Targeting circulating high mobility group box-1 and histones by extracorporeal blood purification as an immunomodulation strategy against critical illnesses.

Both high mobility group box-1 (HMGB1) and histones are major damage-associated molecular patterns (DAPMs) that mediate lethal systemic inflammation, activation of the complement and coagulation system, endothelial injury and multiple organ dysfunction syndrome in critical illnesses. Although accumulating evidence collectively shows that targeting HMGB1 or histones by their specific antibodies or inhibitors could significantly mitigate aberrant immune responses in multiple critically ill animal models, routine clinical use of such agents is still not recommended by any guideline. In contrast, extracorporeal blood purification, which has been widely used to replace dysfunctional organs and remove exogenous or endogenous toxins in intensive care units, may also exert an immunomodulatory effect by eliminating inflammatory mediators such as cytokines, endotoxin, HMGB1 and histones in patients with critical illnesses. In this review, we summarize the multiple immunopathological roles of HMGB1 and histones in mediating inflammation, immune thrombosis and organ dysfunction and discuss the rationale for the removal of these DAMPs using various hemofilters. The latest preclinical and clinical evidence for the use of extracorporeal blood purification to improve the clinical outcome of critically ill patients by targeting circulating HMGB1 and histones is also gathered.

[A new approach to combat the sepsis including COVID-19 by accelerating detoxification of hemolysis-related DAMPs].

Sepsis is one of the leading cause of death worldwide. Recently, several studies suggested that free-hemoglobin and heme derived from hemolysis are important factors which may be associated with severity of septic patients including COVID-19. In other words, hemolysis-derived products enhance the inflammatory responses as damage-associated molecular patterns (DAMPs) in both intravascular and extravascular space. In addition, hemoglobin has vasoconstrictive activity by depleting nitric oxide, whereas heme or Fe2+ produce reactive oxygen species (ROS) through Fenton reaction leading to tissue injury. At present, we have no therapeutic options against sepsis-related hemolysis in clinical settings, however, there might be two therapeutic strategies in this regard. One is supplemental therapy of depleted scavenging proteins such as haptoglobin and hemopexin, the other is activation of the internal scavenging system including macrophage-CD163 pathway. These novel targets against sepsis are also critical for the next pandemic. In this review, we summarize the current issues regarding sepsis-related hemolysis including COVID-19, as well as for future perspectives.

Glycyrrhizin through liquorice intake modulates ACE2 and HMGB1 levels-A pilot study in healthy individuals with implications for COVID-19 and ARDS.

BACKGROUND: Glycyrrhizin, an active component of liquorice root extract, exhibits antiviral and immunomodulatory properties by direct inhibition of the pro-inflammatory alarmin HMGB1 (High-mobility group box 1). OBJECTIVE: The aim of this study was to explore the role of liquorice intake on the viral entry receptor ACE2 (angiotensin-converting enzyme 2) and the immunoregulatory HMGB1 in healthy individuals and to explore HMGB1 expression in coronavirus disease 2019 (COVID-19) or non-COVID-19 in ARDS (acute respiratory distress syndrome patients). MATERIAL AND METHODS: This study enrolled 43 individuals, including hospitalised patients with i) acute respiratory distress syndrome (ARDS) due to COVID-19 (n = 7) or other underlying causes (n = 12), ii) mild COVID-19 (n = 4) and iii) healthy volunteers (n = 20). Healthy individuals took 50 g of liquorice (containing 3% liquorice root extract) daily for 7 days, while blood samples were collected at baseline and on day 3 and 7. Changes in ACE2 and HMGB1 levels were determined by Western blot analysis and enzyme-linked immunosorbent assay, respectively. Additionally, HMGB1 levels were measured in hospitalised COVID-19 patients with mild disease or COVID-19 associated acute respiratory distress syndrome (ARDS) and compared with a non-COVID-19-ARDS group. RESULTS: Liquorice intake significantly reduced after 7 days both cellular membranous ACE2 expression (-51% compared to baseline levels, p = 0.008) and plasma HMGB1 levels (-17% compared to baseline levels, p<0.001) in healthy individuals. Half of the individuals had a reduction in ACE2 levels of at least 30%. HMGB1 levels in patients with mild COVID-19 and ARDS patients with and without COVID-19 were significantly higher compared with those of healthy individuals (+317%, p = 0.002), but they were not different between COVID-19 and non-COVID-19 ARDS. CONCLUSIONS: Liquorice intake modulates ACE2 and HMGB1 levels in healthy individuals. HMGB1 is enhanced in mild COVID-19 and in ARDS with and without COVID-19, warranting evaluation of HMGB1 as a potential treatment target and glycyrrhizin, which is an active component of liquorice root extract, as a potential treatment in COVID-19 and non-COVID-19 respiratory disease.

