key: cord-0778796-41yzg8h8
authors: Hafezi, Bahareh; Chan, Lily; Knapp, Jason P.; Karimi, Negar; Alizadeh, Kimia; Mehrani, Yeganeh; Bridle, Byram W.; Karimi, Khalil
title: Cytokine Storm Syndrome in SARS-CoV-2 Infections: A Functional Role of Mast Cells
date: 2021-07-12
journal: Cells
DOI: 10.3390/cells10071761
sha: 11bd47a91eadefb1e7d20b50de300fc031fa39ae
doc_id: 778796
cord_uid: 41yzg8h8

Cytokine storm syndrome is a cascade of escalated immune responses disposing the immune system to exhaustion, which might ultimately result in organ failure and fatal respiratory distress. Infection with severe acute respiratory syndrome-coronavirus-2 can result in uncontrolled production of cytokines and eventually the development of cytokine storm syndrome. Mast cells may react to viruses in collaboration with other cells and lung autopsy findings from patients that died from the coronavirus disease that emerged in 2019 (COVID-19) showed accumulation of mast cells in the lungs that was thought to be the cause of pulmonary edema, inflammation, and thrombosis. In this review, we present evidence that a cytokine response by mast cells may initiate inappropriate antiviral immune responses and cause the development of cytokine storm syndrome. We also explore the potential of mast cell activators as adjuvants for COVID-19 vaccines and discuss the medications that target the functions of mast cells and could be of value in the treatment of COVID-19. Recognition of the cytokine storm is crucial for proper treatment of patients and preventing the release of mast cell mediators, as impeding the impacts imposed by these mediators could reduce the severity of COVID-19.

During an immune response, the cytokine storm phenomenon arises when homeostasis is not returned, and the pro-inflammatory pathways are without regulation and are hyperactive [1] [2] [3] . Rather than being thought of as a specific disease, the cytokine storm syndrome is considered to be a culminating endpoint to numerous diseases and conditions that occur during an attempt to fight off infections [1, 4] .

Cytokine storm syndrome was initially observed after systemic infections which took on a similar appearance to that of influenza infections. However, it was difficult to identify since it is not directly associated with any one pathogen or insult to a host, but is rather a common product of the host's immune system responding to any number of pathogens or insults [1] . There are some commonly observed signs and symptoms in cytokine storm syndrome such as fever, systemic inflammation, multi-organ failure, and high concentrations of circulating cytokines [1, 5] . It is crucial to determine the underlying cause of the cytokine storm as it will impact the prognosis, symptoms, and treatments that should be administered [1, 2] . An important and difficult distinction that is required to infections, promoting virus survival and/or exacerbation of clinical disease [20] . This could be due to polarization of helper T cells into a T helper-2 phenotype (impairing IFNγ production), failure in cytolytic activity, or promoting infected cell survival by inhibiting apoptosis. Knowing that MCs detect multiple classes of viruses, including both DNA and RNA viruses, one may consider MC responses to viruses an enhanced inflammation that has the potential to be harmful [19] .

Coronaviruses have now become one of the main respiratory pathogens that cause extreme inflammatory outbreaks of acute pneumonia in individuals [21] . Evidence has shown a potential association of MCs with COVID-19, and the activation of MCs located in the submucosa of the respiratory tract by SARS-CoV-2 is known to lead to the release of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α. Moreover, autopsy findings from the lungs of patients that died from COVID-19 showed accumulation of MCs that was speculated to be the cause of pulmonary edema, inflammation, and thrombosis in COVID-19 pathophysiology [16, 22, 23] .

The primary receptor that the SARS-CoV-2 spike (S) protein uses to facilitate viral entry into cells has been identified as angiotensin-converting enzyme (ACE)-2 [24] . The ACE2 protects against lung injury, and its downregulation is associated with serious lung injuries. Increasing ACE2 concentrations can correct for arterial hypoxia and improve pulmonary circulatory haemodynamics [25] . Interestingly, ACE2 serine protease in MCs is known to transform angiotensin I to angiotensin II [26] and is required for SARS-CoV-2 binding and entry into target cells. Glycoprotein spikes on the virus's outer envelope bind to the extracellular domain of the ACE2 receptor and allow the virus to enter the target cell [27] . MCs can give rise to bronchoconstriction, both by initiating a renin-angiotensingenerating system in the lungs and by producing leukotrienes [28] . Transmembrane serine protease 2 (TMPRSS2), which can be produced by MCs, is necessary for the priming of the coronavirus spike protein [16] , and MC-derived serine protease tryptase, has been observed to be essential for SARS-CoV-2 infection [29, 30] . Inhibition of viral entry into the lung cells by serine protease inhibitors such as camostat mesylate has confirmed these findings [31] .

