Cytokine storm in COVID-19: from viral infection to immune responses,diagnosis and therapy

The COVID-19 outbreak is emerging as a significant public health challenge. Excessive production of proinflammatory cytokines, also known as cytokine storm, is a severe clinical syndrome known to develop as a complication of infectious or inflammatory diseases. Clinical evidence suggests that the occurrence of cytokine storm in severe acute respiratory syndrome secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is closely associated with the rapid deterioration and high mortality of severe cases. In this review, we aim to summarize the mechanism of SARS-CoV-2 infection and the subsequent immunological events related to excessive cytokine production and inflammatory responses associated with ACE2-AngII signaling. An overview of the diagnosis and an update on current therapeutic regimens and vaccinations is also provided.     

Cytokines in inflammatory bowel disease

Over the past decade, much has been learned regarding the role of various cytokines in the pathogenesis of inflammatory bowel disease. Several cytokine 'knockout' models in mice have been shown to develop colitis, while alterations in the production of various cytokines has been documented in human Crohn's disease and ulcerative colitis. In recent years, attempts have been made to treat these diseases through modulation of cytokine production or action. This review focuses on the cytokines that have been implicated in the pathogenesis of inflammatory bowel disease. The evidence for and against a role for particular cytokines in intestinal inflammation is reviewed, as is the experimental and clinical data suggesting that cytokines are rational targets for the development of new therapies.     

IL-7 up-regulates the expression of IL-8 from resting and stimulated human blood monocytes.

Blood monocytes are important cellular sources of a vast array of bioactive substances, including regulatory and chemotactic cytokines. The regulation of these cytokines is of critical importance to the expression of acute and chronic inflammatory responses. IL-7, a T and B cell-activating cytokine, has recently been shown to have stimulatory effects on the expression of several monocyte-derived proinflammatory cytokines. We now describe the induction of IL-8 mRNA and extracellular protein from human blood monocytes by IL-7. The up-regulation of IL-8 mRNA by IL-7 was not altered by concomitant treatment with cycloheximide, suggesting that the direct stimulatory effects of IL-7 were not dependent upon de novo protein synthesis. In addition, IL-7 significantly potentiated the production of IL-8 from LPS-, TNF-, and IL-1-treated peripheral blood monocytes. Our findings suggest that IL-7 may play a critical role in the modulation of macrophage-derived cytokine expression and may function in vivo as an important proinflammatory cytokine.     

Inflammatory profile in X‐linked adrenoleukodystrophy patients: Understanding disease progression

X‐linked adrenoleukodystrophy (X‐ALD) is an inherited disease characterized by progressive inflammatory demyelization in the brain, adrenal insufficiency, and an abnormal accumulation of very long chain fatty acids (VLCFA) in tissue and body fluids. Considering that inflammation might be involved in pathophysiology of X‐ALD, we aimed to investigate pro‐ and anti‐inflammatory cytokines in plasma from three different male phenotypes (CCER, AMN, and asymptomatic individuals). Our results showed that asymptomatic patients presented increased levels of pro‐inflammatory cytokines IL‐1β, IL‐2, IL‐8, and TNF‐α and the last one was also higher in AMN phenotype. Besides, asymptomatic patients presented higher levels of anti‐inflammatory cytokines IL‐4 and IL‐10. AMN patients presented higher levels of IL‐2, IL‐5, and IL‐4. We might hypothesize that inflammation in X‐ALD is related to plasmatic VLCFA concentration, since there were positive correlations between C26:0 plasmatic levels and pro‐inflammatory cytokines in asymptomatic and AMN patients and negative correlation between anti‐inflammatory cytokine and C24:0/C22:0 ratio in AMN patients. The present work yields experimental evidence that there is an inflammatory imbalance associated Th1, (IL‐2, IL‐6, and IFN‐γ), Th2 (IL‐4 and IL‐10), and macrophages response (TNF‐α and IL‐1β) in the periphery of asymptomatic and AMN patients, and there is correlation between VLCFA plasmatic levels and inflammatory mediators in X‐ALD. Furthermore, we might also speculate that the increase of plasmatic cytokines in asymptomatic patients could be considered an early biomarker of brain damage and maybe also a predictor of disease progression.     

