IL-1 induces throboxane-A2 (TxA2) in COVID-19 causing inflammation and micro-thrombi: inhibitory effect of the IL-1 receptor antagonist (IL-1Ra).

IL-1 induces a significant number of metabolic and hematological changes. In experimental animals, IL-1 treatments cause hypotension due to rapid reduction of systemic blood pressure, reduced vascular resistance, increased heart rate and leukocyte aggregations. IL-1 causes endothelial dysfunction, the triggering factor of which may be of a different nature including pathogen infection. This dysfunction, which includes macrophage intervention and increased protein permeability, can be mediated by several factors including cytokines and arachidonic acid products. These effects are caused by the induction of IL-1 in various pathologies, including those caused by pathogenic viral infections, including SARS-CoV-2 which provokes COVID-19. Activation of macrophages by coronavirus-19 leads to the release of pro-inflammatory cytokines, metalloproteinases and other proteolytic enzymes that can cause thrombi formation and severe respiratory dysfunction. Patients with COVID-19, seriously ill and hospitalized in intensive care, present systemic inflammation, intravascular coagulopathy with high risk of thrombotic complications, and venous thromboembolism, effects mostly mediated by IL-1. In these patients the lungs are the most critical target organ as it can present an increase in the degradation products of fibrin, fibrinogen and D-dimer, with organ lesions and respiratory failure. It is well known that IL-1 induces itself and another very important pro-inflammatory cytokine, TNF, which also participates in hemodynamic states, including shock syndrome in COVID-19. Both IL-1 and TNF cause pulmonary edema, thrombosis and bleeding. In addition to hypotension and resistance of systemic blood pressure, IL-1 causes leukopenia and thrombocytopenia. The formation of thrombi is the main complication of the circulatory system and functionality of the organ, and represents an important cause of morbidity and mortality. IL-1 causes platelet vascular thrombogenicity also on non-endothelial cells by stimulating the formation of thromboxane A2 which is released into the inflamed environment. IL-1 is the most important immune molecule in inducing fever, since it is involved in the metabolism of arachidonic acid which increases from vascular endothelial organs of the hypothalamus. The pathogenesis of thrombosis, vascular inflammation and angigenesis involves the mediation of the activation of the prostanoid thromboxane A2 receptor. In 1986, in an interesting article (Conti P, Reale M, Fiore S, Cancelli A, Angeletti PU, Dinarello CA. In vitro enhanced thromboxane B2 release by polymorphonuclear leukocytes and macrophages after treatment with human recombinant interleukin 1. Prostaglandins. 1986 Jul;32(1):111-5), we reported for the first time that IL-1 induces thromboxane B2 (TxB2) releases in activated neutrophils and macrophages. An increase in thromboxane can induce leukocyte aggregation and systemic inflammation, which would account for the dramatic thrombi formation and organ dysfunction. Hence, IL-1 stimulates endothelial cell-leukocyte adhesion, and TxB2 production. All these events are supported by the large increase in neutrophils that adhere to the lung and the decrease in lymphocytes. Therefore, ecosanoids such as TxA2 (detected as TxB2) have a powerful action on vascular inflammation and platelet aggregation, mediating the formation of thrombi. The thrombogenesis that occurs in COVID-19 includes platelet and cell aggregation with clotting abnormalities, and anti-clotting inhibitor agents are used in the prevention and therapy of thrombotic diseases. Prevention of or induction of TxA2 avoids thrombi formation induced by IL-1. However, in some serious vascular events where TxA2 increases significantly, it is difficult to inhibit, therefore, it would be much better to prevent its induction and generation by blocking its inductors including IL-1. The inhibition or lack of formation of IL-1 avoids all the above pathological events which can lead to death of the patient. The treatment of innate immune cells producing IL-1 with IL-1 receptor antagonist (IL-1Ra) can avoid hemodynamic changes, septic shock and organ inflammation by carrying out a new therapeutic efficacy on COVID-19 induced by SARS-CoV-2.

Conti P ，Caraffa A ，Gallenga CE ，Ross R ，Kritas SK ，Frydas I ，Younes A ，Di Emidio P ，Ronconi G ，Toniato E ... -  《JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS》

Coronavirus-19 (SARS-CoV-2) induces acute severe lung inflammation via IL-1 causing cytokine storm in COVID-19: a promising inhibitory strategy.

