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Multiple myeloma (MM), the second most common hematologic malignancy, remains incurable, and its incidence is rising. Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a novel treatment, with the potential to improve the survival and quality of life of patients with relapsed/refractory multiple myeloma (rrMM). In this systematic review and meta-analysis, conducted in accordance with PRISMA guidelines, we aim to provide a concise overview of the latest developments in CAR-T therapy, assess their potential implications for clinical practice, and evaluate their efficacy and safety outcomes based on the most up-to-date evidence. A literature search conducted from 1 January 2019 to 12 July 2023 on Medline/PubMed, Scopus, and Web of Science identified 2273 articles, of which 29 fulfilled the specified criteria for inclusion. Our results offer robust evidence supporting CAR-T cell therapy's efficacy in rrMM patients, with an encouraging 83.21% overall response rate (ORR). A generally safe profile was observed, with grade ≥ 3 cytokine release syndrome (CRS) at 7.12% and grade ≥ 3 neurotoxicity at 1.37%. A subgroup analysis revealed a significantly increased ORR in patients with fewer antimyeloma regimens, while grade ≥ 3 CRS was more common in those with a higher proportion of high-risk cytogenetics and prior exposure to BCMA therapy. [ABSTRACT FROM AUTHOR]

In COVID-19, cytokine release syndrome can cause severe lung tissue damage leading to acute respiratory distress syndrome (ARDS). Here, we address the effects of IFNγ, TNFα, IL-1β and IL-6 on the growth arrest of alveolar A549 cells, focusing on the role of the IFN regulatory factor 1 (IRF1) transcription factor. The efficacy of JAK1/2 inhibitor baricitinib has also been tested. A549 WT and IRF1 KO cells were exposed to cytokines for up to 72 h. Cell proliferation and death were evaluated with the resazurin assay, analysis of cell cycle and cycle-regulator proteins, LDH release and Annexin-V positivity; the induction of senescence and senescence-associated secretory phenotype (SASP) was evaluated through β-galactosidase staining and the quantitation of secreted inflammatory mediators. While IL-1 and IL-6 proved ineffective, IFNγ plus TNFα caused a proliferative arrest in A549 WT cells with alterations in cell morphology, along with the acquisition of a secretory phenotype. These effects were STAT and IRF1-dependent since they were prevented by baricitinib and much less evident in IRF1 KO than in WT cells. In alveolar cells, STATs/IRF1 axis is required for cytokine-induced proliferative arrest and the induction of a secretory phenotype. Hence, baricitininb is a promising therapeutic strategy for the attenuation of senescence-associated inflammation. [ABSTRACT FROM AUTHOR]

Efforts to treat cancer using chimeric antigen receptor (CAR)-T therapy have made astonishing progress and clinical trials against hematopoietic malignancies have demonstrated their use. However, there are still disadvantages which need to be addressed: high costs, and side effects such as Graft-versus-Host Disease (GvHD) and Cytokine Release Syndrome (CRS). Therefore, recent efforts have been made to harness the properties of certain immune cells to treat cancer—not just T cells, but also natural killer (NK) cells, macrophages (Mφ), dendritic cells (DC), etc. In this paper, we will introduce immune cell-based cellular therapies that use various immune cells and describe their characteristics and their clinical situation. The development of immune cell-based cancer therapy fully utilizing the unique advantages of each and every immune cell is expected to enhance the survival of tumor patients owing to their high efficiency and fewer side effects. [ABSTRACT FROM AUTHOR]

The pathophysiology of the severe course of COVID-19 is multifactorial and not entirely elucidated. However, it is well known that the hyperinflammatory response and cytokine storm are paramount events leading to further complications. In this paper, we investigated the vascular response in the pathophysiology of severe COVID-19 and aimed to identify novel biomarkers predictive of ICU admission. The study group consisted of 210 patients diagnosed with COVID-19 (age range: 18–93; mean ± SD: 57.78 ± 14.16), while the control group consisted of 80 healthy individuals. We assessed the plasma concentrations of various vascular factors using the Luminex technique. Then, we isolated RNA from blood mononuclear cells and performed a bioinformatics analysis investigating various processes related to vascular response, inflammation and angiogenesis. Our results confirmed that severe COVID-19 is associated with vWF/ADAMTS 13 imbalance. High plasma concentrations of VEGFR and low DPP-IV may be potential predictors of ICU admission. SARS-CoV-2 infection impairs angiogenesis, hinders the generation of nitric oxide, and thus impedes vasodilation. The hypercoagulable state develops mainly in the early stages of the disease, which may contribute to the well-established complications of COVID-19. [ABSTRACT FROM AUTHOR]

Cellular homeostasis is lost or becomes dysfunctional during septic shock due to the activation of the inflammatory response and the deregulation of oxidative stress. Antioxidant therapy administered alongside standard treatment could restore this lost homeostasis. We included 131 patients with septic shock who were treated with standard treatment and vitamin C (Vit C), vitamin E (Vit E), N-acetylcysteine (NAC), or melatonin (MT), in a randomized trial. Organ damage quantified by Sequential Organ Failure Assessment (SOFA) score, and we determined levels of Interleukins (IL) IL1β, Tumor necrosis factor alpha (TNFα), IL-6, monocyte chemoattractant protein-1 (MCP-1), Transforming growth factor B (TGFβ), IL-4, IL-10, IL-12, and Interferon-γ (IFNγ). The SOFA score decreased in patients treated with Vit C, NAC, and MT. Patients treated with MT had statistically significantly reduced of IL-6, IL-8, MCP-1, and IL-10 levels. Lipid peroxidation, Nitrates and nitrites (NO3− and NO2−), glutathione reductase, and superoxide dismutase decreased after treatment with Vit C, Vit E, NAC, and MT. The levels of thiols recovered with the use of Vit E, and all patients treated with antioxidants maintained their selenium levels, in contrast with controls (p = 0.04). The findings regarding oxidative stress markers and cytokines after treatment with antioxidants allow us to consider to future the combined use of antioxidants in a randomized clinical trial with a larger sample to demonstrate the reproducibility of these beneficial effects. [ABSTRACT FROM AUTHOR]

Sepsis results from uncontrolled inflammation, characterized by cytokine storm and immunoparalysis. To assess whether galgravin, a natural lignan isolated from Piper kadsura, can be used to treat sepsis, models of bacterial lipopolysaccharide (LPS)-activated macrophages and LPS-induced endotoxemia mice were used. Galgravin suppressed NF-κB activation in LPS-activated RAW 264.7 macrophages without causing significant cytotoxicity, in which proinflammatory molecules like TNF-α, IL-6, iNOS, and COX-2 were downregulated. In addition, the expression of TNF-α and IL-6 was also suppressed by galgravin in LPS-activated murine bone marrow-derived macrophages. Moreover, galgravin significantly downregulated the mRNA expression of TNF-α, IL-6, and iNOS in the lungs and decreased TNF-α and IL-6 in the serum and IL-6 in the bronchoalveolar lavage fluid of LPS-challenged mice. The COX-2 expression in tissues, including the lung, liver, and kidney, as well as the lung alveolar hemorrhage, was also reduced by galgravin. The present study reveals the anti-inflammatory effects of galgravin in mouse models and implies its potential application in inflammation diseases. [ABSTRACT FROM AUTHOR]

