Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies.

Conti P ，Ronconi G ，Caraffa A ，Gallenga CE ，Ross R ，Frydas I ，Kritas SK ... -  《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》

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》

Coronavirus COV-19/SARS-CoV-2 affects women less than men: clinical response to viral infection.

CoV-19/SARS-CoV-2 is a highly pathogenic virus that causes coronavirus-19 disease (COVID-19) an acute respiratory distress syndrome which provokes serious problems for global health. Studies suggest that there are many differences between men and women in the immune response to CoV-19 infection and inflammatory diseases. Women, compared to men, are less susceptible to viral infections based on a different innate immunity, steroid hormones and factors related to sex chromosomes. The presence of two X chromosomes in women emphasize the immune system even if one is inactive. The immune regulatory genes encoded by X chromosome in female gender causes lower viral load levels, and less inflammation than in man, while CD4+ T cells are higher with better immune response. In addition, women generally produce higher levels of antibodies which remain in the circulation longer. The levels of activation of the immune cells are higher in women than in men, and it is correlated with the trigger of TLR7 and the production of IFN. TLR7 is higher in women than in men and its biallelic expression leads to higher immune responses and increases the resistance to viral infections. TLR7 is expressed in innate immune cells which recognizes single strand RNA virus by promoting the production of antibodies against the virus and the generation of pro-inflammatory cytokines including IL-6 and IL-1 family members. Moreover, in women the production of inflammatory IL-6 after viral infection is lower than in males and is often correlated with a better longevity. In addition, on the X chromosome there are loci that code for the genes involved in the regulation of immune cells such as FOXP3, and transcription factor for Treg involved in virus pathogenesis. The X chromosome influences the immune system by acting on many other proteins, including TLR8, CD40L and CXCR3 which can be over-expressed in women, and influence the response to viral infections and vaccinations. However, the biallelic expression of the X-linked genes can promote harmful autoimmune and inflammatory responses. Cardiovascular diseases are more frequent in males and subjects without cardiovascular dysfunctions infected by CoV-19 have a better prognosis, but these effects are still under study. It is hoped that certain drugs, such as CoV-19 receptor blockers, anti-inflammatories (against rheumatic diseases), monoclonal antibodies, anti-IL-1 and anti-IL-6, the remdesevir drug (analogue adenosine, effective against ebola), hydroxychloroquine (for the treatment of malaria) and vaccines, will open up new strategies and new therapeutic ways to combat this terrible virus.

Conti P ，Younes A 《JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS》

How to reduce the likelihood of coronavirus-19 (CoV-19 or SARS-CoV-2) infection and lung inflammation mediated by IL-1.

SARS-CoV-2, also referred to as CoV-19, is an RNA virus which can cause severe acute respiratory diseases (COVID-19), with serious infection of the lower respiratory tract followed by bronchitis, pneumonia and fibrosis. The severity of the disease depends on the efficiency of the immune system which, if it is weak, cannot stem the infection and its symptoms. The new CoV-19 spreads in the population at a rate of 0.8-3% more than normal flu and mostly affects men, since immune genes are more expressed on the X chromosome. If CoV-19 would spread with a higher incidence rate (over 10%), and affect the people who live in closed communities such as islands, it would cause many more deaths. Moreover, people from the poorest classes are most at risk because of lack of health care and should be given more assistance by the competent authorities. To avoid the aggravation of CoV-19 infection, and the collapse of the health system, individuals should remain at home in quarantine for a period of approximately one month in order to limit viral transmission. In the case of a pandemic, the severe shortage of respirators and protective clothing, due to the enormous demand and insufficient production, could lead the CoV-19 to kill a large number of individuals. At present, there is no drug capable of treating CoV-19 flu, the only therapeutic remedies are those aimed at the side effects caused by the virus, such as inflammation and pulmonary fibrosis, recognized as the first causes of death. One of the COVID-19 treatments involves inhaling a mixture of gaseous hydrogen and oxygen, obtaining better results than with oxygen alone. It was also noted that individuals vaccinated for viral and/or bacterial infectious diseases were less likely to become infected. In addition, germicidal UV radiation "breaks down" the oxygen O2 which then aggregate into O3 (ozone) molecules creating the ozone layer, capable of inhibiting viral replication and improving lung respiration. All these precautions should be taken into consideration to lower the risk of infection by CoV-19. New anti-viral therapies with new drugs should also be taken into consideration. For example, microbes are known to bind TLR, inducing IL-1, a pleiotropic cytokine, highly inflammatory, mediator of fever and fibrosis. Therefore, drugs that suppress IL-1 or IL-1R, also used for the treatment of rheumatoid arthritis are to be taken into consideration to treat COVID-19. We strongly believe that all these devices described above can lead to greater survival and. therefore, reduction in mortality in patients infected with CoV-19.

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