Besides pro-inflammatory cytokines and chemokines, MCs are also known to secrete chymase [32] , a type of serine protease. Chymase activates transforming growth factor beta (TGF-β), and matrix metalloproteinases [MMP] such as MMP-9 [33] which are involved in pulmonary fibrosis. Moreover, thromboxanes and platelet-activating factor (PAF) produced by MCs can lead to microthrombosis in the lungs and cause COVID-19-associated coagulopathy, which has been confirmed in postmortem analysis of patients who died due to COVID-19 [22] .

A study done by Afrin et al. indicated a similarity between the prevalence of MC activation syndrome (MCAS) and that of severe cases of COVID-19. Many aspects of hyper inflammation in patients with COVID-19 seem to be coordinated with MCAS, while drugs which are unlikely to show potency against viral diseases seem to be effective against both MCAS and SARS-CoV-2-induced hyperinflammation [34] . COVID-19 is now widely recognized to be linked to a variety of extra-pulmonary symptoms, such as multisystem inflammatory syndrome (MIS-A). Symptoms of MIS-A and how stress exacerbates them are somewhat similar to those of MCAS [16] .

Often overshadowed by their involvement in pathology, MCs play an important role in protective immunity as multi-equipped pathogen sensors. MCs express a variety of receptors such as Toll-like receptors (TLRs), FcεRI-III/IgE, and cytosolic sensors that allow them to detect a wide range of pathogens such as bacteria and viruses, as well as toxins and allergens [12] . In the detection of viruses, MCs rely on the expression of TLR2, TLR3, TLR7, TLR8, TLR9, melanoma differentiation-associated protein 5 (MDA5), and retinoic acid-inducible gene (RIG)-I [12] . Activation through these sensors leads to the de novo synthesis of cytokines and chemokines for the generation of a virus-focused response as opposed to degranulation mediated through IgE-induced activation [12, 35] . In response to viral infection, MCs not only aid in the innate immune response through recruitment of natural killer cells via production of IL-8, but also influence the adaptive response in numerous ways [36] . For example, MC production of TNF-α recruits dendritic cells (DCs) to the site of infection, which then traffic to draining lymph nodes where antigen presentation takes place [37, 38] . Interestingly, MCs are able to induce CD8 + T cell responses through the modulation of DC phenotype as well as recruit T cells to sites of infection through the production of CCL5 [39] . Due to the ability of MCs to detect a wide array of pathogens and modulate naturally acquired adaptive immunity, many efforts are focused on the identification and characterization of MC activators that may be useful as adjuvants to enhance vaccine-induced immunity.

In roughly a year since the COVID-19 pandemic began, a handful of vaccines with evidence of protective efficacy, such as BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), have been developed and are currently being administered in numerous countries around the world [40, 41] . The majority of the COVID-19 vaccines that have been developed target the SARS-CoV-2 S protein with the goal of generating neutralizing Abs capable of binding to SARS-CoV-2 virions to prevent infection [42] . Unfortunately, numerous SARS-CoV-2 variants with mutations in the S protein have appeared and exhibit reduced sensitivity to certain antibodies that could neutralize earlier forms of the virus [43] [44] [45] [46] . Furthermore, many COVID-19 vaccines appear to be less effective against certain SARS-CoV-2 variants. For example, the AstraZeneca COVID-19 vaccine was found to have only 10.4% efficacy against the B.1.351 (501Y.V2) variant that was first identified in South Africa [47] . To further compound issues, slow vaccination programs have introduced a narrow selection pressure against the S protein into the population, which may further promote the emergence of a full SARS-CoV-2 vaccine escape mutant [48, 49] . These concerns emphasize the need for second-generation COVID-19 vaccines capable of generating a broader immune response that is not only focused on inducing SARS-CoV-2 S protein-neutralizing antibodies. Second-generation vaccines must also prioritize robust anti-SARS-CoV-2 cellular-mediated immunity through the targeting of additional SARS-CoV-2 proteins rich in T cell epitopes, such as the SARS-CoV-2 nucleocapsid protein [50] . Interestingly, recent studies of individuals who recovered from natural infections suggest that T cell-mediated immunity plays a larger role in protection against SARS-CoV-2 than previously thought [51, 52] . Especially important is the T helper cell response induced upon infection. Interestingly, compared with severe cases, people who recovered from mild COVID-19 also had more robust memory CD8 + T cell responses in the respiratory tract [50] . Furthermore, long-term immunity and control of re-infection appears to be largely antibody-independent but T cell-dependent [53] . Considering the ability of MCs to respond to viral infections and enhance T cell responses, we promote the investigation of mast cell activators as adjuvants for COVID-19 vaccines with the goal of enhancing the magnitude and longevity of SARS-CoV-2-specific T cell responses.