Impact of glycosylation on the effect of cytokines. A special focus on oncology

The clinical use of cytokines is largely confined to the field of cancer treatment. Industrial procedures for the preparation of cytokines may or may not affect the glycosylation status of several cytokines. The glycosylation of cytokines may be of importance for the accomplishment of their biological functions, including their biological stability, their interaction with specific receptors and their pharmacokinetic behavior. The purpose of this review is thus to describe and discuss the role of cytokine glycosylation, based on experimental data, and with the clinical perspective on oncology. There is no general rule governing the effects induced by the presence of glycosylation on cytokine activity. Among different cytokines concerned by glycosylation status, data concerning G-CSF are sufficient to translate experimental findings into clinical evidence. For this cytokine, glycosylation confers advantages for both stability and biological activity. Although at weight equivalence, the glycosylated form confers greater biological activity than the non-glycosylated form, clinical studies have demonstrated that efficacy remains the same when glycosylated and non-glycosylated G-CSF are prescribed at bioequivalent doses.     

Chemokines in acute respiratory distress syndrome

A characteristic feature of all inflammatory disorders is the excessive recruitment of leukocytes to the site of inflammation. The loss of control in trafficking these cells contributes to inflammatory diseases. Leukocyte recruitment is a well-orchestrated process that includes several protein families including the large cytokine subfamily of chemotactic cytokines, the chemokines. Chemokines and their receptors are involved in the pathogenesis of several diseases. Acute lung injury that clinically manifests as acute respiratory distress syndrome (ARDS) is caused by an uncontrolled systemic inflammatory response resulting from clinical events including major surgery, trauma, multiple transfusions, severe burns, pancreatitis, and sepsis. Systemic inflammatory response syndrome involves activation of alveolar macrophages and sequestered neutrophils in the lung. The clinical hallmarks of ARDS are severe hypoxemia, diffuse bilateral pulmonary infiltrates, and normal intracardiac filling pressures. The magnitude and duration of the inflammatory process may ultimately determine the outcome in patients with ARDS. Recent evidence shows that activated leukocytes and chemokines play a key role in the pathogenesis of ARDS. The expanding number of antagonists of chemokine receptors for inflammatory disorders may hold promise for new medicines to combat ARDS.     

Staphylococcal Panton-Valentine leukocidin induces pro-inflammatory cytokine production and nuclear factor-kappa B activation in neutrophils

Panton-Valentine leukocidin (PVL) is a cytotoxin secreted by Staphylococcus aureus and associated with severe necrotizing infections. PVL targets polymorphonuclear leukocytes, especially neutrophils, which are the first line of defense against infections. Although PVL can induce neutrophil death by necrosis or apoptosis, the specific inflammatory responses of neutrophils to this toxin are unclear. In this study, both in vivo and in vitro studies demonstrated that recombinant PVL has an important cytotoxic role in human neutrophils, leading to apoptosis at low concentrations and necrosis at high concentrations. Recombinant PVL also increased the levels of pro-inflammatory cytokine secretion from neutrophils. The up-regulation of pro-inflammatory cytokines was due to nuclear factor-kappa B (NF-κB) activation induced by PVL. Moreover, blocking NF-κB inhibited the production of inflammatory cytokines. To test the role of neutrophil immune responses during the pathogenesis of PVL-induced acute lung injury, we used immunocompetent or neutropenic rabbits to develop a model of necrotizing pneumonia. Immunocompetent rabbits challenged with PVL demonstrated increased inflammation containing neutrophilic infiltrates. In addition, there were elevated levels of inflammatory cytokines (IL-6, IL-8, TNF-α and IL-10) and NF-κB in the lung homogenate. In contrast, the lung tissues from neutropenic rabbits contained mild or moderate inflammation, and the levels of inflammatory cytokines and NF-κB increased only slightly. Data from the current study support growing evidence that neutrophils play an important role in the pathogenesis of PVL-induced tissue injury and inflammation. PVL can stimulate neutrophils to release pro-inflammatory mediators, thereby causing an acute inflammatory response. The ability of PVL to induce inflammatory cytokine release may be associated with the activation of NF-κB or its pore-forming properties.     

Mpl ligand or thrombopoietin: Biological activities

Thrombopoietin (TPO) or Mpl ligand is the primary physiological regulator of platelet production. This cytokine is the most potent stimulator of the proliferation and differentiation of MK progenitor and precursor cellsin vitro. It also acts additively or synergistically with several cytokines on progenitor cells from various hematopoietic lineages, including the primitive stem cells. The factor is an extremely potent thrombocytopoietic agent when administrated to normal animals, and it accelerates platelet and erythropoietic recovery in several models of myelosuppression. Phase I/II clinical trials are ongoing with no detectable adverse effects. Mpl ligand does not induce platelet aggregation, but it lowers the platelet sensitivity to physiological dose of agonists. In experimental mouse models, high and chronic dose of Mpl ligand results in myelofibrosis. TPO is constantly produced by the liver and the kidney; its plasmatic clearance occurs by binding to its receptor expressed on megakaryocytes and platelets. However, the full spectrum of the biological effects of this new cytokine is not fully understood, in particular its the role in the terminal stage of platelet production. In the near future, it is likely that new insights will be obtained in the physiopathological mechanisms underlying abnormal platelet production in human.     