Single-cell RNA sequencing uncovers the nuclear decoy lincRNA PIRAT as a regulator of systemic monocyte immunity during COVID-19.

The systemic immune response to viral infection is shaped by master transcription factors, such as NF-κB, STAT1, or PU.1. Although long noncoding RNAs (lncRNAs) have been suggested as important regulators of transcription factor activity, their contributions to the systemic immunopathologies observed during SARS-CoV-2 infection have remained unknown. Here, we employed a targeted single-cell RNA sequencing approach to reveal lncRNAs differentially expressed in blood leukocytes during severe COVID-19. Our results uncover the lncRNA PIRAT (PU.1-induced regulator of alarmin transcription) as a major PU.1 feedback-regulator in monocytes, governing the production of the alarmins S100A8/A9, key drivers of COVID-19 pathogenesis. Knockout and transgene expression, combined with chromatin-occupancy profiling, characterized PIRAT as a nuclear decoy RNA, keeping PU.1 from binding to alarmin promoters and promoting its binding to pseudogenes in naïve monocytes. NF-κB-dependent PIRAT down-regulation during COVID-19 consequently releases a transcriptional brake, fueling alarmin production. Alarmin expression is additionally enhanced by the up-regulation of the lncRNA LUCAT1, which promotes NF-κB-dependent gene expression at the expense of targets of the JAK-STAT pathway. Our results suggest a major role of nuclear noncoding RNA networks in systemic antiviral responses to SARS-CoV-2 in humans.

A simple model of COVID-19 explains disease severity and the effect of treatments.

Considerable effort has been made to better understand why some people suffer from severe COVID-19 while others remain asymptomatic. This has led to important clinical findings; people with severe COVID-19 generally experience persistently high levels of inflammation, slower viral load decay, display a dysregulated type-I interferon response, have less active natural killer cells and increased levels of neutrophil extracellular traps. How these findings are connected to the pathogenesis of COVID-19 remains unclear. We propose a mathematical model that sheds light on this issue by focusing on cells that trigger inflammation through molecular patterns: infected cells carrying pathogen-associated molecular patterns (PAMPs) and damaged cells producing damage-associated molecular patterns (DAMPs). The former signals the presence of pathogens while the latter signals danger such as hypoxia or lack of nutrients. Analyses show that SARS-CoV-2 infections can lead to a self-perpetuating feedback loop between DAMP expressing cells and inflammation, identifying the inability to quickly clear PAMPs and DAMPs as the main contributor to hyperinflammation. The model explains clinical findings and reveal conditions that can increase the likelihood of desired clinical outcome from treatment administration. In particular, the analysis suggest that antivirals need to be administered early during infection to have an impact on disease severity. The simplicity of the model and its high level of consistency with clinical findings motivate its use for the formulation of new treatment strategies.

Serum concentration of extracellular cold-inducible RNA-binding protein is associated with respiratory failure in COVID-19.