Here, we summarize two MC activators capable of enhancing anti-viral adaptive immunity that are worthy of further investigation as potential adjuvants in COVID-19 vaccines. A focus is placed on antibody-and cell-mediated responses and the overall T helper cell response.

Compound 48/80 (c48/80) is a widely studied MC activator and is a potent mucosal adjuvant [35] . It is a synthetic polymer that stimulates the degranulation of MCs in an IgE-independent manner to evoke an inflammatory response [54] . Following activation with c48/80, MCs produce TNF-α which promotes DC and T cell functions. leading to significant trafficking of DCs to draining lymph nodes (DLNs) [37] . Numerous studies have demonstrated the ability of c48/80 to induce high concentrations of serum IgG and mucosal soluble IgA when co-administered intranasally with viral glycoproteins [55] [56] [57] . Additionally, c48/80-adjuvanted responses were shown to enhance protection in challenge models using lethal doses of H1N1 influenza virus, as well as vaccinia virus [56, 57] . Interestingly, a follow up study on influenza demonstrated the inability of c48/80 to enhance protection against H1N5 challenge, suggesting that the adjuvanticity of c48/80 may vary depending on the immunogen utilized [58] . Similarly, the T helper cell responses induced by c48/80 also varied between studies [55, 57] . One study co-administering c48/80 with the hepatitis B virus glycoprotein found a T helper-2-biased response while the studies focusing on the H1N1 influenza found a balanced T helper-1/T helper-2 response [55, 57] . However, it is important to note that the study immunizing with hepatitis B virus glycoprotein utilized a chitosan nanoparticle platform, which may be related to the T helper-2 bias [55] . While the T helper cell response was not characterized in the study utilizing vaccinia virus, c48/80 induced only a modest increase in the number of CD8 + T cells, potentially indicating a T helper-2 bias [56] . In contrast with these studies, one group investigated the ability of c48/80 to enhance CD8 + T cell-mediated protective immunity utilizing the nucleoprotein of the H1N1 influenza virus [59] . This group found that c48/80 induced high levels of IgG1 and IgG2a in similar proportions, indicating a potentially well balanced T helper-1/T helper-2 response [59] . More importantly, it induced a higher number of nucleoprotein-specific CD8 + T cells compared to CD4 + T cells. The c48/80+nucleoprotein combination provided 100% protection in mice when challenged with homologous H1N1 influenza virus and even protected against heterologous challenge using the H9N2 strain of influenza virus [59] . While high concentrations of serum IgG and secretory IgA were produced in these mice, the fact that the nucleoprotein is contained within virus particles and infected cells suggests that the nucleoprotein-specific CD8 + T cells were the main correlate of protection against virus challenge [59] . Based on these studies, c48/80 appears to be a potent mucosal adjuvant capable of inducing protective antibody-and cell-mediated immunity against certain viruses. While potentially promising for use as an adjuvant in COVID-19 vaccines, the immunogen-dependent effect of c48/80 and variability in T helper cell responses necessitates extensive investigation.

When investigating the adjuvant ability of the IL-1 family of cytokines in combination with a recombinant influenza virus hemagglutinin protein via intranasal vaccination, Kayamuro et al. found that only four cytokines, IL-1α, IL-1β, IL-18, and IL-33 correlated with high concentrations of serum IgG and secretory IgA [60] . Upon further analysis, they discovered that the adjuvancy of IL-18 occurred in a MC-dependent manner and led to the recruitment of DCs and T cells to the site of immunization [60] . Upon restimulation of splenocytes in vitro, mice treated with IL-18 as an adjuvant had increased concentrations of both T helper-1-and T helper-2-associated cytokines (IFN-y, IL-4, and IL-5), and enhanced numbers of CD8 + T cells. In an influenza challenge model, IL-18 significantly enhanced protection (100% survival). Additionally, adjuvanting with IL-18 resulted in induction of a balanced ratio of IgG1/IgG2a. As such, IL-18 may be a useful adjuvant for COVID-19 vaccines.

