Exploring the management approaches of cytokines including viral infection and neuroinflammation for neurological disorders.

Considerable evidence supports that cytokines are important mediators of pathophysiologic processes within the central nervous system (CNS). Numerous studies have documented the increased production of various cytokines in the human CNS in various neurological and neuropsychiatric disorders. Deciphering cytokine actions in the intact CNS has important implications for our understanding of the pathogenesis and treatment of these disorders. The purpose of this study is to discuss the recent research on treating cytokine storm and amyloids, including stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's condition, Multi-sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS). Neuroinflammation observed in neurological disorders has a pivotal role in exacerbating Aß burden and tau hyperphosphorylation, suggesting that stimulating cytokines in response to an undesirable external response could be a checkpoint for treating neurological disorders. Furthermore, the pro-inflammatory cytokines help our immune system through a neuroprotective mechanism in clearing viral infection by recruiting mononuclear cells. This study reveals that cytokine applications may play a vital role in providing novel regulation and methods for the therapeutic approach to neurological disorders and the causes of the deregulation, which is responsible for neuroinflammation and viral infection. However, it needs to be further investigated to clarify better the mechanisms of cytokine release in response to various stimuli, which could be the central point for treating neurological disorders.

Interleukin-1 Receptor-Like 2: One Receptor, Three Agonists, and Many Implications.

The interleukin (IL)-1 superfamily of cytokines comprises 11 pro- and anti-inflammatory cytokines, which play essential roles during the immune response. Several pathogenic pathways are initiated by IL-1RL2 (interleukin 1 receptor-like 2) signaling, also known as IL-36R, in the skin, lungs, and gut. IL-36 cytokines promote the secretion of proinflammatory cytokines and chemokines, upregulation of antimicrobial peptides, proliferation mediators, and adhesion molecules on endothelial cells. In addition, the IL-36-IL-1RL2 axis has an essential role against viral infections, including a potential role in COVID-19 pathology. The evidence presented in this review highlights the importance of the axis IL-36-IL-1RL2 in the development of several inflammation-related diseases and the healing process. It suggests that IL-1RL2 ligands have specific roles depending on the tissue or cell source. However, there is still much to discover about this cytokine family, their functions in other organs, and how they accomplish a dual effect in inflammation and healing.

Role of immune mediators in predicting hospitalization of SARS-CoV-2 positive patients.

BACKGROUND: Several immune mediators (IM) including cytokines, chemokines, and their receptors have been suggested to play a role in COVID-19 pathophysiology and severity. AIM: To determine if early IM profiles are predictive of clinical outcome and which of the IMs tested possess the most clinical utility. METHODS: A custom bead-based multiplex assay was used to measure IM concentrations in a cohort of SARS-CoV-2 PCR positive patients (n = 326) with varying disease severities as determined by hospitalization status, length of hospital stay, and survival. Patient groups were compared, and clinical utility was assessed. Correlation plots were constructed to determine if significant relationships exist between the IMs in the setting of COVID-19. RESULTS: In PCR positive SARS-CoV-2 patients, IL-6 was the best predictor of the need for hospitalization and length of stay. Additionally, MCP-1 and sIL-2Rα were moderate predictors of the need for hospitalization. Hospitalized PCR positive SARS-CoV-2 patients displayed a notable correlation between sIL-2Rα and IL-18 (Spearman's ρ = 0.48, P=<0.0001). CONCLUSIONS: IM profiles between non-hospitalized and hospitalized patients were distinct. IL-6 was the best predictor of COVID-19 severity among all the IMs tested.

Characterization of Headache in COVID-19: a Retrospective Multicenter Study.

Headache is the most common neurological symptom in COVID-19, reported in 6.5 to 34% of patients. Few studies have analyzed its characteristics, and some of them included cases without laboratory confirmation or reported only critical patients. We aimed to analyze the clinical characteristics of COVID-19 associated headache in laboratory-confirmed cases. We conducted a retrospective evaluation of patients with COVID-19 and neurological symptoms. Patients who reported headache answered an interview about its clinical characteristics. Twenty-four patients with COVID-19 associated headache completed the interview. Mean age of patients was 53.8 (standard deviation-17.44), and 14 out of 24 (58.3%) were male. The majority (75%) had no previous history of headache. Fever was documented in 19 out of the 24 patients (79.1%). Headache was predominantly bifrontal or holocranial, in pressure, during hours, worsening with cough or physical activity. COVID-19 headache tends to appear in the first days of symptoms, be either frontal or holocranial and last for days. The quality of pain in pressure and the worsening with cough or physical activity were reported in most cases. We have not found any characteristic that could differentiate COVID-19 associated headache from other causes of headache, possibly because of its multifactorial mechanism.