Uncontrolled release of damage-associated molecular patterns (DAMPs) is suggested to be a major trigger for the dysregulated host immune response that leads to severe COVID-19. Cold-inducible RNA-binding protein (CIRP), is a newly identified DAMP that aggravates inflammation and tissue injury, and induces respiratory failure in sepsis. Whether CIRP contributes to the pathogenesis of respiratory failure in COVID-19 has not yet been explored. Aim: To investigate if the concentration of extracellular CIRP (eCIRP) in serum associates with respiratory failure and lung involvement by chest computed tomography (CT) in COVID-19. Methods: Herein we report a prospective observational study of patients with COVID-19 included at two University Hospitals in Sweden between April 2020 and May 2021. Serum from hospitalized patients in Örebro (N=97) were used to assess the association between eCIRP and the level of respiratory support and its correlation with pulmonary involvement on chest CT and inflammatory biomarkers. A cohort of hospitalized and non-hospitalized patients from Umeå (N=78) was used as an external validation cohort. The severity of disease was defined according to the highest degree of respiratory support; mild disease (no oxygen), non-severe hypoxemia (conventional oxygen or high-flow nasal oxygen, HFNO <50% FiO2), and severe hypoxemia (HFNO ≥50% FiO2, mechanical ventilation). Unadjusted and adjusted linear regression was used to evaluate peak eCIRP day 0-4 in respect to severity, age, sex, Charlson comorbidity score, symptom duration, and BMI. Results: Peak eCIRP concentrations were higher in patients with severe hypoxemia and were independently associated with the degree of respiratory support in both cohorts (Örebro; p=0.01, Umeå; p<0.01). The degree of pulmonary involvement measured by CT correlated with eCIRP, rs=0.30, p<0.01 (n=97). Conclusion: High serum levels of eCIRP are associated with acute respiratory failure in COVID-19. Experimental studies are needed to determine if treatments targeting eCIRP reduces the risk of acute respiratory failure in COVID-19.

Multifunctional Role of S100 Protein Family in the Immune System: An Update.

S100 is a broad subfamily of low-molecular weight calcium-binding proteins (9-14 kDa) with structural similarity and functional discrepancy. It is required for inflammation and cellular homeostasis, and can work extracellularly, intracellularly, or both. S100 members participate in a variety of activities in a healthy cell, including calcium storage and transport (calcium homeostasis). S100 isoforms that have previously been shown to play important roles in the immune system as alarmins (DAMPs), antimicrobial peptides, pro-inflammation stimulators, chemo-attractants, and metal scavengers during an innate immune response. Currently, during the pandemic, it was found that several members of the S100 family are implicated in the pathophysiology of COVID-19. Further, S100 family protein members were proposed to be used as a prognostic marker for COVID-19 infection identification using a nasal swab. In the present review, we compiled the vast majority of recent studies that focused on the multifunctionality of S100 proteins in the complex immune system and its associated activities. Furthermore, we shed light on the numerous molecular approaches and signaling cascades regulated by S100 proteins during immune response. In addition, we discussed the involvement of S100 protein members in abnormal defense systems during the pathogenesis of COVID-19.

Deciphering the role of damage-associated molecular patterns and inflammatory responses in acute lung injury.

Acute lung injury (ALI) is characterized by diffuse pulmonary infiltrates and causes great mortality. ALI presents with overproduction of proinflammatory cytokines, cell death, destruction of alveoli-endothelial barriers, and neutrophil infiltration in lung tissues. Damage-associated molecular patterns (DAMPs) are molecules released from damaged cells due to infection, trauma, etc. DAMPs activate innate and adaptive immunity, trigger inflammatory responses, and are important in the initiation and development of ALI. We reviewed the literatures on DAMPs in ALI. Alveolar macrophages (AMs), neutrophils, and epithelial cells (AECs) are important in the pathogenesis of ALI. We comprehensively analyzed the interaction between DAMPs and AMs, alveolar neutrophils, and AECs. During the initial stage of ALI, ruptured cell membranes or destroyed mitochondria release DAMPs. DAMPs activate the inflammasome in nearby sentinel immune cells, such as AMs. AMs produce IL-1ß and other cytokines. These mediators upregulate adhesion molecules of the capillary endothelium that facilitate neutrophil recruitment. The recruited neutrophils detect DAMPs using formyl peptide receptors on the membrane, guiding their migration to the injured site. The accumulation of immune cells, cytokines, chemokines, proteases, etc., results in diffuse alveolar damage and pulmonary hyperpermeability with protein-rich fluid retention. Some clinical studies have shown that patients with ALI with higher circulating DAMPs have higher mortality rates. In conclusion, DAMPs are important in the initiation and progression of ALI. The interactions between DAMPs and AMs, neutrophils, and AECs are important in ALI. This review comprehensively addresses the mechanisms of DAMPs and their interactions in ALI.

