Alterations of cell death pathways, including apoptosis and the neutrophil specific kind of death called NETosis, can represent a potential source of autoantigens. Defects in the clearance of ...apoptotic cells may be responsible for the initiation of systemic autoimmunity in several chronic inflammatory diseases, including systemic lupus erythematosus (SLE). Autoantigens are released mainly from secondary necrotic cells because of a defective clearance of apoptotic cells or an inefficient degradation of DNA-containing neutrophil extracellular traps (NETs). These modified autoantigens are presented by follicular dendritic cells to autoreactive B cells in germinal centers of secondary lymphoid organs. This results in the loss of self-tolerance and production of autoantibodies, a unifying feature of SLE. Immune complexes (IC) are formed from autoantibodies bound to uncleared cellular debris in blood or tissues. Clearance of IC by blood phagocytes, macrophages, and dendritic cells leads to proinflammatory cytokine secretion. In particular, plasmacytoid dendritic cells produce high amounts of interferon-α upon IC uptake, thereby contributing to the interferon signature of patients with SLE. The clearance of antinuclear IC via Fc-gamma receptors is considered a central event in amplifying inflammatory immune responses in SLE. Along with this, the accumulation of cell remnants represents an initiating event of the etiology, while the subsequent generation of autoantibodies against nuclear antigens (including NETs) results in the perpetuation of inflammation and tissue damage in patients with SLE. Here, we discuss the implications of defective clearance of apoptotic cells and NETs in the development of clinical manifestations in SLE.
Gout is characterized by an acute inflammatory reaction and the accumulation of neutrophils in response to monosodium urate (MSU) crystals. Inflammation resolves spontaneously within a few days, ...although MSU crystals can still be detected in the synovial fluid and affected tissues. Here we report that neutrophils recruited to sites of inflammation undergo oxidative burst and form neutrophil extracellular traps (NETs). Under high neutrophil densities, these NETs aggregate and degrade cytokines and chemokines via serine proteases. Tophi, the pathognomonic structures of chronic gout, share characteristics with aggregated NETs, and MSU crystals can induce NETosis and aggregation of NETs. In individuals with impaired NETosis, MSU crystals induce uncontrolled production of inflammatory mediators from neutrophils and persistent inflammation. Furthermore, in models of neutrophilic inflammation, NETosis-deficient mice develop exacerbated and chronic disease that can be reduced by adoptive transfer of aggregated NETs. These findings suggest that aggregated NETs promote the resolution of neutrophilic inflammation by degrading cytokines and chemokines and disrupting neutrophil recruitment and activation.
The inefficient clearance of dying cells can result in the accumulation of apoptotic cell remnants. This occurrence is considered an intrinsic defect that can cause the permanent presence of cellular ...debris responsible for the initiation of systemic autoimmunity in diseases such as systemic lupus erythematosus (SLE). If postapoptotic debris accumulates in germinal centers, activates complement and functions as a survival signal for B cells that have become autoreactive by somatic hypermutation, autoimmunity could arise (etiology). The accumulation of postapoptotic remnants and fragments derived from secondary necrotic cells in the presence of autoantibodies against apoptotic cells or adaptor molecules obliges their pathological elimination and maintains autoinflammation. The autoimmunity that occurs in patients with SLE involves complex antigens that contain nucleic acids, which can function as virus mimetics. Complexes of autoantibodies, proteins and nucleic acids are likely to be mistaken by the immune system for opsonized viruses, resulting in the production of type I interferons, a hallmark of SLE (pathogenesis). The pathogenicity of autoantibodies is thought to strongly increase if autoantigens are accessible for immune-complex formation. The immune complex could be considered a binary pyrogen formed from less proinflammatory components. The accessibility of cognate autoantigens, in turn, is likely to be related to impaired or delayed clearance of apoptotic cells.
Although the control of bone-resorbing osteoclasts through osteocyte-derived RANKL is well defined, little is known about the regulation of osteoclasts by osteocyte death. Indeed, several skeletal ...diseases, such as bone fracture, osteonecrosis, and inflammation are characterized by excessive osteocyte death. Herein we show that osteoclasts sense damage-associated molecular patterns (DAMPs) released by necrotic osteocytes via macrophage-inducible C-type lectin (Mincle), which induced their differentiation and triggered bone loss. Osteoclasts showed robust Mincle expression upon exposure to necrotic osteocytes in vitro and in vivo. RNA sequencing and metabolic analyses demonstrated that Mincle activation triggers osteoclastogenesis via ITAM-based calcium signaling pathways, skewing osteoclast metabolism toward oxidative phosphorylation. Deletion of Mincle in vivo effectively blocked the activation of osteoclasts after induction of osteocyte death, improved fracture repair, and attenuated inflammation-mediated bone loss. Furthermore, in patients with osteonecrosis, Mincle was highly expressed at skeletal sites of osteocyte death and correlated with strong osteoclastic activity. Taken together, these data point to what we believe is a novel DAMP-mediated process that allows osteoclast activation and bone loss in the context of osteocyte death.
Neutrophil extracellular traps (NETs), a web-like structures containing chromatin, have a significant role in assisting the capture and killing of microorganisms by neutrophils during infection. The ...specific engagement of cell-surface receptors by extracellular signaling molecules activates diverse intracellular signaling cascades and regulates neutrophil effector functions, including phagocytosis, reactive oxygen species release, degranulation, and NET formation. However, overproduction of NETs is closely related to the occurrence of inflammation, autoimmune disorders, non-canonical thrombosis and tumor metastasis. Therefore, it is necessary to understand neutrophil activation signals and the subsequent formation of NETs, as well as the related immune regulation. In this review, we provide an overview of the immunoreceptor-mediated regulation of NETosis. The pathways involved in the release of NETs during infection or stimulation by noninfectious substances are discussed in detail. The mechanisms by which neutrophils undergo NETosis help to refine our views on the roles of NETs in immune protection and autoimmune diseases, providing a theoretical basis for research on the immune regulation of NETs.