Inflammation and inflammasomes have been proposed as important regulators of the host–microorganism interaction, playing a key role in morbidity and mortality due to the coronavirus disease 2019 (COVID-19) in subjects with chronic conditions and compromised immune system. The inflammasome consists of a multiprotein complex that finely regulates the activation of caspase-1 and the production and secretion of potent pro-inflammatory cytokines such as IL-1β and IL-18. The pyrin containing NOD (nucleotide-binding oligomerization domain) like receptor (NLRP) is a family of intracellular receptors, sensing patterns associated to pathogens or danger signals and NLRP3 inflammasome is the most deeply analyzed for its involvement in the innate and adaptive immune system as well as its contribution to several autoinflammatory and autoimmune diseases. It is highly expressed in leukocytes and up-regulated in sentinel cells upon inflammatory stimuli. NLRP3 expression has also been reported in B and T lymphocytes, in epithelial cells of oral and genital mucosa, in specific parenchymal cells as cardiomyocytes, and keratinocytes, and chondrocytes. It is well known that a dysregulated activation of the inflammasome is involved in the pathogenesis of different disorders that share the common red line of inflammation in their pathogenetic fingerprint. Here, we review the potential roles of the NLRP3 inflammasome in cardiovascular events, liver damage, pulmonary diseases, and in that wide range of systemic inflammatory syndromes named as a cytokine storm. [ABSTRACT FROM AUTHOR]

Hypercytokinemia, or cytokine storm, often complicates the treatment of viral and bacterial infections, including COVID-19, leading to the risk of thrombosis. However, the use of currently available direct anticoagulants for the treatment of COVID-19 patients is limited due to safety reasons. Therefore, the development of new anticoagulants remains an urgent task for organic and medicinal chemistry. At the same time, new drugs that combine anticoagulant properties with antiviral or antidiabetic activity could be helpfull in the treatment of COVID-19 patients, especially those suffering from such concomitant diseases as arterial hypertension or diabetes. We have synthesized a number of novel substituted azoloazines, some of which have previously been identified as compounds with pronounced antiviral, antibacterial, antidiabetic, antiaggregant, and anticoagulant activity. Two compounds from the family of 1,2,4-triazolo[1,5-a]pyrimidines have demonstrated anticoagulant activity at a level exceeding or at least comparable with that of dabigatran etexilate as the reference compound. 7,5-Di(2-thienyl)-4,5-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine has shown the highest ability to prolong the thrombin time, surpassing this reference drug by 2.2 times. This compound has also exhibited anticoagulant activity associated with the inhibition of thrombin (factor IIa). Moreover, the anticoagulant effect of this substance becomes enhanced under the conditions of a systemic inflammatory reaction. [ABSTRACT FROM AUTHOR]

Inflammation is an important immune response to pathogen invasion, but excessive inflammation leads to tissue injury and even cytokine storm. Therefore, proper response is needed depending on the intensity of the infection. Ras guanine nucleotide releasing protein 3 (RasGRP3) is a regulator of the TLR-mediated response. In low-intensity inflammation, it negatively regulates production of pro-inflammatory cytokines, especially IL-6. Citri Reticulatae Pericarpium, the peel of Citrus reticulata Blanco, is a major medicinal herb in Korean medicine. The present study aims to investigate whether the Citri Reticulatae Pericarpium extract (CRE) has immunomodulatory activity using the Raw264.7 macrophage. Also, we investigated the effect of CRE on RasGRP3 expression. In the present study, CRE reduced IL-6 production in the low-LPS environment (1 ng/mL) and did not in the high-LPS environment (100 ng/mL). The suppression of IL-6 production in the low-LPS environment (1 ng/mL) was abolished after the pretreatment of RasGRP3 siRNA. The reduced RasGRP3 protein content by 100 ng/mL LPS treatment was increased by CRE treatment. Additionally, nobiletin, a major component of CRE showed a suppressive effect on IL-6 production in the low-LPS environment (1 ng/mL). The present results suggest that CRE alleviates inflammatory response via activating RasGRP3 expression in low-intensity inflammation. [ABSTRACT FROM AUTHOR]

Coronavirus disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a "cytokine storm", and neuroinflammation. COVID-19's upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by the formation of Lewy bodies made primarily of the α-synuclein protein encoded by the synuclein alpha (SNCA) gene. We hypothesize that COVID-19 may modulate PD progression through neuroinflammation induced by cytokine storms. This study aimed to elucidate the possible mechanisms and signaling pathways involved in COVID-19-triggered pathology associated with neurodegenerative diseases like PD. This study presents the analysis of the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN's Ingenuity Pathway Analysis (IPA), the study identified the NISP as a top-five canonical pathway/signaling pathway and SNCA as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and SNCA to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of SNCA, and subsequently PD, through a dataset of intermediary molecules. Downstream effect analysis was further used to quantify the downregulation of ACE2 on SNCA activation. [ABSTRACT FROM AUTHOR]