As mentioned in the previous sections, the role of cytokine storm syndrome has been established in the pathogenesis of COVID-19, and the contribution of MCs to this phenomenon is now established [22] . Activated MCs release proinflammatory cytokines and are mediators of bronchoconstriction resulting in life-threatening inflammatory reactions and pulmonary problems [61] . Therefore, preventing the release of MC mediators or impeding the impacts imposed by these mediators could potentially reduce the severity of COVID-19. Here, we summarize the pharmacologic therapies that have the potential to suppress SARS-CoV-2-induced cytokine storms ( Table 1 ). The medications that target the performance of MCs could be of value in the treatment plans of COVID-19 and require further evaluation. Moreover, the variations in the pharmacodynamics, pharmacokinet-ics, administration routes, drug interactions, safety, and costs of the medications in each category necessitate more precise assessment and comparison for clinical usage. 

TNF-α is released by MC [69] and considered one of the leading mediators of acute inflammation, the activation of which can also trigger IL-1 and IL-6 production [70] , both of which can be produced by a variety of cells, including MCs. High concentrations of TNF-α were reported in both plasma and tissues of patients with COVID-19 [71] . Anti-TNF-α medications, namely adalimumab, infliximab, etanercept, certolizumab, and golimumab are effective as immunotherapies in patients with autoimmune inflammation and severe bilateral lung lesions [72] [73] [74] . The efficacy and acceptable safety of these agents make them promising candidates to be tested for the potential to control cytokine storms in patients with COVID-19 [73] .

MCs secrete IL-1 [75, 76] and IL-1 activates MCs to release inflammatory chemical mediators, and cytokines/chemokines [77] . Therefore, IL-1 inhibition could be considered a potential method to dampen cytokine storms and associated injuries in patients with COVID-19.

This agent blocks the binding of IL-1α and IL-1β to IL-1 receptors. it has been evaluated for use in patients with COVID-19 [78] . In an open-label case series study in France, anakinra was administered to nine patients with COVID-19 who were at high risk of worsening disease. In five to eight days, computerized tomography scans of the chests of all patients revealed the cessation of expansion of lesions [63] . A pilot study in Italy reported promising outcomes following early high-dose intravenous administration of anakinra in five moderate-to-severe cases of COVID-19 [64] . Another large retrospective cohort study in Italy examined anakinra in COVID-19 patients with ARDS and hyperinflammation [78] .

MCs produce IL-6 in response to viruses [79] and serum IL-6 has been shown to be a valuable biomarker of COVID-19 [80, 81] . Some monoclonal antibodies competitively bind to both membranous and soluble receptors of IL-6, leading to the blockade of the signals mediated by IL-6.

Tocilizumab (Actemra) is a recombinant humanized monoclonal antibody with the potential of inhibiting all membranous or soluble receptors for IL-6 [82] . This agent has been taken into consideration for cytokine release syndrome [83] and retrospective studies in COVID-19 patients demonstrated that tocilizumab might be clinically beneficial [65, 66] . Clinical trials on the safety and efficacy of tocilizumab have been performed (NCT04335071, ChiCTR2000029765, and NCT04317092) and the medication has been recommended in protocols, such as the COVID-19 care handbook by the Italian Society of Infectious and Tropical Diseases [84] .

This is a chimeric monoclonal antibody that blocks IL-6 by binding to it and studies suggested that this medication holds potential for the treatment of COVID-19 [85, 86] .

This agent is a monoclonal engineered humanized antibody that binds directly to IL-6 with high affinity [87] . It is being tested in the United States in a phase 2 study in patients with COVID-19 (NCT04348500).

This fully human monoclonal antibody under the generic name Kevzara, can bind to both soluble and membrane-bound IL-6 receptors and was first approved for treatment of rheumatoid arthritis [88] . It is under evaluation for efficacy and safety in a double-blind, phase 2/3 clinical trial of hospitalized patients with severe COVID-19 (NCT04315298).