Following strong activation signals, several types of immune cells reportedly release chromatin and granular proteins into the extracellular space, forming DNA traps. This process is especially ...prominent in neutrophils but also occurs in other innate immune cells such as macrophages, eosinophils, basophils and mast cells. Initial reports demonstrated that extracellular traps belong to the bactericidal and anti-fungal armamentarium of leukocytes, but subsequent studies also linked trap formation to a variety of human diseases. These pathological roles of extracellular DNA traps are now the focus of intensive biomedical research. The type of pathology associated with the release of extracellular DNA traps is mainly determined by the site of trap formation and the way in which these traps are further processed. Targeting the formation of aberrant extracellular DNA traps or promoting their efficient clearance are attractive goals for future therapeutic interventions, but the manifold actions of extracellular DNA traps complicate these approaches.
The critical size for strong interaction of hydrophobic particles with phospholipid bilayers has been predicted to be 10 nm. Because of the wide spreading of nonpolar nanoparticles (NPs) in the ...environment, we aimed to reveal the ability of living organisms to entrap NPs via formation of neutrophil extracellular traps (NETs). Upon interaction with various cell types and tissues, 10- to 40-nm-sized NPs induce fast (<20 min) damage of plasma membranes and instability of the lysosomal compartment, leading to the immediate formation of NETs. In contrast, particles sized 100–1,000 nm behaved rather inertly. Resulting NET formation (NETosis) was accompanied by an inflammatory reaction intrinsically endowed with its own resolution, demonstrated in lungs and air pouches of mice. Persistence of small NPs in joints caused unremitting arthritis and bone remodeling. Small NPs coinjected with antigen exerted adjuvant-like activity. This report demonstrates a cellular mechanism that explains how small NPs activate the NETosis pathway and drive their entrapping and resolution of the initial inflammatory response.
Crystals cause injury in numerous disorders, and induce inflammation via the NLRP3 inflammasome, however, it remains unclear how crystals induce cell death. Here we report that crystals of calcium ...oxalate, monosodium urate, calcium pyrophosphate dihydrate and cystine trigger caspase-independent cell death in five different cell types, which is blocked by necrostatin-1. RNA interference for receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain like (MLKL), two core proteins of the necroptosis pathway, blocks crystal cytotoxicity. Consistent with this, deficiency of RIPK3 or MLKL prevents oxalate crystal-induced acute kidney injury. The related tissue inflammation drives TNF-α-related necroptosis. Also in human oxalate crystal-related acute kidney injury, dying tubular cells stain positive for phosphorylated MLKL. Furthermore, necrostatin-1 and necrosulfonamide, an inhibitor for human MLKL suppress crystal-induced cell death in human renal progenitor cells. Together, TNF-α/TNFR1, RIPK1, RIPK3 and MLKL are molecular targets to limit crystal-induced cytotoxicity, tissue injury and organ failure.
Coronavirus induced disease 2019 (COVID-19) can be complicated by severe organ damage leading to dysfunction of the lungs and other organs. The processes that trigger organ damage in COVID-19 are ...incompletely understood.
Samples were donated from hospitalized patients. Sera, plasma, and autopsy-derived tissue sections were examined employing flow cytometry, enzyme-linked immunosorbent assays, and immunohistochemistry.
Here, we show that severe COVID-19 is characterized by a highly pronounced formation of neutrophil extracellular traps (NETs) inside the micro-vessels. Intravascular aggregation of NETs leads to rapid occlusion of the affected vessels, disturbed microcirculation, and organ damage. In severe COVID-19, neutrophil granulocytes are strongly activated and adopt a so-called low-density phenotype, prone to spontaneously form NETs. In accordance, markers indicating NET turnover are consistently increased in COVID-19 and linked to disease severity. Histopathology of the lungs and other organs from COVID-19 patients showed congestions of numerous micro-vessels by aggregated NETs associated with endothelial damage.
These data suggest that organ dysfunction in severe COVID-19 is associated with excessive NET formation and vascular damage.
Deutsche Forschungsgemeinschaft (DFG), EU, Volkswagen-Stiftung
We present a photonically-excited antenna array at E-band for scanning by beam switching in wireless links. First, we discuss the proposed technique applied to photonic-enabled (sub)millimeter-wave ...transmitters. Next, we present our implementation; it consists of two sub-arrays of stacked patches as primary feeds of a Polytetrafluoroethylene (PTFE) lens, with one photodiode feeding each sub-array. To validate the assembly, the return loss and radiation patterns have been measured for one of the sub-arrays excited with a coplanar probe. In turn, the lens illuminated by one of the sub-arrays yields a directivity of 27 dBi. The radiation patterns measured for the transmitter module (including the lens) are in very good agreement with full-wave simulations, and they show that excitation of one of either sub-arrays allows beam switching between <inline-formula><tex-math notation="LaTeX">\pm 2.7^\circ</tex-math></inline-formula> with a beam crossover at <inline-formula><tex-math notation="LaTeX">-3\, \mathrm{dB}</tex-math></inline-formula>. Finally, we have tested the transmitter in a 0.6 m wireless link. Depending on the position of the detector and on which sub-array is excited, we have accomplished 5 Gbps transmission for on-off-keying modulation and direct detection (BER <inline-formula><tex-math notation="LaTeX">=10^{-11}</tex-math></inline-formula>). The system constitutes an initial proof of photonic-assisted beam switching for mm-wave transmitters enabling broadband operation with a directive and switchable beam.
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