Inflammation has been described for two millennia, but cellular aspects and the paradigm involving different mediators have been identified in the recent century. Two main groups of molecules, the prostaglandins (PG) and the cytokines, have been discovered and play a major role in inflammatory processes. The activation of prostaglandins PGE2, PGD2 and PGI2 results in prominent symptoms during cardiovascular and rheumatoid diseases. The balance between pro- and anti-inflammatory compounds is nowadays a challenge for more targeted therapeutic approaches. The first cytokine was described more than a century ago and is now a part of different families of cytokines (38 interleukins), including the IL-1 and IL-6 families and TNF and TGFβ families. Cytokines can perform a dual role, being growth promotors or inhibitors and having pro- and anti-inflammatory properties. The complex interactions between cytokines, vascular cells and immune cells are responsible for dramatic conditions and lead to the concept of cytokine storm observed during sepsis, multi-organ failure and, recently, in some cases of COVID-19 infection. Cytokines such as interferon and hematopoietic growth factor have been used as therapy. Alternatively, the inhibition of cytokine functions has been largely developed using anti-interleukin or anti-TNF monoclonal antibodies in the treatment of sepsis or chronic inflammation. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies has made great progress, but there are still some problems. First, T cells from tumor patients show an exhaustion phenotype; thus, the persistence and function of the CAR-Ts are poor, and achieving a satisfactory curative effect is difficult. Second, some patients initially respond well but quickly develop antigen-negative tumor recurrence. Thirdly, CAR-T treatment is not effective in some patients and is accompanied by severe side effects, such as cytokine release syndrome (CRS) and neurotoxicity. The solution to these problems is to reduce the toxicity and enhance the efficacy of CAR-T therapy. In this paper, we describe various strategies for reducing the toxicity and enhancing the efficacy of CAR-T therapy in hematological malignancies. In the first section, strategies for modifying CAR-Ts using gene-editing technologies or combining them with other anti-tumor drugs to enhance the efficacy of CAR-T therapy are introduced. The second section describes some methods in which the design and construction of CAR-Ts differ from the conventional process. The aim of these methods is to enhance the anti-tumor activity of CAR-Ts and prevent tumor recurrence. The third section describes modifying the CAR structure or installing safety switches to radically reduce CAR-T toxicity or regulating inflammatory cytokines to control the symptoms of CAR-T-associated toxicity. Together, the knowledge summarized herein will aid in designing better-suited and safer CAR-T treatment strategies. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues to be more readily adopted and indications increase, the field's recognition of emerging toxicities will continue to grow. Among the adverse events associated with CAR T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are the most common toxicities, while thrombotic events represent an under-reported, life-endangering complication. To determine thrombosis incidence post CAR T-cell therapy, we performed a multi-center, retrospective study on CAR T-cell therapy adult patients (N = 140) from Indiana University Simon Cancer Center and the University of North Carolina Medical Center treated from 2017 to 2022 for relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL, N = 3), diffuse large B-cell lymphoma (DLBCL, N = 92), follicular lymphoma (FL, N = 9), mantle cell lymphoma (MCL, N = 2), and multiple myeloma (MM, N = 34). We report 10 (7.14%) thrombotic events related to CAR T-cell therapy (DLBCL: N = 8, FL: N = 1, MM: N = 1) including 9 primary venous events and 1 arterial event that occurred with median time of 23.5 days post CAR T-cell infusion. In search of parameters associated with such events, we performed multivariate analyses of coagulation parameters (i.e., PT, PTT, and D-Dimer), scoring for adverse events (Padua Score and ISTH DIC Score) and grading for CAR T-cell toxicity severity (CRS grade and ICANS grade) and found that D-Dimer peak elevation and ICANS grade were significantly associated with post-CAR T-cell infusion thrombosis. While the pathophysiology of CAR T-cell associated coagulopathy remains unknown, our study serves to develop awareness of these emerging and unusual complications. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome is an acute respiratory failure caused by cytokine storms; highly pathogenic influenza A virus infection can induce cytokine storms. The innate immune response is vital in this cytokine storm, acting by activating the transcription factor NF-κB. Tissue injury releases a danger-associated molecular pattern that provides positive feedback for NF-κB activation. Exogenous mesenchymal stem cells can also modulate immune responses by producing potent immunosuppressive substances, such as prostaglandin E2. Prostaglandin E2 is a critical mediator that regulates various physiological and pathological processes through autocrine or paracrine mechanisms. Activation of prostaglandin E2 results in the accumulation of unphosphorylated β-catenin in the cytoplasm, which subsequently reaches the nucleus to inhibit the transcription factor NF-κB. The inhibition of NF-κB by β-catenin is a mechanism that reduces inflammation. [ABSTRACT FROM AUTHOR]

Although the exact mechanism of the pathogenesis of coronavirus SARS-CoV-2 (COVID-19) is not fully understood, oxidative stress and the release of pro-inflammatory cytokines have been highlighted as playing a vital role in the pathogenesis of the disease. In this sense, alternative treatments are needed to reduce the level of inflammation caused by COVID-19. Therefore, this study aimed to investigate the potential effect of red photobiomodulation (PBM) as an attractive therapy to downregulate the cytokine storm caused by COVID-19 in a zebrafish model. RT-qPCR analyses and protein–protein interaction prediction among SARS-CoV-2 and Danio rerio proteins showed that recombinant Spike protein (rSpike) was responsible for generating systemic inflammatory processes with significantly increased levels of pro-inflammatory (il1b, il6, tnfa, and nfkbiab), oxidative stress (romo1) and energy metabolism (slc2a1a and coa1) mRNA markers, with a pattern similar to those observed in COVID-19 cases in humans. On the other hand, PBM treatment was able to decrease the mRNA levels of these pro-inflammatory and oxidative stress markers compared with rSpike in various tissues, promoting an anti-inflammatory response. Conversely, PBM promotes cellular and tissue repair of injured tissues and significantly increases the survival rate of rSpike-inoculated individuals. Additionally, metabolomics analysis showed that the most-impacted metabolic pathways between PBM and the rSpike treated groups were related to steroid metabolism, immune system, and lipid metabolism. Together, our findings suggest that the inflammatory process is an incisive feature of COVID-19 and red PBM can be used as a novel therapeutic agent for COVID-19 by regulating the inflammatory response. Nevertheless, the need for more clinical trials remains, and there is a significant gap to overcome before clinical trials can commence. [ABSTRACT FROM AUTHOR]

The effects SARS-CoV-2 inflicts on human physiology, especially in patients who developed COVID-19, can range from flu-like symptoms to death, and although many lives have been lost during the pandemic, others have faced the resolution of aggressive neoplasms that once proclaimed a poor prognosis following traditional treatments. The purpose of this review was to analyze several fortunate case reports and their associated biomolecular pathways to further explore new avenues that might provide oncological treatments in the future of medicine. We included papers that discussed cases in which patients affected by COVID-19 suffered beneficial changes in their cancer status. Multiple mechanisms which elicited a reactivation of the host's immune system included cross-reactivity with viral antigens and downregulation of neoplastic cells. We were able to identify important cases presenting the resolution/remission of different aggressive neoplasms, for which most of the time, standard-of-care treatments offered little to no prospect towards a cure. The intricacy of the defense mechanisms humans have adopted against cancer cells through the millennia are still not well understood, but SARS-CoV-2 has demonstrated that the same ruinous cytokine storm which has taken so many lives can paradoxically be the answer we have been looking for to recalibrate the immunological system to retarget and vanquish malignancies. [ABSTRACT FROM AUTHOR]

Hemodynamic disturbance, a rise in neutrophil-to-lymphocyte ratio (NLR) and release of inflammatory cytokines into blood, is a bad prognostic indicator in severe COVID-19 and other diseases involving cytokine storm syndrome (CSS). The purpose of this study was to explore if zymosan, a known stimulator of the innate immune system, could reproduce these changes in pigs. Pigs were instrumented for hemodynamic analysis and, after i.v. administration of zymosan, serial blood samples were taken to measure blood cell changes, cytokine gene transcription in PBMC and blood levels of inflammatory cytokines, using qPCR and ELISA. Zymosan bolus (0.1 mg/kg) elicited transient hemodynamic disturbance within minutes without detectable cytokine or blood cell changes. In contrast, infusion of 1 mg/kg zymosan triggered maximal pulmonary hypertension with tachycardia, lasting for 30 min. This was followed by a transient granulopenia and then, up to 6 h, major granulocytosis, resulting in a 3–4-fold increase in NLR. These changes were paralleled by massive transcription and/or rise in IL-6, TNF-alpha, CCL-2, CXCL-10, and IL-1RA in blood. There was significant correlation between lymphopenia and IL-6 gene expression. We conclude that the presented model may enable mechanistic studies on late-stage COVID-19 and CSS, as well as streamlined drug testing against these conditions. [ABSTRACT FROM AUTHOR]