The Intersection of Parkinson's Disease, Viral Infections, and COVID-19.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of human COVID-19, not only causes flu-like symptoms and gut microbiome complications but a large number of infected individuals also experience a host of neurological symptoms including loss of smell and taste, seizures, difficulty concentrating, decreased alertness, and brain inflammation. Although SARS-CoV-2 infections are not more prevalent in Parkinson's disease patients, a higher mortality rate has been reported not only associated with older age and longer disease duration, but also through several mechanisms, such as interactions with the brain dopaminergic system and through systemic inflammatory responses. Indeed, a number of the neurological symptoms seen in COVID-19 patients, as well as the alterations in the gut microbiome, are also prevalent in patients with Parkinson's disease. Furthermore, biochemical pathways such as oxidative stress, inflammation, and protein aggregation have shared commonalities between Parkinson's disease and COVID-19 disease progression. In this review, we describe and compare the numerous similarities and intersections between neurodegeneration in Parkinson's disease and RNA viral infections, emphasizing the current SARS-CoV-2 global health crisis.

Does remote ischaemic conditioning reduce inflammation? A focus on innate immunity and cytokine response.

The benefits of remote ischaemic conditioning (RIC) have been difficult to translate to humans, when considering traditional outcome measures, such as mortality and heart failure. This paper reviews the recent literature of the anti-inflammatory effects of RIC, with a particular focus on the innate immune response and cytokine inhibition. Given the current COVID-19 pandemic, the inflammatory hypothesis of cardiac protection is an attractive target on which to re-purpose such novel therapies. A PubMed/MEDLINE™ search was performed on July 13th 2020, for the key terms RIC, cytokines, the innate immune system and inflammation. Data suggest that RIC attenuates inflammation in animals by immune conditioning, cytokine inhibition, cell survival and the release of anti-inflammatory exosomes. It is proposed that RIC inhibits cytokine release via a reduction in nuclear factor kappa beta (NF-κB)-mediated NLRP3 inflammasome production. In vivo, RIC attenuates pro-inflammatory cytokine release in myocardial/cerebral infarction and LPS models of endotoxaemia. In the latter group, cytokine inhibition is associated with a profound survival benefit. Further clinical trials should establish whether the benefits of RIC in inflammation can be observed in humans. Moreover, we must consider whether uncomplicated MI and elective surgery are the most suitable clinical conditions in which to test this hypothesis.

Healing after COVID-19: are survivors at risk for pulmonary fibrosis?

The novel SARS-CoV-2 coronavirus, which is responsible for COVID-19 disease, was first reported in Wuhan, China, in December of 2019. The virus rapidly spread, and the World Health Organization declared a pandemic by March 2020. With millions of confirmed cases worldwide, there is growing concern and considerable debate regarding the potential for coronavirus infection to contribute to an appreciable burden of chronic respiratory symptoms or fibrotic disease among recovered individuals. Because the first case of COVID-19 was documented less than one year ago, data regarding long-term clinical outcomes are not yet available, and predictions for long-term outcome are speculative at best. However, due to the staggering number of cases and the severity of disease in many individuals, there is a critical need to consider the potential long-term implications of COVID-19. This review examines current basic and clinical data regarding fibrogenic mechanisms of viral injury in the context of SARS-CoV-2. Several intersecting mechanisms between coronavirus infection and fibrotic pathways are discussed to highlight factors and processes that may be targetable to improve patient outcome. Reports of post-infection sequelae from previous coronavirus outbreaks are presented toward the goal of improved recognition of potential contributing risk factors for fibrotic disease.

The cytokine storm in COVID-19: Further advances in our understanding the role of specific chemokines involved.