Emerging role of mitochondrial DAMPs, aberrant mitochondrial dynamics and anomalous mitophagy in gut mucosal pathogenesis.

Gastroduodenal inflammation and ulcerative injuries are increasing due to expanding socio-economic stress, unhealthy food habits-lifestyle, smoking, alcoholism and usage of medicines like non-steroidal anti-inflammatory drugs. In fact, gastrointestinal (GI) complications, associated with the prevailing COVID-19 pandemic, further, poses a challenge to global healthcare towards safeguarding the GI tract. Emerging evidences have discretely identified mitochondrial dysfunctions as common etiological denominators in diseases. However, it is worth realizing that mitochondrial dysfunctions are not just consequences of diseases. Rather, damaged mitochondria severely aggravate the pathogenesis thereby qualifying as perpetrable factors worth of prophylactic and therapeutic targeting. Oxidative and nitrosative stress due to endogenous and exogenous stimuli triggers mitochondrial injury causing production of mitochondrial damage associated molecular patterns (mtDAMPs), which, in a feed-forward loop, inflicts inflammatory tissue damage. Mitochondrial structural dynamics and mitophagy are crucial quality control parameters determining the extent of mitopathology and disease outcomes. Interestingly, apart from endogenous factors, mitochondria also crosstalk and in turn get detrimentally affected by gut pathobionts colonized during luminal dysbiosis. Although mitopathology is documented in various pre-clinical/clinical studies, a comprehensive account appreciating the mitochondrial basis of GI mucosal pathogenesis is largely lacking. Here we critically discuss the molecular events impinging on mitochondria along with the interplay of mitochondria-derived factors in fueling mucosal damage. We specifically emphasize on the potential role of aberrant mitochondrial dynamics, anomalous mitophagy, mitochondrial lipoxidation and ferroptosis as emerging regulators of GI mucosal pathogenesis. We finally discuss about the prospect of mitochondrial targeting for next-generation drug discovery against GI disorders.

Differential Regulation of ATP- and UTP-Evoked Prostaglandin E2 and IL-6 Production from Human Airway Epithelial Cells.

The airway epithelial cells (AECs) lining the conducting passageways of the lung secrete a variety of immunomodulatory factors. Among these, PGE2 limits lung inflammation and promotes bronchodilation. By contrast, IL-6 drives intense airway inflammation, remodeling, and fibrosis. The signaling that differentiates the production of these opposing mediators is not understood. In this study, we find that the production of PGE2 and IL-6 following stimulation of human AECs by the damage-associated molecular pattern extracellular ATP shares a common requirement for Ca2+ release-activated Ca2+ (CRAC) channels. ATP-mediated synthesis of PGE2 required activation of metabotropic P2Y2 receptors and CRAC channel-mediated cytosolic phospholipase A2 signaling. By contrast, ATP-evoked synthesis of IL-6 occurred via activation of ionotropic P2X receptors and CRAC channel-mediated calcineurin/NFAT signaling. In contrast to ATP, which elicited the production of both PGE2 and IL-6, the uridine nucleotide, UTP, stimulated PGE2 but not IL-6 production. These results reveal that human AECs employ unique receptor-specific signaling mechanisms with CRAC channels as a signaling nexus to regulate release of opposing immunomodulatory mediators. Collectively, our results identify P2Y2 receptors, CRAC channels, and P2X receptors as potential intervention targets for airway diseases.

ADP-ribosylation in evasion, promotion and exacerbation of immune responses.

