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Autophagy is well equipped functionally to isolate microbial pathogens in autophagosomes and to carry out their clearance by dismemberment in the course of catabolic processes in the lysosome. Clearly, this is a non-metabolic function of autophagy that impacts strongly on the immune system. While in a preceding article on neutrophils, eosinophils, mast cells, and natural killer cells our focus was on the role of autophagy in regulating innate immune cell differentiation, degranulation, phagocytosis and extracellular trap formation, here we discuss monocytes/macrophages and dendritic cells, specifically, the influence of autophagy on functional cellular responses, such as phagocytosis, antigen presentation, cytokine production, control of inflammasome activation, tolerance and the consequences for overall host defense.Involvement of autophagy in cellular functions of monocytes, macrophages and dendritic cells.

Autophagy is an evolutionally conserved, highly regulated catabolic process that combines cellular functions required for the regulation of metabolic balance under conditions of stress with those needed for the degradation of damaged cell organelles via the lysosomal machinery. The importance of autophagy for cell homeostasis and survival has long been appreciated. Recent data suggest that autophagy is also involved in non-metabolic functions that impact the immune system. Here, we reflect in two review articles the recent literature pointing to an important role for autophagy in innate immune cells. In this article, we focus on neutrophils, eosinophils, mast cells, and natural killer cells. We mainly discuss the influence of autophagy on functional cellular responses and its importance for overall host defense. In the companion review, we present the role of autophagy in the functions performed by monocytes/macrophages and dendritic cells.Involvement of autophagy in cellular functions of neutrophils, eosinophils, basophils, NK cells, and mast cells.

Eosinophils are specialized white blood cells, which are involved in the pathology of diverse allergic and nonallergic inflammatory diseases. Eosinophils are traditionally known as cytotoxic effector cells but have been suggested to additionally play a role in immunomodulation and maintenance of homeostasis. The exact role of these granule-containing leukocytes in health and diseases is still a matter of debate. Degranulation is one of the key effector functions of eosinophils in response to diverse stimuli. The different degranulation patterns occurring in eosinophils (piecemeal degranulation, exocytosis and cytolysis) have been extensively studied in the last few years. However, the exact mechanism of the diverse degranulation types remains unknown and is still under investigation. In this review, we focus on recent findings and highlight the diversity of stimulation and methods used to evaluate eosinophil degranulation.

Extracellular DNA trap formation is a cellular function of neutrophils, eosinophils, and basophils that facilitates the immobilization and killing of invading microorganisms in the extracellular milieu. To form extracellular traps, granulocytes release a scaffold consisting of mitochondrial DNA in association with granule proteins. As we understand more about the molecular mechanism for the formation of extracellular DNA traps, the in vivo function of this phenomenon under pathological conditions remains an enigma. In this article, we critically review the literature to summarize the evidence for extracellular DNA trap formation under in vivo conditions. Extracellular DNA traps have not only been detected in infectious diseases but also in chronic inflammatory diseases, as well as in cancer. While on the one hand, extracellular DNA traps clearly exhibit an important function in host defense, it appears that they can also contribute to the maintenance of inflammation and metastasis, suggesting that they may represent an interesting drug target for such pathological conditions.

Optic atrophy 1 (OPA1) is a mitochondrial inner membrane protein that has an important role in mitochondrial fusion and structural integrity. Dysfunctional OPA1 mutations cause atrophy of the optic nerve leading to blindness. Here, we show that OPA1 has an important role in the innate immune system. Using conditional knockout mice lacking Opa1 in neutrophils ( Opa1 N∆ ), we report that lack of OPA1 reduces the activity of mitochondrial electron transport complex I in neutrophils. This then causes a decline in adenosine-triphosphate (ATP) production through glycolysis due to lowered NAD + availability. Additionally, we show that OPA1-dependent ATP production in these cells is required for microtubule network assembly and for the formation of neutrophil extracellular traps. Finally, we show that Opa1 N∆ mice exhibit a reduced antibacterial defense capability against Pseudomonas aeruginosa . Optic atrophy 1 (OPA1) is known to be important for mitochondrial fusion and structural integrity. Here, using OPA1 knockout mice, the authors show a detrimental effect on host defense capabilities against pathogen infections. This study reports a critical role for OPA1 in innate immunity.