Into the Eye of the Cytokine Storm

Summary: The cytokine storm has captured the attention of the public and the scientific community alike, and while the general notion of an excessive or uncontrolled release of proinflammatory cytokines is well known, the concept of a cytokine storm and the biological consequences of cytokine overproduction are not clearly defined. Cytokine storms are associated with a wide variety of infectious and noninfectious diseases. The term was popularized largely in the context of avian H5N1 influenza virus infection, bringing the term into popular media. In this review, we focus on the cytokine storm in the context of virus infection, and we highlight how high-throughput genomic methods are revealing the importance of the kinetics of cytokine gene expression and the remarkable degree of redundancy and overlap in cytokine signaling. We also address evidence for and against the role of the cytokine storm in the pathology of clinical and infectious disease and discuss why it has been so difficult to use knowledge of the cytokine storm and immunomodulatory therapies to improve the clinical outcomes for patients with severe acute infections.     

Cytokine gene regulation by PGE(2), LTB(4) and PAF

The initial response of the host to noxious stimuli produces a nonspecific inflammatory response. A more specific immune response is believed to be modulated by two classes of molecules: lipid mediators (PG, LT and PAF) and cytokines, synthesized by phagocytes and parenchyreal cells. In this review we discuss the increasing evidence of the interrelationship between eicosanoids, PAF and cytokines: IL-1 and TNF induce PG synthesis in various cells and PG, in turn, modulate cytokine production. We focused on the regulatory effects of LTB(4), PGE(2) and PAF on cytokine gene expression.     

产白介素-17T细胞在肺部细菌感染中的研究进展

目前产白介素-17(IL-17)T细胞主要包括了产IL-17 CD4+T细胞即Th17细胞、产IL-17γδT细胞和产IL-17 CD8+T细胞等。随着对Th17这一系细胞功能研究的不断深入,发现它们能通过产生IL-17和IL-22等细胞因子参与炎症反应。该文将对产IL-17 T细胞在肺部细菌感染中所起作用的最近研究进展进行综述。     

Rho GTPases in the regulation of pulmonary vascular barrier function

Pulmonary endothelial permeability is an important determinant of vascular adaptation to changes in oxygen tension, blood pressure, levels of growth factors or inflammatory cytokines. The Ras homologous (Rho) family of guanosine triphosphate phosphatases (Rho GTPases), key regulators of the actin cytoskeleton, regulate endothelial barrier function in response to a variety of environmental factors and signalling agents via the reorganization of the actin cytoskeleton, changes in receptor trafficking or the phosphorylation of junctional proteins. This review provides a brief summary of recent knowledge on Rho-GTPase-mediated effects on pulmonary endothelial barrier function and focuses in particular on their role in pulmonary vascular disorders, including pulmonary hypertension, chronic obstructive pulmonary disease, acute lung injury and acute respiratory distress syndrome.     

Prostanoids and their receptors that modulate dendritic cell-mediated immunity

Dendritic cells (DC) are essential for the initiation of immune responses by capturing, processing and presenting antigens to T cells. In addition to their important role as professional APC, they are able to produce immunosuppressive and pro-inflammatory prostanoids from arachidonic acid (AA) by the action of cyclooxygenase (COX) enzymes. In an autocrine and paracrine fashion, the secreted lipid mediators subsequently modulate the maturation, cytokine production, Th-cell polarizing ability, chemokine receptor expression, migration, and apoptosis of these extremely versatile APC. The biological actions of prostanoids, including their effects on APC-mediated immunity and acute inflammatory responses, are exerted by G protein-coupled receptors on plasma membrane. Some COX metabolites act as anti-inflammatory lipid mediators by binding to nuclear receptors and modulating DC functions. Although the role of cytokines in DC function has been studied extensively, the effects of prostanoids on DC biology have only recently become the focus of investigation. This review summarizes the current knowledge about the role of prostanoids and their receptors in modulating DC function and the subsequent immune responses.     