SARS-Cov-2 infection causes local and systemic inflammation mediated by pro-inflammatory cytokines and COX-2 eicosanoid products with metabolic dysfunction and tissue damage that can lead to patient death. These effects are primarily induced by IL-1 cytokines, which are involved in the elevation of hepatic acute phase proteins and fever. IL-1 has a broad spectrum of biological activities and participates in both innate and acquired immunity. In infections, IL-1 induces gene expression and synthesis of several cytokines/chemokines in both macrophages and mast cells (MCs). The activation of MCs triggers the secretion of mediators stored in the granules, and the de novo synthesis of pro-inflammatory cytokines. In microorganism infections, the release of IL-1 macrophage acts on adhesion molecules and endothelial cells leading to hypotension and septic shock syndrome. IL-1 activated by SARS-CoV-2 stimulates the secretion of TNF, IL-6 and other cytokines, a pro-inflammatory complex that can lead to cytokine storm and be deleterious in both lung and systemically. In SARS-CoV-2 septic shock, severe metabolic cellular abnormalities occur which can lead to death. Here, we report that SARS-CoV-2 induces IL-1 in macrophages and MCs causing the induction of gene expression and activation of other pro-inflammatory cytokines. Since IL-1 is toxic, its production from ubiquitous MCs and macrophages activated by SARS-CoV-2 can also provokes both gastrointestinal and brain disorders. Furthermore, in these immune cells, IL-1 also elevates nitric oxide, and the release of inflammatory arachidonic acid products such as prostaglndins and thromboxane A2. All together these effects can generate cytokine storm and be the primary cause of severe inflammation with respiratory distress and death. Although, IL-1 administered in low doses may be protective; when it is produced in high doses in infectious diseases can be detrimental, therefore, IL-1 blockade has been studied in many human diseases including sepsis, resulting that blocking it is absolutely necessary. This definitely nurtures hope for a new effective therapeutic treatment. Recently, two interesting anti-IL-1 cytokines have been widely described: IL-37 and IL-1Ra. IL-37, by blocking IL-1, has been observed to have anti-inflammatory action in rodents in vivo and in transfected cells. It has been reported that IL-37 is a very powerful protein which inhibits inflammation and its inhibition can be a valid therapeutic strategy. IL-37 is a natural suppressor of inflammation that is generated through a caspase-1 that cleaves pro-IL-37 into mature IL-37 which translocates to the nucleus and inhibits the transcription of pro-inflammatory genes; while IL-1Ra inhibits inflammation by binding IL-1 to its IL-1R (receptor). We firmly believe that blocking IL-1 with an anti-inflammatory cytokine such as IL-37 and/or IL-1Ra is an effective valid therapy in a wide spectrum of inflammatory disorders including SARS-CoV-2-induced COVID-19. Here, we propose for the first time that IL-37, by blocking IL-1, may have an important role in the therapy of COVID-19.

Conti P ，Caraffa A ，Gallenga CE ，Ross R ，Kritas SK ，Frydas I ，Younes A ，Ronconi G ... -  《JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS》

Mast cells activated by SARS-CoV-2 release histamine which increases IL-1 levels causing cytokine storm and inflammatory reaction in COVID-19.

SARS-CoV-2 virus is an infectious agent commonly found in certain mammalian animal species and today also in humans. SARS-CoV-2, can cause a pandemic infection with severe acute lung injury respiratory distress syndrome in patients with COVID-19, that can lead to patient death across all ages. The pathology associated with pandemic infection is linked to an over-response of immune cells, including virus-activated macrophages and mast cells (MCs). The local inflammatory response in the lung that occurs after exposure to SARS-CoV-2 is due to a complex network of activated inflammatory innate immune cells and structural lung cells such as bronchial epithelial cells, endothelial cells and fibroblasts. Bronchial epithelial cells and fibroblasts activated by SARS-CoV-2 can result in the up-regulation of pro-inflammatory cytokines and induction of MC differentiation. In addition, endothelial cells which control leukocyte traffic through the expression of adhesion molecules are also able to amplify leukocyte activation by generating interleukin (IL)-1, IL-6 and CXC chemokines. In this pathologic environment, the activation of mast cells (MCs) causes the release of histamine, proteases, cytokines, chemokines and arachidonic acid compounds, such as prostaglandin D2 and leukotrienes, all of which are involved in the inflammatory network. Histamine is stored endogenously within the secretory granules of MCs and is released into the vessels after cell stimulation. Histamine is involved in the expression of chemokine IL-8 and cytokine IL-6, an effect that can be inhibited by histamine receptor antagonists. IL-1 is a pleiotropic cytokine that is mainly active in inflammation and immunity. Alveolar macrophages activated by SARS-CoV-2 through the TLR produce IL-1 which stimulates MCs to produce IL-6. IL-1 in combination with IL-6 leads to excessive inflammation which can be lethal. In an interesting study published several years ago (by E. Vannier et al., 1993), it was found that histamine as well as IL-1 are implicated in the pathogenesis of pulmonary inflammatory reaction, after micorganism immune cell activation. IL-1 in combination with histamine can cause a strong increase of IL-1 levels and, consequently, a higher degree of inflammation. However, it has been reported that histamine alone has no effect on IL-1 production. Furthermore, histamine enhances IL-1-induced IL-6 gene expression and protein synthesis via H2 receptors in peripheral monocytes. Therefore, since MCs are large producers of histamine in inflammatory reactions, this vasoactive amine, by increasing the production of IL-1, can amplify the inflammatory process in the lung infected with SARS-CoV-2. Here, we have proposed for the first time an emerging role for histamine released by MCs which in combination with IL-1 can cause an increase in lung inflammation induced by the viral infection SARS-CoV-2.

