this system can also become saturated. A frequent adverse consequence of massive and/or chronic haemolysis is kidney injury, which contributes to the morbidity and mortality of chronic haemolytic diseases. Intravascular destruction of RBCs and the resulting accumulation of haemoproteins can induce kidney injury via a number of mechanisms, including oxidative stress and cytotoxicity pathways, through the formation of intratubular casts and through direct as well as indirect proinflammatory effects, the latter via the activation of neutrophils and monocytes. Understanding of the detailed pathophysiology of haemolysis-induced kidney injury offers opportunities for the design and implementation of new therapeutic strategies to counteract the unfavourable and potentially fatal effects of haemolysis on the kidney

    Bacterial pathogens evade host defense responses by manipulating inhibitory signaling.

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    <p>A. <i>M. catarrhalis</i>, <i>N. meningitidis</i>, Group B <i>Streptococcus</i> and <i>Staphylococcus aureus</i> evolved specific virulence factors to engage inhibitory receptors, which co-ligate with and attenuate pattern recognition receptor (PRR) signaling. B. <i>Escherichia coli</i> escapes macrophage receptor with collagenous structure (MARCO)–dependent killing through hijacking of inhibitory ITAM signaling. Non-opsonized <i>E. coli</i> binds to FcγRIII with low affinity and induces weak phosphorylation of the FcR common γ chain (FcRγ), leading to recruitment of SHP-1. In turn, SHP-1 dephosphorylates PI3K and abrogates MARCO-dependent phagocytosis. C. Upon infection, <i>Helicobacter pylori</i> translocates the ITIM-containing virulence protein, CagA, into host cells, and CagA-SHP-2 interactions lead to dephosphorylation of activated STAT1 and epidermal growth factor receptor (EGFR). This abrogates IFN-γ signaling and human β-defensin 3 (hBD3) synthesis, and enhances bacterial survival. D. During infection with the bacterium enteropathogenic <i>E. coli</i> (EPEC), the intimin receptor (Tir) translocates into the epithelial cell. The intracellular tail of EPEC Tir recruits host cell phosphatases SHP-1 and SHP-2. As a result, the activation of TRAF6 is inhibited, and EPEC-induced expression of pro-inflammatory cytokines is suppressed. E. <i>Salmonella</i> and <i>Yersinia</i> secrete protein tyrosine phosphatases SptP and YopH, respectively. SptP targets the protein tyrosine kinase SYK in mast cells and suppresses degranulation. During in vivo infection, YopH targets the signaling adaptor SLP-76 in neutrophils. This leads to reduced calcium responses and IL-10 production.</p

    Negative modulation of inflammatory responses against pathogens by ITIM-bearing inhibitory receptors.

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    <p>Invasion of the host by bacteria results in the appearance of pathogen-associated molecular patterns (PAMPs). These danger signals are sensed by pattern recognition receptors (PRRs), including TLRs, on the surface of sentinel cells. Bacteria can be opsonized with antibodies and are recognized by cell surface Fc receptors (FcRs) associated with the immunoreceptor tyrosine-based activation motif (ITAM)-containing FcR common γ chain. FcRs generally transmit activating signals through activation of the protein tyrosine kinase SYK, while diverse signaling cascades (such as activation of MAPK, NF-κB, and PI3K) are relayed by PRRs. The inflammatory response against non-self is essential to combat invading bacteria. On the other hand, the antibacterial response needs to be controlled to prevent collateral tissue damage. Inhibitory receptors often possess immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within their intracellular tails. Following receptor engagement, tyrosine residues within the ITIMs are phosphorylated and become docking sites for cytosolic protein tyrosine phosphatases, such as SHP-1 and SHP-2. These negative regulatory proteins terminate activating signals delivered by PRRs and/or ITAM-coupled FcRs and contribute to dampening of the inflammatory response. MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB; PI3K, phosphoinositide 3-kinase.</p

    Signal Inhibitory Receptor on Leukocytes-1 Limits the Formation of Neutrophil Extracellular Traps, but Preserves Intracellular Bacterial Killing

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    In response to microbial invasion, neutrophils release neutrophil extracellular traps (NETs) to trap and kill extracellular microbes. Alternatively, NET formation can result in tissue damage in inflammatory conditions and may perpetuate autoimmune disease. Intervention strategies that are aimed at modifying pathogenic NET formation should ideally preserve other neutrophil antimicrobial functions. We now show that signal inhibitory receptor on leukocytes-1 (SIRL-1) attenuates NET release by human neutrophils in response to distinct triggers, including opsonized Staphylococcus aureus and inflammatory danger signals. NET release has different kinetics depending on the stimulus, and rapid NET formation is independent of NADPH oxidase activity. In line with this, we show that NET release and reactive oxygen species production upon challenge with opsonized S. aureus require different signaling events. Importantly, engagement of SIRL-1 does not affect bacterially induced production of reactive oxygen species, and intracellular bacterial killing by neutrophils remains intact. Thus, our studies define SIRL-1 as an intervention point of benefit to suppress NET formation in disease while preserving intracellular antimicrobial defense

    Ligation of Signal Inhibitory Receptor on Leukocytes-1 Suppresses the Release of Neutrophil Extracellular Traps in Systemic Lupus Erythematosus

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    <div><p>Neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of systemic Lupus erythematosus (SLE), since netting neutrophils release potentially immunogenic autoantigens including histones, LL37, human neutrophil peptide (HNP), and self-DNA. In turn, these NETs activate plasmacytoid dendritic cells resulting in aggravation of inflammation and disease. How suppression of NET formation can be targeted for treatment has not been reported yet. Signal Inhibitory Receptor on Leukocytes-1 (SIRL-1) is a surface molecule exclusively expressed on phagocytes. We recently identified SIRL-1 as a negative regulator of human neutrophil function. Here, we determine whether ligation of SIRL-1 prevents the pathogenic release of NETs in SLE. Peripheral blood neutrophils from SLE patients with mild to moderate disease activity and healthy donors were freshly isolated. NET release was assessed spontaneously or after exposure to anti-neutrophil antibodies or plasma obtained from SLE patients. The formation of NETs was determined by microscopic evaluation using DNA dyes and immunostaining of NET components, as well as by live cell imaging. We show that SLE neutrophils spontaneously release NETs. NET formation is enhanced by stimulation with antibodies against LL37. Inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and MEK-ERK signaling prevents NET release in response to these antibodies. Signaling via the inhibitory receptor SIRL-1 was induced by ligation with anti-SIRL-1 specific antibodies. Both spontaneous and anti-neutrophil antibody-induced NET formation is suppressed by engagement of SIRL-1. Furthermore, NET release by healthy neutrophils exposed to SLE plasma is inhibited by SIRL-1 ligation. Thus, SIRL-1 engagement can dampen spontaneous and anti-neutrophil antibody-induced NET formation in SLE, likely by suppressing NAPDH oxidase and MEK-ERK activity. Together, these findings reveal a regulatory role for SIRL-1 in NET formation, potentially providing a novel therapeutic target to break the pathogenic loop in SLE.</p> </div
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