SARS-COV-2 infection represents the greatest pandemic of the world, counting daily increasing number of subjects positive to the virus and, sadly, increasing number of deaths. Current studies reported that the cytokine/chemokine network is crucial in the onset and maintenance of the "cytokine storm", the event occurring in those patients in whom the progression of COVID-19 will progress, in most cases, to a very severe and potentially threatening disease. Detecting a possible "immune signature" in patients, as assessed by chemokines status in patients with COVID-19, could be helpful for individual risk stratification for developing a more or less severe clinical course of the disease. The present review is specifically aimed at overviewing current evidences provided by in vitro and in vivo studies addressing the issue of which chemokines seems to be involved, at least at present, in COVID-19. Currently available experimental and clinical studies regarding those chemokines more deeply studied in COVID-19, with a specific focus on their role in the cytokine storm and ultimately with their ability to predict the clinical course of the disease, will be taken into account. Moreover, similarities and differences between chemokines and cytokines, which both contribute to the onset of the pro-inflammatory loop characterizing SARS-COV-2 infection, will be briefly discussed. Future studies will rapidly accumulate in the next months and their results will hopefully provide more insights as to the complex physiopathology of COVID-19-related cytokine storm. This will likely make the present review somehow "dated" in a short time, but still the present review provides an overview of the scenario of the current knowledge on this topic.

Interferons and other cytokines, genetics and beyond in COVID-19 and autoimmunity.

Interferons are the best antiviral agents in vitro against SARS-CoV-2 so far and genetic defects in their signaling cascade or neutralization of alfa-interferons by autoantibodies come with more severe COVID-19. However, there is more, as the SARS-CoV-2 dysregulates not only innate immune mechanisms but also T and B cell repertoires. Most genetic, hematological and immunological studies in COVID-19 are at present phenomenological. However, these and antecedent studies contain the seed grains to resolve many unanswered questions and a whole range of testable hypotheses. What are the links, if existing, between genetics and the occurrence of interferon-neutralizing antibodies? Are NAGGED (neutralizing and generated by gene defect) antibodies involved or not? Is the autoimmune process cause or consequence of virus infection? What are the roles played by cytokine posttranslational modifications, such as proteolysis, glycosylation, citrullination and others? How is systemic autoimmunity linked with type 1 interferons? These questions place cytokines and growth factors at pole positions as keys to unlock basic mechanisms of infection and (auto)immunity. Related to cytokine research, (1) COVID-19 patients develop neutralizing autoantibodies, mainly against alpha interferons and it is not yet established whether this is the consequence or cause of virus replication. (2) The glycosylation of recombinant interferon-beta protects against breaking tolerance and the development of neutralizing antibodies. (3) SARS-CoV-2 induces severe inflammation and release of extracellular proteases leading to remnant epitopes, e.g. of cytokines. (4) In the rare event of homozygous cytokine gene segment deletions, observed neutralizing antibodies may be named NAGGED antibodies. (5) Severe cytolysis releases intracellular content into the extracellular milieu and leads to regulated degradation of intracellular proteins and selection of antibody repertoires, similar to those observed in patients with systemic lupus erythematosus. (6) Systematic studies of novel autoimmune diseases on single cytokines will complement the present picture about interferons. (7) Interferon neutralization in COVID-19 constitutes a preamble of more studies about cytokine-regulated proteolysis in the control of autoimmunity. Here we reformulate these seven conjectures into testable questions for future research.

Coronaviruses and Integrin αvß3: Does Thyroid Hormone Modify the Relationship?

BACKGROUND: Uptake of coronaviruses by target cells involves binding of the virus by cell ectoenzymes. For the etiologic agent of COVID-19 (SARS-CoV-2), a receptor has been identified as angiotensin-converting enzyme-2 (ACE2). Recently it has been suggested that plasma membrane integrins may be involved in the internalization and replication of clinically important coronaviruses. For example, integrin αvß3 is involved in the cell uptake of a model porcine enteric α-coronavirus that causes human epidemics. ACE2 modulates the intracellular signaling generated by integrins. OBJECTIVE: We propose that the cellular internalization of αvß3 applies to uptake of coronaviruses bound to the integrin, and we evaluate the possibility that clinical host T4 may contribute to target cell uptake of coronavirus and to the consequence of cell uptake of the virus. DISCUSSION AND CONCLUSIONS: The viral binding domain of the integrin is near the Arg-Gly-Asp (RGD) peptide-binding site and RGD molecules can affect virus binding. In this same locale on integrin αvß3 is the receptor for thyroid hormone analogues, particularly, L-thyroxine (T4). By binding to the integrin, T4 has been shown to modulate the affinity of the integrin for other proteins, to control internalization of αvß3 and to regulate the expression of a panel of cytokine genes, some of which are components of the 'cytokine storm' of viral infections. If T4 does influence coronavirus uptake by target cells, other thyroid hormone analogues, such as deaminated T4 and deaminated 3,5,3'-triiodo-L-thyronine (T3), are candidate agents to block the virus-relevant actions of T4 at integrin αvß3 and possibly restrict virus uptake.

