Neutrophil Extracellular Traps in Inflammatory Bowel Disease: Pathogenic Mechanisms and Clinical Translation

The Inflammatory Bowel Diseases (IBD), Ulcerative Colitis (UC) and Crohn’s Disease (CD) are characterised by chronic non-resolving gut mucosal inflammation involving innate and adaptive immune responses. Neutrophils, usually regarded as first responders in inflammation, are a key presence in the gut mucosal inflammatory milieu in IBD. Here, we review the role of neutrophil extracellular trap (NET) formation as a potential effector disease mechanism. NETs are extracellular webs of chromatin, microbicidal proteins and oxidative enzymes that are released by neutrophils to contain pathogens. NETs contribute to the pathogenesis of several immune-mediated diseases such as systemic lupus erythematosus and rheumatoid arthritis; and recently, as a major tissue damaging process involved in the host response to severe acute respiratory syndrome coronavirus 2 infection. NETs are pertinent as a defence mechanism at the gut mucosal interphase exposed to high levels of bacteria, viruses and fungi. On the other hand, NETs can also potentiate and perpetuate gut inflammation. In this review, we discuss the broad protective vs. pathogenic roles of NETs, explanatory factors that could lead to an increase in NET formation in IBD and how NETs may contribute to gut inflammation and IBD-related complications. Finally, we summarise therapeutic opportunities to target NETs in IBD

Mechanisms and disease relevance of neutrophil extracellular trap formation

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

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

De socio-professionele status van bekende Vlaamse populaire muziekartiesten

nrpages: 33status: publishe

Bacterial Immune Evasion through Manipulation of Host Inhibitory Immune Signaling

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.

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.

<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