Genetically engineered T and NK cells expressing a chimeric antigen receptor (CAR) are promising cytotoxic cells for the treatment of hematological malignancies and solid tumors. Despite the successful therapies using CAR-T cells, they have some disadvantages, such as cytokine release syndrome (CRS), neurotoxicity, or graft-versus-host-disease (GVHD). CAR-NK cells have lack or minimal cytokine release syndrome and neurotoxicity, but also multiple mechanisms of cytotoxic activity. NK cells are suitable for developing an "off the shelf" therapeutic product that causes little or no graft versus host disease (GvHD), but they are more sensitive to apoptosis and have low levels of gene expression compared to CAR-T cells. To avoid these adverse effects, further developments need to be considered to enhance the effectiveness of adoptive cellular immunotherapy. A promising approach to enhance the effectiveness of adoptive cellular immunotherapy is overcoming terminal differentiation or senescence and exhaustion of T cells. In this case, EVs derived from immune cells in combination therapy with drugs may be considered in the treatment of cancer patients, especially effector T and NK cells-derived exosomes with the cytotoxic activity of their original cells. [ABSTRACT FROM AUTHOR]

Coronavirus SARS-CoV-2 has represented, and still represents, a real challenge from a clinical, diagnostic and therapeutic point of view. During acute infection, the increased levels of pro-inflammatory cytokines, which are involved in the pathology of disease and the development of SARS-CoV-2-induced acute respiratory disease syndrome, the life-threatening form of this infection, are correlated with patient survival and disease severity. IL-33, a key cytokine involved in both innate and adaptive immune responses in mucosal organs, can increase airway inflammation, mucus secretion and Th2 cytokine synthesis in the lungs, following respiratory infections. Similar to cases of exposure to known respiratory virus infections, exposure to SARS-CoV-2 induces the expression of IL-33, correlating with T-cell activation and lung disease severity. In this work, we analyse current evidence regarding the immunological role of IL-33 in patients affected by COVID-19, to evaluate not only the clinical impact correlated to its production but also to identify possible future immunological therapies that can block the most expressed inflammatory molecules, preventing worsening of the disease and saving patient lives. [ABSTRACT FROM AUTHOR]

Systemic juvenile idiopathic arthritis (sJIA) and its complication, macrophage activation syndrome (sJIA-MAS), are rare but sometimes very serious or even critical diseases of childhood that can occasionally be characterized by nonspecific clinical signs and symptoms at onset—such as non-remitting high fever, headache, rash, or arthralgia—and are biologically accompanied by an increase in acute-phase reactants. For a correct positive diagnosis, it is necessary to rule out bacterial or viral infections, neoplasia, and other immune-mediated inflammatory diseases. Delays in diagnosis will result in late initiation of targeted therapy. A set of biomarkers is useful to distinguish sJIA or sJIA-MAS from similar clinical entities, especially when arthritis is absent. Biomarkers should be accessible to many patients, with convenient production and acquisition prices for pediatric medical laboratories, as well as being easy to determine, having high sensitivity and specificity, and correlating with pathophysiological disease pathways. The aim of this review was to identify the newest and most powerful biomarkers and their synergistic interaction for easy and accurate recognition of sJIA and sJIA-MAS, so as to immediately guide clinicians in correct diagnosis and in predicting disease outcomes, the response to treatment, and the risk of relapses. Biomarkers constitute an exciting field of research, especially due to the heterogeneous nature of cytokine storm syndromes (CSSs) in the COVID era. They must be selected with utmost care—a fact supported by the increasingly improved genetic and pathophysiological comprehension of sJIA, but also of CSS—so that new classification systems may soon be developed to define homogeneous groups of patients, although each with a distinct disease. [ABSTRACT FROM AUTHOR]

The human innate and adaptive immune systems consist of effector cells producing cytokines (interleukins, interferons, chemokines, and numerous other mediators). Usually, a fragile equilibrium of pro- and anti-inflammation effects is maintained by complex regulatory mechanisms. Disturbances of this homeostasis can lead to intricate chain reactions resulting in a massive release of cytokines. This may result in a drastic self-reinforcement of various feedback mechanisms, which can ultimately lead to systemic damage, multi-organ failure, or death. Not only pathogens can initiate such disturbances, but also congenital diseases or immunomodulatory therapies. Due to the complex and diverse interactions within the innate and adaptive immune systems, the understanding of this important clinical syndrome is incomplete to date and effective therapeutic approaches remain scarce. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has had a deep impact on people worldwide since late 2019 when SARS-CoV-2 was first identified in Wuhan, China. In addition to its effect on public health, it has affected humans in various aspects of life, including social, economic, cultural, and political. It is also true that researchers have made vigorous efforts to overcome COVID-19 throughout the world, but they still have a long way to go. Accordingly, innumerable therapeutics and vaccine candidates have been studied for their efficacies and have been tried clinically in a very short span of time. For example, the versatility of extracellular vesicles, which are membrane-bound particles released from all types of cells, have recently been highlighted in terms of their effectiveness, biocompatibility, and safety in the fight against COVID-19. Thus, here, we tried to explain the use of extracellular vesicles as therapeutics and for the development of vaccines against COVID-19. Along with the mechanisms and a comprehensive background of their application in trapping the coronavirus or controlling the cytokine storm, we also discuss the obstacles to the clinical use of extracellular vesicles and how these could be resolved in the future. [ABSTRACT FROM AUTHOR]

COVID-19 pathogenesis develops in two phases. First, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 spreads within the epithelial cells of the mucosa of upper and, possibly, lower respiratory tracts. While the virus dissemination can be controlled by an emerging adaptive host immune response, if the virus diffuses to the pulmonary alveoli, a potentially lethal mechanism can arise in the second phase. It consists of an uncontrolled burst of cytokines/inflammatory factors (i.e., cytokine storm), leading to the insurgence of respiratory symptoms and, consequently, multi-organ failures. Messenger (m)RNA-based vaccines represent the most innovative approach in terms of prophylaxis against SARS-CoV-2-induced disease. The cumulating data indicate that the response to mRNA vaccines is basically ineffective to counteract the viral replication in the upper respiratory tracts, while showing efficacy in containing the development of severe disease. Considering that the antiviral immunity elicited by intramuscularly delivered mRNA vaccines is expected to show similar quantitative and qualitative features in upper and lower respiratory tracts, the different outcomes appear surprising and deserve accurate consideration. In this review, a still unexplored mechanism accounting for the mRNA vaccine effect against severe disease is proposed. Based on well-established experimental evidence, a possible inhibitory effect on alveolar macrophages as a consequence of the diffusion of the extracellular and/or cell-associated Spike protein can be envisioned as a key event counteracting the cytokine storm. This benefit, however, may be associated with defects in the immune functions of macrophages in other tissues whose possible consequences deserve careful evaluation. [ABSTRACT FROM AUTHOR]

