J Biol Regul Homeost Agents. 2020 Feb 4;34(1). doi: 10.23812/20-Editorial-Kritas. [Epub ahead of print]
Mast cells contribute to coronavirus-induced inflammation: new anti-inflammatory strategy.
- 1 Department of Microbiology and Infectious Diseases, School of Veterinary Medicine, Aristotle University of Thessaloniki, Macedonia, Greece.
- 2 Clinica dei Pazienti del Territorio, Fondazione Policlinico Gemelli, Rome, Italy.
- 3 School of Pharmacy, University of Camerino, Camerino, Italy.
- 4 Department of Biomedical Sciences and Specialist Surgery, Section of Ophthalmology, University of Ferrara, Ferrara, Italy.
- 5 University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA.
- 6 Postgraduate Medical School, University of Chieti, Chieti, Italy.
Coronavirus can cause respiratory syndrome which to date has affected about twelve thousand individuals, especially in China. Coronavirus is interspecies and can also be transmitted from man to man, with an incubation ranging from 1 to 14 days. Human coronavirus infections can induce not only mild to severe respiratory diseases, but also inflammation, high fever, cough, acute respiratory tract infection and dysfunction of internal organs that may lead to death. Coronavirus infection (regardless of the various types of corona virus) is primarily attacked by immune cells including mast cells (MCs), which are located in the submucosa of the respiratory tract and in the nasal cavity and represent a barrier of protection against microorganisms. Viral activate MCs release early inflammatory chemical copounds including histamine and protease; while late activation provoke the generation of pro-inflammatory IL-1 family members including IL-1, IL-6 and IL-33. Here, we propose for the first time that inflammation by coronavirus maybe inhibited by anti-inflammatory cytokines belonging to the IL-1 family members.
Coronavirus, immunity, infection, inflammation, mast cell
Virus infections are certainly increasing globally, they can cause both an epidemic spread, but also a pandemic one in different countries, as was the case with the avian influenza virus H5N1 (motivity 35%) and SARS (Severe Acute Respiratory Syndrome) (mortality 10%) (1).
Middle East respiratory syndrome caused by coronavirus first appeared in 2012 and since then, over seventeen thousand patients have been infected worldwide (especially in Cina) of which about 900 have died (a number destined to increase), this is in accordance with the World Health Organization (WHO ) (2). There are several types of coronavirus, they can be transformed and become interspecies and have an incubation ranging approximately from 1 to 14 days (1). They are of unknown origin, although they could originate from various animals such as snakes, bats, pigs, or dromedary camels which are the main host and which in these animals can cause acute diarrhea, gastroenteritis, villous atrophy, poor absorption and death (2). Human-to-human virus transmission also occurs in healthcare facilities and communities.
Coronavirus often have highly pathogenic activity in animals but today it has been seen that with its particular pathogenic proteins, they can cause more or less serious respiratory diseases both in adults and in children. Moreover, coronavirus is one of the major respiratory pathogens now come to the fore, which causes serious inflammatory outbreaks of acute pneumonia in individuals (3). Therefore, human coronavirus infections can induce not only mild to severe diseases, but also systemic inflammation, high fever, cough, acute respiratory tract infection and dysfunction of internal organs that can lead to death. Coronavirus is classified as an RNA virus, with a genome that can often escape the innate immune system, especially if it is malfunctioning (4). Regardless of the various types of corona virus, the entry of the virus into the organism activates innate immunity, which intervene in the first instance to engulf the invader. The severity of the disease lies in the ability of innate immunity cells to stem viral infection (5). Stronger is the innate immune system, less is the ability of the virus to replicate itself, suppress the immunity and therefore to induce the pathological state. In the case of innate immune suppression by the virus, adaptive immunity is also inhibited, as the coronavirus is capable of producing viral enzymes and proteases that damage the immunity and inhibit the signaling pathways of type I interferon (IFN), along with the nuclear factor-κB, facilitating the innate immune evasion (6).
In light of all above, new anti-cronavirus strategies are needed to fight the disease, in order to avoid the infection. Experiments in the laboratory on rodents show that inoculating various different types of coronavirus, all induce an innate and adaptive immune response, but also an acute encephalomyelitis with invasion of the virus throughout the brain (7). Therefore, the virus mainly settles in the white matter causing chronic neuroinflammation and demyelination. The disease causes the activation of T and B cells which are attracted to the place of infection by specific chemokines (8). Coronavirus infection is primarily attacked by immune cells, but the virus has developed viral proteins over time that counteract the innate immune system (9). Some viral proteins antagonize interferon (IFN) and stimulate inflammatory proteins including IL-1 family members cytokines (10). The abnormal production of cytokines aggravates the inflammatory state and pathogenesis of the disease as also happens in SARS. There are several types of coronaviruses with variable morphogenesis of the envelope and production of different proteins (11).
The protein E of the envelope is very small but capable of influencing the replication of the viral genome, accentuating the pathogenicity and may causing strong inflammation and death of the patient. In addition, protein E activates the inflammasome in the tissues and causes increased edema with lethal results for humans. Immune Treg cells expressing IL-2 receptor, the CD4 receptor and the FoxP3 transcription factor, are cells that regulate immune status, tolerance in humans and are generated in the thymus (12). Corona virus-induced type 1 Treg cells which produces anti-inflammatory IL-10 protecting the body from the most aggressive forms of infection. The development of therapeutic anti-viral agents based on strengthening the immune system has been one of the main objectives of modern medicine. The immune response to the virus can be enhanced with the administration of antigens, adjuvants and vaccines. The vaccines that normally protect us from bacterial and viral infections, in the case of coronavirus, is not currently available and the experimental ones have not proved to be effective, although some vaccine have exerted a slight protective effect (13). We believe that coronavirus infection, as well as other pathogenic microorganism infections, can be combated by preventing contagion and boosting the immune system.