Noncoding RNAs: modulators and modulatable players during infection-induced stress response.

The human genome has an almost equal distribution of unique and transposable genetic elements. Although at the transcriptome level, a relatively higher contribution from transposable elements derived RNA has been reported. This is further highlighted with evidence from pervasive transcription. Of the total RNA, noncoding RNAs (ncRNAs) are significant contributors to the transcriptome pool with sizeable fraction from repetitive elements of the human genome, inclusive of Long Interspersed Nuclear Elements (LINEs) and Short Interspersed Nuclear Elements (SINEs). ncRNAs are increasingly being implicated in diverse functional roles especially during conditions of stress. These stress responses are driven through diverse mediators, inclusive of long and short ncRNAs. ncRNAs such as MALAT1, GAS5, miR-204 and miR-199a-5p have been functionally involved during oxidative stress, endoplasmic reticulum (ER) stress and unfolded protein response (UPR). Also, within SINEs, Alu RNAs derived from primate-specific Alu repeats with ~11% human genome contribution, playing a significant role. Pathogenic diseases, including the recent COVID-19, leads to differential regulation of ncRNAs. Although, limited evidence suggests the need for an inquest into the role of ncRNAs in determining the host response towards pathogen challenge.

Strategies to DAMPen COVID-19-mediated lung and systemic inflammation and vascular injury.

Approximately 15%-20% of patients infected with SARS-CoV-2 coronavirus (COVID-19) progress beyond mild and self-limited disease to require supplemental oxygen for severe pneumonia; 5% of COVID-19-infected patients further develop acute respiratory distress syndrome (ARDS) and multiorgan failure. Despite mortality rates surpassing 40%, key insights into COVID-19-induced ARDS pathology have not been fully elucidated and multiple unmet needs remain. This review focuses on the unmet need for effective therapies that target unchecked innate immunity-driven inflammation which drives unchecked vascular permeability, multiorgan dysfunction and ARDS mortality. Additional unmet needs including the lack of insights into factors predicting pathogenic hyperinflammatory viral host responses, limited approaches to address the vast disease heterogeneity in ARDS, and the absence of clinically-useful ARDS biomarkers. We review unmet needs persisting in COVID-19-induced ARDS in the context of the potential role for damage-associated molecular pattern proteins in lung and systemic hyperinflammatory host responses to SARS-CoV-2 infection that ultimately drive multiorgan dysfunction and ARDS mortality. Insights into promising stratification-enhancing, biomarker-based strategies in COVID-19 and non-COVID ARDS may enable the design of successful clinical trials of promising therapies.

Preventing the development of severe COVID-19 by modifying immunothrombosis.

BACKGROUND: COVID-19-associated acute respiratory distress syndrome (ARDS) is associated with significant morbidity and high levels of mortality. This paper describes the processes involved in the pathophysiology of COVID-19 from the initial infection and subsequent destruction of type II alveolar epithelial cells by SARS-CoV-2 and culminating in the development of ARDS. MAIN BODY: The activation of alveolar cells and alveolar macrophages leads to the release of large quantities of proinflammatory cytokines and chemokines and their translocation into the pulmonary vasculature. The presence of these inflammatory mediators in the vascular compartment leads to the activation of vascular endothelial cells platelets and neutrophils and the subsequent formation of platelet neutrophil complexes. These complexes in concert with activated endothelial cells interact to create a state of immunothrombosis. The consequence of immunothrombosis include hypercoagulation, accelerating inflammation, fibrin deposition, migration of neutrophil extracellular traps (NETs) producing neutrophils into the alveolar apace, activation of the NLRP3 inflammazome, increased alveolar macrophage destruction and massive tissue damage by pyroptosis and necroptosis Therapeutic combinations aimed at ameliorating immunothrombosis and preventing the development of severe COVID-19 are discussed in detail.

Neurobiochemical Cross-talk Between COVID-19 and Alzheimer's Disease.