Hypercytokinemia, found in SARS-CoV-2 infection, contributes to multiple organ dysfunctions with acute respiratory distress syndrome, shock etc. The aim of this study was to describe cytokine storm signatures in patients with acute COVID-19 and to investigate their influence on severity of the infection. Plasma levels of 47 cytokines were investigated in 73 patients with moderate and severe COVID-19 (41 and 32, respectively) and 11 healthy donors (HD). The most elevated levels comparing patients and the HD were observed for seven pro-inflammatory cytokines (IL-6, IL-8, IL-15, IL-18, IL-27, IFNγ, TNFα), three chemokines (GROα, IP-10, MIG), two anti-inflammatory cytokines (IL-1RA, IL-10), and two growth factors (G-CSF, M-CSF). The patients with severe disease had significantly higher levels of FGF-2/FGF-basic, IL-1β, and IL-7 compared to the HD. The two groups of patients differed from each other only based on the levels of EGF, eotaxin, and IL-12 p40. Pneumonia lung injury, characterized by computer tomography, positively correlated with levels of EGF, IP-10, MCP-3 levels and negatively with IL-12 p40. Pro-inflammatory factors including IL-6, TNFα, and IP-10 negatively correlated with the frequency of the circulating T-helper17-like cells (Th17-like) and follicular Th cells that are crucial to develop SARS-CoV-2-specific plasma cells and memory B cells. Obtained data on the cytokine levels illustrate their influence on progression and severity of COVID-19. [ABSTRACT FROM AUTHOR]

Contemporary anticancer immunotherapy with chimeric antigen receptor T-cell (CAR-T) therapy has dramatically changed the treatment of many hematologic malignancies previously associated with poor prognosis. The clinical improvement and the survival benefit unveiled the risk of cardiotoxicity, ranging from minimal effects to severe cardiac adverse events, including death. Immunotherapy should also be proposed even in patients with pre-existing cardiovascular risk factors, thereby increasing the potential harm of cardiotoxicity. CAR-T therapy frequently results in cytokine release syndrome (CRS), and inflammatory activation is sustained by circulating cytokines that foster a positive feedback mechanism. Prompt diagnosis and treatment of CAR-T cardiotoxicity might significantly improve outcomes and reduce the burden associated with cardiovascular complications. Clinical and echocardiographic examinations are crucial to perform a tailored evaluation and follow-up during CAR-T treatment. This review aims to summarize the pathophysiology, clinical implications, and echocardiographic assessment of CAR-T-related cardiotoxicity to enlighten new avenues for future research. [ABSTRACT FROM AUTHOR]

Herein, we elucidate the biophysical aspects of the interaction of an important protein, Interleukin-6 (IL6), which is involved in cytokine storm syndrome, with a natural product with anti-inflammatory activity, piperine. Despite the role of piperine in the inhibition of the transcriptional protein NF-κB pathway responsible for activation of IL6 gene expression, there are no studies to the best of our knowledge regarding the characterisation of the molecular interaction of the IL6-piperine complex. In this context, the characterisation was performed with spectroscopic experiments aided by molecular modelling. Fluorescence spectroscopy alongside van't Hoff analyses showed that the complexation event is a spontaneous process driven by non-specific interactions. Circular dichroism aided by molecular dynamics revealed that piperine caused local α-helix reduction. Molecular docking and molecular dynamics disclosed the microenvironment of interaction as non-polar amino acid residues. Although piperine has three available hydrogen bond acceptors, only one hydrogen-bond was formed during our simulation experiments, reinforcing the major role of non-specific interactions that we observed experimentally. Root mean square deviation (RMSD) and hydrodynamic radii revealed that the IL6-piperine complex was stable during 800 ns of simulation. Taken together, these results can support ongoing IL6 drug discovery efforts. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is characterized by immune activation in response to viral spread, in severe cases leading to the development of cytokine storm syndrome (CSS) and increased mortality. Despite its importance in prognosis, the pathophysiological mechanisms of CSS in COVID-19 remain to be defined. Towards this goal, we analyzed cytokine profiles and their interrelation in regard to anti-cytokine treatment with tocilizumab in 98 hospitalized patients with COVID-19. We performed a multiplex measurement of 41 circulating cytokines in the plasma of patients on admission and 3–5 days after, during the follow-up. Then we analyzed the patient groups separated in two ways: according to the clusterization of their blood cytokines and based on the administration of tocilizumab therapy. Patients with and without CSS formed distinct clusters according to their cytokine concentration changes. However, the tocilizumab therapy, administered based on the standard clinical and laboratory criteria, did not fully correspond to those clusters of CSS. Furthermore, among all cytokines, IL-6, IL-1RA, IL-10, and G-CSF demonstrated the most prominent differences between patients with and without clinical endpoints, while only IL-1RA was prognostically significant in both groups of patients with and without tocilizumab therapy, decreasing in the former and increasing in the latter during the follow-up period. Thus, CSS in COVID-19, characterized by a correlated release of multiple cytokines, does not fully correspond to the standard parameters of disease severity. Analysis of the cytokine signature, including the IL-1RA level in addition to standard clinical and laboratory parameters may be useful to define the onset of a cytokine storm in COVID-19 as well as the indications for anti-cytokine therapy. [ABSTRACT FROM AUTHOR]

Coronavirus 2019 disease (COVID-19) is caused by different variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in December of 2019. COVID-19 pathogenesis is complex and involves a dysregulated renin angiotensin system. Severe courses of the disease are associated with a dysregulated immunological response known as cytokine storm. Many scientists have demonstrated that SARS-CoV-2 impacts oxidative homeostasis and stimulates the production of reactive oxygen species (ROS). In addition, the virus inhibits glutathione (GSH) and nuclear factor erythroid 2-related factor 2 (NRF2)—a major antioxidant which induces expression of protective proteins and prevents ROS damage. Furthermore, the virus stimulates NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasomes which play a significant role in inducing a cytokine storm. A variety of agents with antioxidant properties have shown beneficial effects in experimental and clinical studies of COVID-19. This review aims to present mechanisms of oxidative stress induced by SARS-CoV-2 and to discuss whether antioxidative drugs can counteract detrimental outcomes of a cytokine storm. [ABSTRACT FROM AUTHOR]

In the beginning of the third year of the fight against COVID-19, the virus remains at least still one step ahead in the pandemic "war". The key reasons are evolving lineages and mutations, resulting in an increase of transmissibility and ability to evade immune system. However, from the immunologic point of view, the cytokine storm (CS) remains a poorly understood and difficult to combat culprit of the extended number of in-hospital admissions and deaths. It is not fully clear whether the cytokine release is a harmful result of suppression of the immune system or a positive reaction necessary to clear the virus. To develop methods of appropriate treatment and therefore decrease the mortality of the so-called COVID-19-CS, we need to look deeply inside its pathogenesis, which is the purpose of this review. [ABSTRACT FROM AUTHOR]