ADP-ribosylation is the addition of one or more (up to some hundreds) ADP-ribose moieties to acceptor proteins. This evolutionary ancient post-translational modification (PTM) is involved in fundamental processes including DNA repair, inflammation, cell death, differentiation and proliferation, among others. ADP-ribosylation is catalysed by two major families of enzymes: the cholera toxin-like ADP-ribosyltransferases (ARTCs) and the diphtheria toxin-like ADP-ribosyltransferases (ARTDs, also known as PARPs). ARTCs sense and use extracellular NAD, which may represent a danger signal, whereas ARTDs are present in the cell nucleus and/or cytoplasm. ARTCs mono-ADP-ribosylate their substrates, whereas ARTDs, according to the specific family member, are able to mono- or poly-ADP-ribosylate target proteins or are devoid of enzymatic activity. Both mono- and poly-ADP-ribosylation are dynamic processes, as specific hydrolases are able to remove single or polymeric ADP moieties. This dynamic equilibrium between addition and degradation provides plasticity for fast adaptation, a feature being particularly relevant to immune cell functions. ADP-ribosylation regulates differentiation and functions of myeloid, T and B cells. It also regulates the expression of cytokines and chemokines, production of antibodies, isotype switch and the expression of several immune mediators. Alterations in these processes involve ADP-ribosylation in virtually any acute and chronic inflammatory/immune-mediated disease. Besides, pathogens developed mechanisms to contrast the action of ADP-ribosylating enzymes by using their own hydrolases and/or to exploit this PTM to sustain their virulence. In the present review, we summarize and discuss recent findings on the role of ADP-ribosylation in immunobiology, immune evasion/subversion by pathogens and immune-mediated diseases.

Hematopoietic progenitor cell liabilities and alarmins S100A8/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults.

Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs) and molecular markers of inflammaging (ELISA) with the cardiorespiratory phenotype and prospective adverse events of individuals classified according to levels of frailty. Two cohorts of older adults were enrolled in the study. In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. Moreover higher frailty was associated with increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. We then studied a cohort of 104 more frail individuals (average age: 81 years) with multidomain health deficits. Reduced levels of circulating HSPCs and increased S100A8/A9 concentrations were independently associated with the frailty index. Remarkably, low HSPCs and high S100A8/A9 simultaneously predicted major adverse cardiovascular events at 1-year follow-up after adjustment for age and frailty index. In conclusion, inflammaging characterized by alarmin and pro-inflammatory cytokines in pre-frail individuals is mirrored by the pauperization of HSPCs in frail older people with comorbidities. S100A8/A9 is upregulated within HSPCs, identifying a phenotype that associates with poor cardiovascular outcomes.

The impact of DAMP-mediated inflammation in severe COVID-19 and related disorders.

The host response to SARS-CoV-2, the virus that causes COVID-19, is highly heterogeneous, ranging from mild/asymptomatic to severe. The moderate to severe forms of COVID-19 often require hospitalization, are associated with a high rate of mortality, and appear to be caused by an inappropriately exaggerated inflammatory response to the virus. Emerging data confirm the involvement of both innate and adaptive immune pathways both in protection from SARS-CoV-2, and in driving the pathology of severe COVID-19. In particular, innate immune cells including neutrophils appear to be key players in the inflammation that causes the vicious cycle of damage and inflammation that underlies the symptomatology of severe COVID-19. Several recent studies support a link between damage and inflammation, with damage-associated molecular patterns (DAMPs) playing a key role in the pathology of severe COVID-19. In this review, we put into perspective the role of DAMPs and of components of the DAMP-signaling cascade, including Siglecs and their cognate ligands CD24 and CD52, in COVID-19. Further, we review clinical data on proposed therapeutics targeting DAMP pathways to treat SARS-CoV-2 infection and the regulation of these signaling cascades in COVID-19. We also discuss the potential impact of DAMP-mediated inflammation in other indications related to COVID-19, such as ARDS, endothelial dysfunction, hypercoagulation, and sepsis.

Divergent COVID-19 Disease Trajectories Predicted by a DAMP-Centered Immune Network Model.

COVID-19 presentations range from mild to moderate through severe disease but also manifest with persistent illness or viral recrudescence. We hypothesized that the spectrum of COVID-19 disease manifestations was a consequence of SARS-CoV-2-mediated delay in the pathogen-associated molecular pattern (PAMP) response, including dampened type I interferon signaling, thereby shifting the balance of the immune response to be dominated by damage-associated molecular pattern (DAMP) signaling. To test the hypothesis, we constructed a parsimonious mechanistic mathematical model. After calibration of the model for initial viral load and then by varying a few key parameters, we show that the core model generates four distinct viral load, immune response and associated disease trajectories termed "patient archetypes", whose temporal dynamics are reflected in clinical data from hospitalized COVID-19 patients. The model also accounts for responses to corticosteroid therapy and predicts that vaccine-induced neutralizing antibodies and cellular memory will be protective, including from severe COVID-19 disease. This generalizable modeling framework could be used to analyze protective and pathogenic immune responses to diverse viral infections.