The interplay between inflammation and metabolism in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by extensive synovitis resulting in erosions of articular cartilage and marginal bone that lead to joint destruction. The autoimmune process in RA depends on the activation of immune cells, which use intracellular kinases to respond to external stimuli such as cytokines, immune complexes, and antigens. An intricate cytokine network participates in inflammation and in perpetuation of disease by positive feedback loops promoting systemic disorder. The widespread systemic effects mediated by pro-inflammatory cytokines in RA impact on metabolism and in particular in lymphocyte metabolism. Moreover, RA pathobiology seems to share some common pathways with atherosclerosis, including endothelial dysfunction that is related to underlying chronic inflammation. The extent of the metabolic changes and the types of metabolites seen may be good markers of cytokine-mediated inflammatory processes in RA. Altered metabolic fingerprints may be useful in predicting the development of RA in patients with early arthritis as well as in the evaluation of the treatment response. Evidence supports the role of metabolomic analysis as a novel and nontargeted approach for identifying potential biomarkers and for improving the clinical and therapeutical management of patients with chronic inflammatory diseases. Here, we review the metabolic changes occurring in the pathogenesis of RA as well as the implication of the metabolic features in the treatment response.     

Interleukin-1 and neuronal injury

Interleukin-1 is a pro-inflammatory cytokine that has numerous biological effects, including activation of many inflammatory processes (through activation of T cells, for example), induction of expression of acute-phase proteins, an important function in neuroimmune responses and direct effects on the brain itself. There is now extensive evidence to support the direct involvement of interleukin-1 in the neuronal injury that occurs in both acute and chronic neurodegenerative disorders. This article discusses the key evidence of a role for interleukin-1 in acute neurodegeneration - for example, stroke and brain trauma - and provides a rationale for targeting the interleukin-1 system as a therapeutic strategy.     

Dual biological effects of the cytokines interleukin-10 and interferon-γ

It is generally thought that each cytokine exerts either immune stimulatory (inflammatory) or immune inhibitory (antiinflammatory or regulatory) biological activities. However, multiple cytokines can enact both inhibitory and stimulatory effects on the immune system. Two of these cytokines are interleukin (IL)-10 and interferon-gamma (IFNγ). IL-10 has demonstrated antitumor immunity even though it has been known for years as an immunoregulatory protein. Generally perceived as an immune stimulatory cytokine, IFNγ can also induce inhibitory molecule expression including B7-H1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), and arginase on multiple cell populations (dendritic cells, tumor cells, and vascular endothelial cells). In this review, we will summarize current knowledge of the dual roles of both of these cytokines and stress the previously underappreciated stimulatory role of IL-10 and inhibitory role of IFNγ in the context of malignancy. Our progressive understanding of the dual effects of these cytokines is important for dissecting cytokine-associated pathology and provides new avenues for developing effective immune therapy against human diseases, including cancer.     

Increased Blood Levels of Growth Factors,Proinflammatory Cytokines,and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes

The production of several cytokines could be dysregulated in type 1 diabetes (T1D). In particular, the activation of T helper (Th) type 1 (Th₁) cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th₁₇ pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α), Th₁₇ cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8), but not human leukocyte antigen (HLA) genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.     

The NLRP3 inflammasome and COVID-19: Activation,pathogenesis and therapeutic strategies

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits a wide spectrum of clinical presentations, ranging from asymptomatic cases to severe pneumonia or even death. In severe COVID-19 cases, an increased level of proinflammatory cytokines has been observed in the bloodstream, forming the so-called “cytokine storm”. Generally, nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation intensely induces cytokine production as an inflammatory response to viral infection. Therefore, the NLRP3 inflammasome can be a potential target for the treatment of COVID-19. Hence, this review first introduces the canonical NLRP3 inflammasome activation pathway. Second, we review the cellular/molecular mechanisms of NLRP3 inflammasome activation by SARS-CoV-2 infection (e.g., viroporins, ion flux and the complement cascade). Furthermore, we describe the involvement of the NLRP3 inflammasome in the pathogenesis of COVID-19 (e.g., cytokine storm, respiratory manifestations, cardiovascular comorbidity and neurological symptoms). Finally, we also propose several promising inhibitors targeting the NLRP3 inflammasome, cytokine products and neutrophils to provide novel therapeutic strategies for COVID-19.     

Gastrin-releasing peptide,substance P and cytokines in rheumatoid arthritis

Many studies have shown that modulation of cytokine function is effective in ameliorating symptoms of rheumatoid arthritis. Neuropeptides have recently been shown to have powerful effects on the production and release of cytokines and have also been shown to exert potent proinflammatory and anti-inflammatory effects in animal models of inflammatory diseases. An analysis of cytokine and neuropeptide content of synovial fluid from patients with rheumatoid arthritis has revealed a significant correlation between two neuropeptides, bombesin/gastrin-releasing peptide and substance P, and the proinflammatory cytokine interleukin-6 as well as the erythrocyte sedimentation rate. These findings provide further evidence for a role of neuropeptides and cytokines in the pathophysiology of rheumatoid arthritis, as well as suggesting additional approaches for the development of novel therapeutic interventions.