Dysregulation of the immune response plays an important role in the progression of SARS-CoV-2 infection. A "cytokine storm", which is a phenomenon associated with uncontrolled production of large amounts of cytokines, very often affects patients with COVID-19. Elevated activity of chemotactic cytokines, called chemokines, can lead to serious consequences. CXCL10 has an ability to activate its receptor CXCR3, predominantly expressed on macrophages, T lymphocytes, dendritic cells, natural killer cells, and B cells. So, it has been suggested that the chemokine CXCL10, through CXCR3, is associated with inflammatory diseases and may be involved in the development of COVID-19. Therefore, in this review paper, we focus on the role of CXCL10 overactivity in the pathogenesis of COVID-19. We performed an extensive literature search for our investigation using the MEDLINE/PubMed database. Increased concentrations of CXCL10 were observed in COVID-19. Elevated levels of CXCL10 were reported to be associated with a severe course and disease progression. Published studies revealed that CXCL10 may be a very good predictive biomarker of patient outcome in COVID-19, and that markedly elevated CXCL10 levels are connected with ARDS and neurological complications. It has been observed that an effective treatment for SARS-CoV-2 leads to inhibition of "cytokine storm", as well as reduction of CXCL10 concentrations. It seems that modulation of the CXCL10–CXCR3 axis may be an effective therapeutic target of COVID-19. This review describes the potential role of CXCL10 in the pathogenesis of COVID-19, as well as its potential immune–therapeutic significance. However, future studies should aim to confirm the prognostic, clinical, and therapeutic role of CXCL10 in SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Ran Binding Protein 2 (RanBP2 or Nucleoporin358) is one of the main components of the cytoplasmic filaments of the nuclear pore complex. Mutations in the RANBP2 gene are associated with acute necrotizing encephalopathy type 1 (ANE1), a rare condition where patients experience a sharp rise in cytokine production in response to viral infection and undergo hyperinflammation, seizures, coma, and a high rate of mortality. Despite this, it remains unclear howRanBP2 and its ANE1-associated mutations contribute to pathology. Mounting evidence has shown that RanBP2 interacts with distinct viruses to regulate viral infection. In addition, RanBP2 may regulate innate immune response pathways. This review summarizes recent advances in our understanding of how mutations in RANBP2 contribute to ANE1 and discusses how RanBP2 interacts with distinct viruses and affects viral infection. Recent findings indicate that RanBP2 might be an important therapeutic target, not only in the suppression of ANE1-driven cytokine storms, but also to combat hyperinflammation in response to viral infections. [ABSTRACT FROM AUTHOR]

Preventing the cytokine storm observed in COVID-19 is a crucial goal for reducing the occurrence of severe acute respiratory failure and improving outcomes. Here, we identify Aldo-Keto Reductase 1B10 (AKR1B10) as a key enzyme involved in the expression of pro-inflammatory cytokines. The analysis of transcriptomic data from lung samples of patients who died from COVID-19 demonstrates an increased expression of the gene encoding AKR1B10. Measurements of the AKR1B10 protein in sera from hospitalised COVID-19 patients suggests a significant link between AKR1B10 levels and the severity of the disease. In macrophages and lung cells, the over-expression of AKR1B10 induces the expression of the pro-inflammatory cytokines Interleukin-6 (IL-6), Interleukin-1β (IL-1β) and Tumor Necrosis Factor a (TNFα), supporting the biological plausibility of an AKR1B10 involvement in the COVID-19-related cytokine storm. When macrophages were stressed by lipopolysaccharides (LPS) exposure and treated by Zopolrestat, an AKR1B10 inhibitor, the LPS-induced production of IL-6, IL-1β, and TNFα is significantly reduced, reinforcing the hypothesis that the pro-inflammatory expression of cytokines is AKR1B10-dependant. Finally, we also show that AKR1B10 can be secreted and transferred via extracellular vesicles between different cell types, suggesting that this protein may also contribute to the multi-organ systemic impact of COVID-19. These experiments highlight a relationship between AKR1B10 production and severe forms of COVID-19. Our data indicate that AKR1B10 participates in the activation of cytokines production and suggest that modulation of AKR1B10 activity might be an actionable pharmacological target in COVID-19 management. [ABSTRACT FROM AUTHOR]

COVID-19 infection is associated with a broad spectrum of presentations, but alveolar capillary microthrombi have been described as a common finding in COVID-19 patients, appearing as a consequence of a severe endothelial injury with endothelial cell membrane disruption. These observations clearly point to the identification of a COVID-19-associated coagulopathy, which may contribute to thrombosis, multi-organ damage, and cause of severity and fatality. One significant finding that emerges in prothrombotic abnormalities observed in COVID-19 patients is that the coagulation alterations are mainly mediated by the activation of platelets and intrinsically related to viral-mediated endothelial inflammation. Beyond the well-known role in hemostasis, the ability of platelets to also release various potent cytokines and chemokines has elevated these small cells from simple cell fragments to crucial modulators in the blood, including their inflammatory functions, that have a large influence on the immune response during infectious disease. Indeed, platelets are involved in the pathogenesis of acute lung injury also by promoting NET formation and affecting vascular permeability. Specifically, the deposition by activated platelets of the chemokine platelet factor 4 at sites of inflammation promotes adhesion of neutrophils on endothelial cells and thrombogenesis, and it seems deeply involved in the phenomenon of vaccine-induced thrombocytopenia and thrombosis. Importantly, the hyperactivated platelet phenotype along with evidence of cytokine storm, high levels of P-selectin, D-dimer, and, on the other hand, decreased levels of fibrinogen, von Willebrand factor, and thrombocytopenia may be considered suitable biomarkers that distinguish the late stage of COVID-19 progression in critically ill patients. [ABSTRACT FROM AUTHOR]

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology. Recent studies have demonstrated that the hallmark of AOSD is a cytokine storm, which is characterized by the excessive production of interleukin (IL)-1, IL-6, IL-18, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), suggesting how pro-inflammatory cytokines play an important role in the pathogenesis of this disease. Actually, a certain proportion of patients (around 17–32%) with severe clinical symptoms achieves only partial remission or is resistant to both first-line corticosteroids and second-line DMARDs. These patients are defined as refractory AOSD patients, requiring higher dosage glucocorticoids, longer treatment duration, or the simultaneous introduction of immunosuppressive drugs, further leading to AOSD relapses. In this narrative review, we will analyze the latest literature data to unravel potential pathogenetic factors associated with specific patterns of AOSD disease or relapses in order to identify biomarkers that may guide clinical decisions, eventually leading to new therapeutic options. [ABSTRACT FROM AUTHOR]

Cytokine storm is a phenomenon characterized by strong elevated circulating cytokines that most often occur after an overreactive immune system is activated by an acute systemic infection. A variety of cells participate in cytokine storm induction and progression, with profiles of cytokines released during cytokine storm varying from disease to disease. This review focuses on pathophysiological mechanisms underlying cytokine storm induction and progression induced by pathogenic invasive infectious diseases. Strategies for targeted treatment of various types of infection-induced cytokine storms are described from both host and pathogen perspectives. In summary, current studies indicate that cytokine storm-targeted therapies can effectively alleviate tissue damage while promoting the clearance of invading pathogens. Based on this premise, "multi-omics" immune system profiling should facilitate the development of more effective therapeutic strategies to alleviate cytokine storms caused by various diseases. [ABSTRACT FROM AUTHOR]

The "normal" immune response to an insult triggers a highly regulated response determined by the interaction of various immunocompetent cells with pro- and anti-inflammatory cytokines. Under pathologic conditions, the massive elevation of cytokine levels ("cytokine storm") could not be controlled until the recent development of hemoadsorption devices that are able to extract a variety of different DAMPs, PAMPs, and metabolic products from the blood. CytoSorb® has been approved for adjunctive sepsis therapy since 2011. This review aims to summarize theoretical knowledge, in vitro results, and clinical findings to provide the clinician with pragmatic guidance for daily practice. English-language and peer-reviewed literature identified by a selective literature search in PubMed and published between January 2016 and May 2021 was included. Hemoadsorption can be used successfully as adjunct to a complex therapeutic regimen for various conditions. To the contrary, this nonspecific intervention may potentially worsen patient outcomes in complex immunological processes. CytoSorb® therapy appears to be safe and useful in various diseases (e.g., rhabdomyolysis, liver failure, or intoxications) as well as in septic shock or cytokine release syndrome, although a conclusive assessment of treatment benefit is not possible and no survival benefit has yet been demonstrated in randomized controlled trials. [ABSTRACT FROM AUTHOR]