COVID-19, the global threat to humanity, shares etiological cofactors with multiple diseases including Alzheimer's disease (AD). Understanding the common links between COVID-19 and AD would harness strategizing therapeutic approaches against both. Considering the urgency of formulating COVID-19 medication, its AD association and manifestations have been reviewed here, putting emphasis on memory and learning disruption. COVID-19 and AD share common links with respect to angiotensin-converting enzyme 2 (ACE2) receptors and pro-inflammatory markers such as interleukin-1 (IL-1), IL-6, cytoskeleton-associated protein 4 (CKAP4), galectin-9 (GAL-9 or Gal-9), and APOE4 allele. Common etiological factors and common manifestations described in this review would aid in developing therapeutic strategies for both COVID-19 and AD and thus impact on eradicating the ongoing global threat. Thus, people suffering from COVID-19 or who have come round of it as well as people at risk of developing AD or already suffering from AD, would be benefitted.

Cytokine storm and use of anakinra in a patient with COVID-19.

We present a case of a 50-year-old man with COVID-19 infection and acute respiratory distress syndrome as a result of a cytokine storm and use of anakinra, an interleukin 1-receptor antagonist that is normally used in the treatment of autoinflammatory disorders in adult patients. We saw a reduction in oxygen requirement and improvements in inflammatory markers and ferritin. Although we cannot determine its clinical efficacy from one case study, it may have a positive effect on the proinflammatory state that is associated with cytokine storm in COVID-19 infection.

Cross-Talk Between Key Players in Patients with COVID-19 and Ischemic Stroke: A Review on Neurobiological Insight of the Pandemic.

The global pandemic of novel coronavirus disease 2019 (COVID-19) has taken the entire human race by surprise and led to an unprecedented number of mortalities worldwide so far. Current clinical studies have interpreted that angiotensin-converting enzyme 2 (ACE2) is the host receptor for severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). In addition, ACE2 is the major component of the renin-angiotensin system. ACE2 deteriorates angiotensin II, a peptide that is responsible for the promotion of stroke. The downregulation of ACE2 further activates an immunological cascade. Thus, researchers need to explore and examine the possible links between COVID-19 and ischemic stroke (IS). Human ACE2 expression level and pattern in various tissues might be decisive for the vulnerability, symptoms, and treatment outcomes of the SARS-CoV-2 infection. The swift increase in the knowledge of SARS-CoV-2 has given creditable evidence that SARS-CoV-2 infected patients also encounter neurological deficits. As the SARS-CoV-2 binds to ACE2, it will hamper the activity of ACE2 in providing neuroprotection, especially in the case of stroke patients. Due to the downregulation of ACE2, the inflammatory response is activated in the ischemic penumbra. The COVID-19 pandemic has affected people with various pre-existing diseases, including IS, in such a way that these patients need special care and attention for their survival. Several clinical trials are currently ongoing worldwide as well as many other projects are in different stages of conceptualization and planning to facilitate the effective management of stroke patients with COVID-19 infection.

Possible mechanisms responsible for acute coronary events in COVID-19.

The novel coronavirus (SARS-CoV-2) is primarily a respiratory pathogen and its clinical manifestations are dominated by respiratory symptoms, the most severe of which is acute respiratory distress syndrome (ARDS). However, COVID-19 is increasingly recognized to cause an overwhelming inflammatory response and cytokine storm leading to end organ damage. End organ damage to heart is one of the most severe complications of COVID-19 that increases the risk of death. We proposed a two-fold mechanism responsible for causing acute coronary events in patients with COVID-19 infection: Cytokine storm leading to rapid onset formation of new coronary plaques along with destabilization of pre-existing plaques and direct myocardial injury secondary to acute systemic viral infection. A well-coordinated immune response is the first line innate immunity against a viral infection. However, an uncoordinated response and hypersecretion of cytokines and chemokines lead to immune related damage to the human body. Human Coronavirus (HCoV) infection causes infiltration of inflammatory cells that cause excessive production of cytokines, proteases, coagulation factors, oxygen radicals and vasoactive molecules causing endothelial damage, disruption of fibrous cap and initiation of formation of thrombus. Systemic viral infections also cause vasoconstriction leading to narrowing of vascular lumen and stimulation of platelet activation via shear stress. The resultant cytokine storm causes secretion of hypercoagulable tissue factor without consequential increase in counter-regulatory pathways such as AT-III, activated protein C and plasminogen activator type 1. Lastly, influx of CD4+ T-cells in cardiac vasculature results in an increased production of cytokines that stimulate smooth muscle cells to migrate into the intima and generate collagen and other fibrous products leading to advancement of fatty streaks to advanced atherosclerotic lesions. Direct myocardial damage and cytokine storm leading to destabilization of pre-existing plaques and accelerated formation of new plaques are the two instigating mechanisms for acute coronary syndromes in COVID-19.