Mast cells (MCs)
MCs, are immune cells derive from the hematopoietic precursor cells (bone marrow CD34+), which mature and reside in virtually all vascularized tissue (14). MCs are located perivascularly in proximity to neurons and they differentiation and proliferation are regulated by the stem cell factor (SCF), which binds the surface kit-receptor. After activation, MC produce inflammatory mediators, including proteases and pro-inflammatory cytokines, participating in host response, as for example, skin diseases, and asthma (14). MCs are involved in innate and adaptive immune systems, playing a role in autoimmunity, infections, tissue damage, and inflammatory signals (15). MCs express TLR which can be quickly recognized by pathogens including the viruses that activate them in the airways and respiratory tract causing serious damage. When you properly activate, MCs generate biologically active substances including chemokines and cytokines without degranulation. MCs are responsible for allergic reactions, but also participate in inflammation and defend the body against bacterial helminthic and viral infections. MCs can be classically activated by IgE and specific antigen, but also by bacteria, and virus.
In the early response of the host, IgE stimulates MCs via FcεRI high-affinity receptor (1 x 1010M-1), which bound to the FcεRI and causes receptor aggregation and a series of biochemical events (14). Activated MCs release immediately chemical mediators and/or late production of pro-inflammatory proteins such as cytokines and chemokines (16). Therefore, virus activated MCs may provoke the release, after seconds, of stored chemical mediators such as histamine, tryptases and chimase. In addition, after hours of incubation, activated MCs secrete synthesized cytokines including IL-6, IL-1, IL-31, IL-33 and TNF, and chemokines CC5, CCL2, MCP-1 and CXCL8 which attracts white blood cells in to the inflammatory sites (16). All these compounds have a major role in inflammation. MCs produce stored and synthesized highly inflammatory TNF, both intra-cellular and extra-cellular. MCs innate immune cells are real sentinels of the human body, ready to attack immediately the external invaders which can be harmful to the cells, tissues and organs. MCs release IL-33 a member of the IL-1 family of cytokines, which is considered a cytokine called “alarmin”. MCs are peripherally located near dendritic cells, in communication with sensory nerves that cross-talk with brain cells, including microglia. MCs protect the body from infections caused by bacterium and virus (17). These cells, communicating with the external environment, neutralize various pathogens, but in doing so they also produce pro-inflammatory compounds which can be harmful for the body. Stressful and chronic conditions, predispose people to pathogenic infections including those caused by coronavirus. In fact, neurotransmitters, including substance p, that are generated in stress, can activate immune cells such as MCs to produce pro-inflammatory cytokines and chemical mediators of inflammation (18).
Experiments with coronavirus in mice have shown that this pathogenic RNA microorganism can activate the cells of both innate and adaptive immune system, including MCs. These cells are located in the submucosa of the respiratory tract and in the nasal cavity and represent the protective cells that are at the forefront in fighting viral and bacterial agents (19). They are involved in many biological processes where induce the secretion of a broad spectrum of cytokines and chemokines. In addition, MCs activating viruses cause the release of some specific chemokines such as the ligand 5 (CCL5) which attracts the CD8 T immune cells that defend the lung tissue and fights viral infection (20). Epithelial cells represent a physical barrier to the entry of microorganisms including viruses. The cross-talk between viruses and epithelial cells causes the production of immune mediators in order to defend the body. Viruses develop particular mechanisms to invade the body and immune cells including MCs. The host response to RNA virus invasion activates TLR3 on MCs with an anti-viral IFN production (positive effect) (21); but often the virus only causes sensitization of MCs with the synthesis of IgE that bind to the FceRI receptor and trigger a violent inflammatory reaction (negative effect). Therefore, the function of MCs towards viral infections is not yet clear. However, RNA viruses stimulate MCs to produce IFN gamma e CXCL8 chemokine resulting in the recruitment of NK cells that also produce type I interferons (IFNs) which are anti-viral cytokines.
In addition, type I IFNs enhance the cytotoxic activity of NK cells against virus infected cells (22). So, in this case, MCs are anti-viral immune cells through the above mechanism. On the other hand, virus stimulate mucosa MCs to release pro-inflammatory cytokines such as TNF, IL-1, IL-6 and proteases, which aggravate the inflammatory state.
Virus-activated MCs produce histamine, prostaglandin D2 (PGD2), and leukotriene C4 (LTC4) which induces acute bronchoconstriction and lung inflammation.
Therefore, we can conclude that viral infections can activate MCs which respond with a dual effects, a positive one helping the immune system to fight infection, and negative causing the release of chemical mediators of inflammation and the secretion of pro-inflammatory cytokines such as IL-1, IL-33, IL-18, and TNF aggravating the pathological state of the patient.
IL-37 is a member of the IL-1 family of cytokines, which is activated by caspase-1 and suppresses transcription of pro-inflammatory genes and immune responses.
Since IL-37 is an inhibitors of IL-1 a potent pro-inflammatory cytokine (23), we believe that this anti-inflammatory cytokine may suppress fever and inflammation provoked by coronavirus, so as to reduce the number of deaths.
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