Innate and adaptive immune responses have a well-known link and represent the distinctive origins of several diseases, many of which may be the consequence of the loss of balance between these two responses. Indeed, autoinflammation and autoimmunity represent the two extremes of a continuous spectrum of pathologic conditions with numerous overlaps in different pathologies. A common characteristic of these dysregulations is represented by hyperinflammation, which is an exaggerated response of the immune system, especially involving white blood cells, macrophages, and inflammasome activation with the hyperproduction of cytokines in response to various triggering stimuli. Moreover, hyperinflammation is of great interest, as it is one of the main manifestations of COVID-19 infection, and the cytokine storm and its most important components are the targets of the pharmacological treatments used to combat COVID-19 damage. In this context, the purpose of our review is to provide a focus on the pathogenesis of autoinflammation and, in particular, of hyperinflammation in order to generate insights for the identification of new therapeutic targets and strategies. [ABSTRACT FROM AUTHOR]

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection; it carries a risk for mortality, considerably exceeding that of a mere infection. Sepsis is the leading cause for acute kidney injury (AKI) and the requirement for renal replacement therapy (RRT) in intensive care unit (ICU) patients. Almost every second critically ill patient with sepsis will develop AKI. In septic shock, the dysregulated host response to infectious pathogens leads to a cytokine storm with uncontrolled production and release of humoral proinflammatory mediators that evoke cellular toxicity and promote the development of organ dysfunction and increased mortality. In addition to treating AKI, RRT techniques can be employed for extracorporeal adsorption of inflammatory mediators using specifically developed adsorption membranes, hemoperfusion sorbent cartridges or columns; these techniques are intended to decrease the level and early deleterious effects of circulating proinflammatory cytokines and endotoxins during the first hours and days of septic shock treatment, in order to improve patient outcomes. Several methods and devices, such as high cut-off membranes, the Oxiris®-AN69 membrane, CytoSorb® and HA380 cytokine hemoadsorption, polymyxin B endotoxin adsorption, and plasmapheresis have been examined in small study series or are under evaluation as ways of improving patient outcomes in septic shock. However, to date, the data on actual outcome benefits have remained controversial, as discussed in this review. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic with high infectivity and mortality has caused severe social and economic impacts worldwide. Growing reports of COVID-19 patients with multi-organ damage indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) may also disturb the cardiovascular system. Herein, we used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) as the in vitro platform to examine the consequence of SARS-CoV2 infection on iCMs. Differentiated iCMs expressed the primary SARS-CoV2 receptor angiotensin-converting enzyme-II (ACE2) and the transmembrane protease serine type 2 (TMPRSS2) receptor suggesting the susceptibility of iCMs to SARS-CoV2. Following the infection of iCMs with SARS-CoV2, the viral nucleocapsid (N) protein was detected in the host cells, demonstrating the successful infection. Bioinformatics analysis revealed that the SARS-CoV2 infection upregulates several inflammation-related genes, including the proinflammatory cytokine tumor necrosis factor-α (TNF-α). The pretreatment of iCMs with TNF-α for 24 h, significantly increased the expression of ACE2 and TMPRSS2, SASR-CoV2 entry receptors. The TNF-α pretreatment enhanced the entry of GFP-expressing SARS-CoV2 pseudovirus into iCMs, and the neutralization of TNF-α ameliorated the TNF-α-enhanced viral entry. Collectively, SARS-CoV2 elevated TNF-α expression, which in turn enhanced the SARS-CoV2 viral entry. Our findings suggest that, TNF-α may participate in the cytokine storm and aggravate the myocardial damage in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Bifidobacteria are some of the major agents that shaped the immune system of many members of the animal kingdom during their evolution. Over recent years, the question of concrete mechanisms underlying the immunomodulatory properties of bifidobacteria has been addressed in both animal and human studies. A possible candidate for this role has been discovered recently. The PFNA cluster, consisting of five core genes, pkb2, fn3, aaa-atp, duf58, tgm, has been found in all gut-dwelling autochthonous bifidobacterial species of humans. The sensory region of the species-specific serine-threonine protein kinase (PKB2), the transmembrane region of the microbial transglutaminase (TGM), and the type-III fibronectin domain-containing protein (FN3) encoded by the I gene imply that the PFNA cluster might be implicated in the interaction between bacteria and the host immune system. Moreover, the FN3 protein encoded by one of the genes making up the PFNA cluster, contains domains and motifs of cytokine receptors capable of selectively binding TNF-α. The PFNA cluster could play an important role for sensing signals of the immune system. Among the practical implications of this finding is the creation of anti-inflammatory drugs aimed at alleviating cytokine storms, one of the dire consequences resulting from SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Sepsis is characterized by a dysregulated immune response to infections that causes life-threatening organ dysfunction and even death. When infections occur, bacterial cell wall components (endotoxin or lipopolysaccharide), known as pathogen-associated molecular patterns, bind to pattern recognition receptors, such as toll-like receptors, to initiate an inflammatory response for pathogen elimination. However, strong activation of the immune system leads to cellular dysfunction and ultimately organ failure. Damage-associated molecular patterns (DAMPs), which are released by injured host cells, are well-recognized triggers that result in the elevation of inflammatory cytokine levels. A cytokine storm is thus amplified and sustained in this vicious cycle. Interestingly, during sepsis, neutrophils transition from powerful antimicrobial protectors into dangerous mediators of tissue injury and organ dysfunction. Thus, the concept of blood purification has evolved to include inflammatory cells and mediators. In this review, we summarize recent advances in knowledge regarding the role of lipopolysaccharides, cytokines, DAMPs, and neutrophils in the pathogenesis of sepsis. Additionally, we discuss the potential of blood purification, especially the adsorption technology, for removing immune cells and molecular mediators, thereby serving as a therapeutic strategy against sepsis. Finally, we describe the concept of our immune-modulating blood purification system. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) can be divided by lineage into myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs). They both are present in mucosal tissues and regulate the immune response by secreting chemokines and cytokines. Inflammatory bowel diseases (IBDs) are characterized by a leaky intestinal barrier and the consequent translocation of bacterial lipopolysaccharide (LPS) to the basolateral side. This results in DCs activation, but the response of pDCs is still poorly characterized. In the present study, we compared mDCs and pDCs responses to LPS administration. We present a broad panel of DCs secreted factors, including cytokines, chemokines, and growth factors. Our recent studies demonstrated the anti-inflammatory effects of quercetin administration, but to date, there is no evidence about quercetin's effects on pDCs. The results of the present study demonstrate that pDCs can respond to LPS and that quercetin exposure modulates soluble factors release through the same molecular pathway used by mDCs (Slpi, Hmox1, and AP-1). [ABSTRACT FROM AUTHOR]