[...]under physiological conditions in healthy individuals, nuclear DNA release following activation of neutrophils encountering microorganisms is still controversial and the question has, in fact, been raised whether a NETosis in this format would be at all beneficial to the host (4). [...]the existence of extranuclear histones, namely pools of H1 and H3 in the cytoplasm, has also been reported (15). [...]one has argued that the presence of citrulline-containing proteins in extracellular proteins, and presumably in NETs, is an argument in favor of NETosis. [...]subsequent studies using DNA sequencing methods have established that NETs are generally composed of mtDNA [Yousefi et al. [...]neutrophils can release nuclear DNA upon encountering bacteria capable of secreting pore-forming enzymes/toxins. [...]under in vitro conditions, neutrophils stimulated with PMA may first form mtDNA-containing NETs before undergoing a subsequent necrotic cell death. [...]it has been reported that NETosis could actually represent a necroptosis (30).

Eosinophils and their mediators play a crucial role in various reactive states such as bacterial and viral infections, chronic inflammatory disorders, and certain hematologic malignancies. Depending on the underlying pathology, molecular defect(s), and the cytokine- and mediator-cascades involved, peripheral blood and tissue hypereosinophilia (HE) may develop and may lead to organ dysfunction or even organ damage which usually leads to the diagnosis of a HE syndrome (HES). In some of these patients, the etiology and impact of HE remain unclear. These patients are diagnosed with idiopathic HE. In other patients, HES is diagnosed but the etiology remains unknown — these patients are classified as idiopathic HES. For patients with HES, early therapeutic application of agents reducing eosinophil counts is usually effective in avoiding irreversible organ damage. Therefore, it is important to systematically explore various diagnostic markers and to correctly identify the disease elicitors and etiology. Depending on the presence and type of underlying disease, HES are classified into primary (clonal) HES, reactive HES, and idiopathic HES. In most of these patients, effective therapies can be administered. The current article provides an overview of the pathogenesis of eosinophil-associated disorders, with special emphasis on the molecular, immunological, and clinical complexity of HE and HES. In addition, diagnostic criteria and the classification of eosinophil disorders are reviewed in light of new developments in the field.

Eosinophil infiltration is a common finding in a broad spectrum of skin diseases, despite the fact that the skin is devoid of eosinophils under physiologic conditions. Although cutaneous eosinophilia is reactive, cytokine-mediated in most cases, diseases with an intrinsic mutation-mediated clonal expansion of eosinophils can also manifest on the skin. As eosinophils are involved in host defense, regulate immune responses, generate pruritus, induce remodeling and fibrosis, and can cause tissue damage, they have the capacity to actively contribute to the pathogenesis of diseases. Recent research provided deeper insights in the mechanisms, e.g., bacterial and viral clearance, blister formation, recruitment of cytotoxic T cells, and generation of pruritus, by which eosinophils might come into action. This review aims at providing an overview on the clinical presentations of eosinophil-associated dermatoses and the current understanding of their pathogenic role in these diseases. Further, we discuss the effects of therapies targeting eosinophils.

Autophagy is a highly conserved lysosomal degradation system that involves the creation of autophagosomes, which eventually fuse with lysosomes and breakdown misfolded proteins and damaged organelles with their enzymes. Autophagy is widely known for its function in cellular homeostasis under physiological and pathological settings. Defects in autophagy have been implicated in the pathophysiology of a variety of human diseases. The new line of evidence suggests that autophagy is inextricably linked to skin disorders. This review summarizes the principles behind autophagy and highlights current findings of autophagy’s role in skin disorders and strategies for therapeutic modulation.

Necroptosis is a form of regulated necrosis and is dependent on a signaling pathway involving receptor interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). Necroptosis is considered to have important functions in inflammation and, based on studies with animal disease models, is believed likely to be involved in the pathogenesis of many human inflammatory diseases. In neutrophils, necroptosis has recently been reported to be triggered by tumor necrosis factor (TNF) stimulation, ligation of adhesion receptors, exposure to monosodium urate (MSU) crystals, or phagocytosis of Staphylococcus aureus ( S. aureus ). Because neutrophils are involved in many kinds of tissue inflammation and disease, neutrophil necroptosis probably plays a vital role in such processes. Dissecting the signaling pathway of neutrophil necroptotic death may help to identify novel drug targets for inflammatory or autoimmune diseases. In this review, we discuss different mechanisms which regulate neutrophil necroptosis and are thus potentially important in neutrophil-associated disorders.