Mechanisms of Immunothrombosis by SARS-CoV-2.

SARS-CoV-2 contains certain molecules that are related to the presence of immunothrombosis. Here, we review the pathogen and damage-associated molecular patterns. We also study the imbalance of different molecules participating in immunothrombosis, such as tissue factor, factors of the contact system, histones, and the role of cells, such as endothelial cells, platelets, and neutrophil extracellular traps. Regarding the pathogenetic mechanism, we discuss clinical trials, case-control studies, comparative and translational studies, and observational studies of regulatory or inhibitory molecules, more specifically, extracellular DNA and RNA, histones, sensors for RNA and DNA, as well as heparin and heparinoids. Overall, it appears that a network of cells and molecules identified in this axis is simultaneously but differentially affecting patients at different stages of COVID-19, and this is characterized by endothelial damage, microthrombosis, and inflammation.

The Role of Epithelial Damage in the Pulmonary Immune Response.

Pulmonary epithelial cells are widely considered to be the first line of defence in the lung and are responsible for coordinating the innate immune response to injury and subsequent repair. Consequently, epithelial cells communicate with multiple cell types including immune cells and fibroblasts to promote acute inflammation and normal wound healing in response to damage. However, aberrant epithelial cell death and damage are hallmarks of pulmonary disease, with necrotic cell death and cellular senescence contributing to disease pathogenesis in numerous respiratory diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and coronavirus disease (COVID)-19. In this review, we summarise the literature that demonstrates that epithelial damage plays a pivotal role in the dysregulation of the immune response leading to tissue destruction and abnormal remodelling in several chronic diseases. Specifically, we highlight the role of epithelial-derived damage-associated molecular patterns (DAMPs) and senescence in shaping the immune response and assess their contribution to inflammatory and fibrotic signalling pathways in the lung.

Interferon-Independent Restriction of RNA Virus Entry and Replication by a Class of Damage-Associated Molecular Patterns.

Mammalian cells detect microbial molecules known as pathogen-associated molecular patterns (PAMPs) as indicators of potential infection. Upon PAMP detection, diverse defensive responses are induced by the host, including those that promote inflammation and cell-intrinsic antimicrobial activities. Host-encoded molecules released from dying or damaged cells, known as damage-associated molecular patterns (DAMPs), also induce defensive responses. Both DAMPs and PAMPs are recognized for their inflammatory potential, but only the latter are well established to stimulate cell-intrinsic host defense. Here, we report a class of DAMPs that engender an antiviral state in human epithelial cells. These DAMPs include oxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine), PGPC (1-palmitoyl-2-glutaryl phosphatidylcholine), and POVPC [1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine], oxidized lipids that are naturally released from dead or dying cells. Exposing cells to these DAMPs prior to vesicular stomatitis virus (VSV) infection limits viral replication. Mechanistically, these DAMPs prevent viral entry, thereby limiting the percentage of cells that are productively infected and consequently restricting viral load. We found that the antiviral actions of oxidized lipids are distinct from those mediated by the PAMP Poly I:C, in that the former induces a more rapid antiviral response without the induction of the interferon response. These data support a model whereby interferon-independent defensive activities can be induced by DAMPs, which may limit viral replication before PAMP-mediated interferon responses are induced. This antiviral activity may impact viruses that disrupt interferon responses in the oxygenated environment of the lung, such as influenza virus and SARS-CoV-2.IMPORTANCE In this work, we explored how a class of oxidized lipids, spontaneously created during tissue damage and unprogrammed cell lysis, block the earliest events in RNA virus infection in the human epithelium. This gives us novel insight into the ways that we view infection models, unveiling a built-in mechanism to slow viral growth that neither engages the interferon response nor is subject to known viral antagonism. These oxidized phospholipids act prior to infection, allowing time for other, better-known innate immune mechanisms to take effect. This discovery broadens our understanding of host defenses, introducing a soluble factor that alters the cellular environment to protect from RNA virus infection.