COVID-19 is mainly considered a respiratory illness, but since SARS-CoV-2 uses the angiotensin converting enzyme 2 receptor (ACE2) to enter human cells, the kidney is also a target of the viral infection. Acute kidney injury (AKI) is the most alarming condition in COVID-19 patients. Recent studies have confirmed the direct entry of SARS-CoV-2 into the renal cells, namely podocytes and proximal tubular cells, but this is not the only pathomechanism of kidney damage. Hypovolemia, cytokine storm and collapsing glomerulopathy also play an important role. An increasing number of papers suggest a strong association between AKI development and higher mortality in COVID-19 patients, hence our interest in the matter. Although knowledge about the role of kidneys in SARS-CoV-2 infection is changing dynamically and is yet to be fully investigated, we present an insight into the possible pathomechanisms of AKI in COVID-19, its clinical features, risk factors, impact on hospitalization and possible ways for its management via renal replacement therapy. [ABSTRACT FROM AUTHOR]

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known transcription factor best recognised as one of the main regulators of the oxidative stress response. Beyond playing a crucial role in cell defence by transactivating cytoprotective genes encoding antioxidant and detoxifying enzymes, Nrf2 is also implicated in a wide network regulating anti-inflammatory response and metabolic reprogramming. Such a broad spectrum of actions renders the factor a key regulator of cell fate and a strategic player in the control of cell transformation and response to viral infections. The Nrf2 protective roles in normal cells account for its anti-tumour and anti-viral functions. However, Nrf2 overstimulation often occurs in tumour cells and a complex correlation of Nrf2 with cancer initiation and progression has been widely described. Therefore, if on one hand, Nrf2 has a dual role in cancer, on the other hand, the factor seems to display a univocal function in preventing inflammation and cytokine storm that occur under viral infections, specifically in coronavirus disease 19 (COVID-19). In such a variegate context, the present review aims to dissect the roles of Nrf2 in both cancer and COVID-19, two widespread diseases that represent a cause of major concern today. In particular, the review describes the molecular aspects of Nrf2 signalling in both pathological situations and the most recent findings about the advantages of Nrf2 inhibition or activation as possible strategies for cancer and COVID-19 treatment respectively. [ABSTRACT FROM AUTHOR]

The outbreak of the coronavirus disease 2019 (COVID-19) began at the end of 2019. COVID-19 is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patients with COVID-19 may exhibit poor clinical outcomes. Some patients with severe COVID-19 experience cytokine release syndrome (CRS) or a cytokine storm—elevated levels of hyperactivated immune cells—and circulating pro-inflammatory cytokines, including interleukin (IL)-1β and IL-18. This severe inflammatory response can lead to organ damage/failure and even death. The inflammasome is an intracellular immune complex that is responsible for the secretion of IL-1β and IL-18 in various human diseases. Recently, there has been a growing number of studies revealing a link between the inflammasome and COVID-19. Therefore, this article summarizes the current literature regarding the inflammasome complex and COVID-19. [ABSTRACT FROM AUTHOR]

Cytokines are a broad group of small regulatory proteins with many biological functions involved in regulating the hematopoietic and immune systems. However, in pathological conditions, hyperactivation of the cytokine network constitutes the fundamental event in cytokine release syndrome (CRS). During the last few decades, the development of therapeutic monoclonal antibodies and T-cell therapies has rapidly evolved, and CRS can be a serious adverse event related to these treatments. CRS is a set of toxic adverse events that can be observed during infection or following the administration of antibodies for therapeutic purposes and, more recently, during T-cell-engaging therapies. CRS is triggered by on-target effects induced by binding of chimeric antigen receptor (CAR) T cells or bispecific antibody to its antigen and by subsequent activation of bystander immune and non-immune cells. CRS is associated with high circulating concentrations of several pro-inflammatory cytokines, including interleukins, interferons, tumor necrosis factors, colony-stimulating factors, and transforming growth factors. Recently, considerable developments have been achieved with regard to preventing and controlling CRS, but it remains an unmet clinical need. This review comprehensively summarizes the pathophysiology, clinical presentation, and treatment of CRS caused by T-cell-engaging therapies utilized in the treatment of hematological malignancies. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic examines not only the state of actual health care but also the state of fundamental medicine in various countries. Pro-inflammatory processes extend far beyond the classical concepts of inflammation. They manifest themselves in a variety of ways, beginning with extreme physiology, then allostasis at low-grade inflammation, and finally the shockogenic phenomenon of "inflammatory systemic microcirculation". The pathogenetic core of critical situations, including COVID-19, is this phenomenon. Microcirculatory abnormalities, on the other hand, lie at the heart of a specific type of general pathological process known as systemic inflammation (SI). Systemic inflammatory response, cytokine release, cytokine storm, and thrombo-inflammatory syndrome are all terms that refer to different aspects of SI. As a result, the metabolic syndrome model does not adequately reflect the pathophysiology of persistent low-grade systemic inflammation (ChSLGI). Diseases associated with ChSLGI, on the other hand, are risk factors for a severe COVID-19 course. The review examines the role of hypoxia, metabolic dysfunction, scavenger receptors, and pattern-recognition receptors, as well as the processes of the hemophagocytic syndrome, in the systemic alteration and development of SI in COVID-19. [ABSTRACT FROM AUTHOR]

A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lysosome functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes. [ABSTRACT FROM AUTHOR]

COVID-19 is a pandemic respiratory disease caused by the SARS−CoV−2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient's death. This article summarizes the current knowledge regarding the potential effect of estrogens and other modulators of estrogen receptors on COVID-19. While estrogen receptor activation shows complex effects on the patient's organism, such as an influence on the cardiovascular/pulmonary/immune system which includes lower production of cytokines responsible for the cytokine storm, the receptor-independent effects directly inhibits viral replication. Furthermore, it inhibits the interaction of IL-6 with its receptor complex. Interestingly, in addition to natural hormones, phytestrogens and even synthetic molecules are able to interact with the estrogen receptor and exhibit some anti-COVID-19 activity. From this point of view, estrogen receptor modulators have the potential to be included in the anti-COVID-19 therapeutic arsenal. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is poorly understood so far. Cases: Severe pancytopenia with grade 2-3 anemia was marked 2–3 months after treatment. Laboratory evaluation revealed undetectable levels of haptoglobin with increased reticulocyte counts. Coomb's tests were negative, no schistocytes were detected on blood smear, and infectious causes were ruled out. Increased erythropoiesis without lymphoma infiltration was noted on bone marrow biopsy. A spontaneous increase in haptoglobin and hemoglobin levels was observed after several weeks. For one patient, peripheral CAR-T levels were monitored over time. We observed a decline at the same time as hemoglobin levels began to rise, implying a potential causality. Conclusion: To our knowledge, we describe the first two cases of Coombs-negative hemolytic anemia after CAR-T treatment for B-cell lymphoma. We encourage routine monitoring for hemolytic anemia after CAR-T treatment and also encourage further investigations on the underlying mechanism. [ABSTRACT FROM AUTHOR]