Conti P ，Caraffa A ，Tetè G ，Gallenga CE ，Ross R ，Kritas SK ，Frydas I ，Younes A ，Di Emidio P ，Ronconi G ... -  《JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS》

Monoclonal antibody therapy in COVID-19.

Acute severe respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-2019 (COVID-19) which is associated with inflammation, thrombosis edema, hemorrhage, intra-alveolar fibrin deposition, and vascular and pulmonary damage. In COVID-19, the coronavirus activates macrophages by inducing the generation of pro-inflammatory cytokines [interleukin (IL)-1, IL-6, IL-18 and TNF] that can damage endothelial cells, activate platelets and neutrophils to produce thromboxane A2 (TxA2), and mediate thrombus generation. In severe cases, all these phenomena can lead to patient death. The binding of SARS-CoV-2 to the Toll Like Receptor (TLR) results in the release of pro-IL-1β that is cleaved by caspase-1, followed by the production of active mature IL-1β which is the most important cytokine in causing fever and inflammation. Its activation in COVID-19 can cause a "cytokine storm" with serious biological and clinical consequences. Blockade of IL-1 with inhibitory and anti-inflammatory cytokines represents a new therapeutic strategy also for COVID-19. Recently, very rare allergic reactions to vaccines have been reported, with phenomena of pulmonary thrombosis. These side effects have raised substantial concern in the population. Highly allergic subjects should therefore be vaccinated under strict medical supervision. COVID-19 has accelerated vaccine therapy but also the use of drugs and monoclonal antibodies (mABs) which have been used in COVID-19 therapy. They are primarily adopted to treat high-risk mild-to-moderate non-hospitalized patients, and it has been noted that the administration of two mABs gave better results. mABs, other than polyclonal plasma antibodies from infected subjects with SARS-CoV-2, are produced in the laboratory and are intended to fight SARS-CoV-2. They bind specifically to the antigenic determinant of the spike protein, inhibiting the pathogenicity of the virus. The most suitable individuals for mAB therapy are people at particular risk, such as the elderly and those with serious chronic diseases including diabetics, hypertension and obesity, including subjects suffering from cardiovascular diseases. These antibodies have a well-predetermined target, they bind mainly to the protein S (formed by the S1A, B, C and D subtypes), located on the viral surface, and to the S2 protein that acts as a fuser between the virus and the cell membrane. Since mABs are derived from a single splenic immune cell, they are identical and form a cell clone which can neutralize SARS-CoV-2 by binding to the epitope of the virus. However, this COVID-19 therapy may cause several side effects such as mild pain, bleeding, bruising of the skin, soreness, swelling, thrombotic-type episodes, arterial hypertension, changes in heart activity, slowed bone marrow activity, impaired renal function, diarrhea, fatigue, nausea, vomiting, allergic reaction, fever, and possible subsequent infection may occur at the site of injection. In conclusion, the studies promoting mAB therapy in COVID-19 are very promising but the results are not yet definitive and more investigations are needed to certify both their good neutralizing effects of SARS-CoV-2, and to eliminate, or at least mitigate, the harmful side effects.

Conti P ，Pregliasco FE ，Calvisi V ，Caraffa Al ，Gallenga CE ，Kritas SK ，Ronconi G ... -  《JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS》

Covid-19: The Rollercoaster of Fibrin(Ogen), D-Dimer, Von Willebrand Factor, P-Selectin and Their Interactions with Endothelial Cells, Platelets and Erythrocytes.

Grobler C ，Maphumulo SC ，Grobbelaar LM ，Bredenkamp JC ，Laubscher GJ ，Lourens PJ ，Steenkamp J ，Kell DB ，Pretorius E ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》