DAMPening COVID-19 Severity by Attenuating Danger Signals.

COVID-19 might lead to multi-organ failure and, in some cases, to death. The COVID-19 severity is associated with a "cytokine storm." Danger-associated molecular patterns (DAMPs) are proinflammatory molecules that can activate pattern recognition receptors, such as toll-like receptors (TLRs). DAMPs and TLRs have not received much attention in COVID-19 but can explain some of the gender-, weight- and age-dependent effects. In females and males, TLRs are differentially expressed, likely contributing to higher COVID-19 severity in males. DAMPs and cytokines associated with COVID-19 mortality are elevated in obese and elderly individuals, which might explain the higher risk for severer COVID-19 in these groups. Adenosine signaling inhibits the TLR/NF-κB pathway and, through this, decreases inflammation and DAMPs' effects. As vaccines will not be effective in all susceptible individuals and as new vaccine-resistant SARS-CoV-2 mutants might develop, it remains mandatory to find means to dampen COVID-19 disease severity, especially in high-risk groups. We propose that the regulation of DAMPs via adenosine signaling enhancement might be an effective way to lower the severity of COVID-19 and prevent multiple organ failure in the absence of severe side effects.

Network-based repurposing identifies anti-alarmins as drug candidates to control severe lung inflammation in COVID-19.

While establishing worldwide collective immunity with anti SARS-CoV-2 vaccines, COVID-19 remains a major health issue with dramatic ensuing economic consequences. In the transition, repurposing existing drugs remains the fastest cost-effective approach to alleviate the burden on health services, most particularly by reducing the incidence of the acute respiratory distress syndrome associated with severe COVID-19. We undertook a computational repurposing approach to identify candidate therapeutic drugs to control progression towards severe airways inflammation during COVID-19. Molecular profiling data were obtained from public sources regarding SARS-CoV-2 infected epithelial or endothelial cells, immune dysregulations associated with severe COVID-19 and lung inflammation induced by other respiratory viruses. From these data, we generated a protein-protein interactome modeling the evolution of lung inflammation during COVID-19 from inception to an established cytokine release syndrome. This predictive model assembling severe COVID-19-related proteins supports a role for known contributors to the cytokine storm such as IL1ß, IL6, TNFα, JAK2, but also less prominent actors such as IL17, IL23 and C5a. Importantly our analysis points out to alarmins such as TSLP, IL33, members of the S100 family and their receptors (ST2, RAGE) as targets of major therapeutic interest. By evaluating the network-based distances between severe COVID-19-related proteins and known drug targets, network computing identified drugs which could be repurposed to prevent or slow down progression towards severe airways inflammation. This analysis confirmed the interest of dexamethasone, JAK2 inhibitors, estrogens and further identified various drugs either available or in development interacting with the aforementioned targets. We most particularly recommend considering various inhibitors of alarmins or their receptors, currently receiving little attention in this indication, as candidate treatments for severe COVID-19.

The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis.

Pulmonary fibrosis is a chronic debilitating condition characterized by progressive deposition of connective tissue, leading to a steady restriction of lung elasticity, a decline in lung function, and a median survival of 4.5 years. The leading causes of pulmonary fibrosis are inhalation of foreign particles (such as silicosis and pneumoconiosis), infections (such as post COVID-19), autoimmune diseases (such as systemic autoimmune diseases of the connective tissue), and idiopathic pulmonary fibrosis. The therapeutics currently available for pulmonary fibrosis only modestly slow the progression of the disease. This review is centered on the interplay of damage-associated molecular pattern (DAMP) molecules, Toll-like receptor 4 (TLR4), and inflammatory cytokines (such as TNF-α, IL-1ß, and IL-17) as they contribute to the pathogenesis of pulmonary fibrosis, and the possible avenues to develop effective therapeutics that disrupt this interplay.