This medicine prevents the binding of IL-6 to membrane receptors [89] . Therefore, it can hinder the biological effects of this cytokine and could be examined for the control of cytokine storms caused by SARS-CoV-2.

JAK3 [90, 91] , a member of the Janus family protein-tyrosine kinases, is expressed in MCs and the JAK1/JAK2-inhibitor ruxolitinib inhibits MC degranulation and cytokine release [92] . Therefore, another potential approach for suppressing cytokine storms is to target the JAK-STAT pathway and interrupt the signaling pathways of cytokines. The advantage of these medications over cytokine-specific antibodies is the inhibition of several cytokines at once [93] .

Baricitinib is a selective inhibitor of JAK1 and JAK2 and believed to interfere with the signaling of key cytokines that are produced abundantly in COVID-19, including IL-2, IL-6, IL-7, and granulocyte monocyte colony-stimulating factor [94] . It has also been suggested to be capable of inhibiting viral entry into cells [95] . An open-label study in Italy (NCT04358614) indicated a significant reduction in the concentration of C-reactive protein, improved oxygen saturation, and reduced fever [67] . Several other clinical trials are being initiated to evaluate baricitinib in patients with COVID-19.

Ruxolitinib under the generic name Jakafi is also a selective inhibitor of JAK1 and JAK2 [73, 74] . Some clinical trials are examining this drug in cases of COVID-19. Fedratinib is a highly selective inhibitor of JAK2 and a modest inhibitor of JAK1 and JAK3 [93] showed efficacy against cytokine storms caused by COVID-19 via the downregulation of T helper-17-associated cytokines [68] . Other JAK inhibitors that could be taken into consideration for COVID-19 include upadacitinib, oclacitinib, peficitinib, and tofacitinib, which inhibit various JAKs or combinations thereof [74] . However, two concerns remain about the administration of anti-JAK drugs; the blockade of IFN-α, which is an essential cytokine against viral infections, and the risk of thrombocytopenia and/or thrombosis.

There are a variety of drugs that target functional aspects of MC biology. These are shown in Table 2 and could be a useful set of therapeutic agents in the clinical toolbox to control cytokine storms that occur in patients diagnosed with COVID-19. 

This group of medications block the degranulation of MCs and prevent the secretion of histamine and other mediators, leading to diminished cytokine release by diverse cell types [93] . MC stabilizers are categorized as synthetic, semi-synthetic, and plantderived [125] and have the potential to dampen cytokine storms in cases of COVID-19.

Cromolyn sodium was originally introduced to treat allergic asthma and has quickly shown to be effective for treating disorders related to MCs such as mastocytosis, allergic rhinitis, conjunctivitis, and intestinal allergies. Cromolyn sodium has been shown to act as a G-protein-coupled receptor 35 (GPR35) agonist that is expressed in human MCs. Interestingly, GPR35 mRNA is upregulated upon challenge with IgE antibodies [96] , suggesting that GPR35 may be a potential target for using cromolyn sodium in the treatment of asthma. Previous studies on the pharmacological actions of cromolyn sodium indicate that it prevents the release of mediators from mast cells [126] , although recent studies employing mouse [127] and human [128] cultured MCs questioned cromolyn sodium function as a MC stabilizer agent. Regardless, the mechanism of action for this agent has been noted as inhibiting the activity of protein kinase C and transport of chloride into MCs [97] . Furthermore, cromolyn blocks the activity of macrophages, the release of eicosanoids and cytokines, and the expression of adhesion molecules [98] . It was reported that in a mouse model of influenza, this agent regulated the expression of IL-6, TNF-α, TLR3, and TRIF, leading to the improvement of injuries and inflammatory reactions in the nose, trachea, and lungs [99] . Cromolyn sodium was also shown to potently inhibit Nsp12, which is a conserved coronavirus protein acting as an RNA-dependent RNA polymerase in viral replication and transcription [100] . Furthermore, this medication was found to exert a direct impact on chloride and calcium ion channels in coronaviruses interfering with their biologic cycle [93, 129] . It should be taken into consideration that cromolyn sodium is currently deemed to be effective in decreasing inflammation and cytokine storms in patients with COVID-19 [130, 131] .

As another MC stabilizer, ketotifen exerts an antagonistic effect against the histamine-1 receptor [101] . It was suggested to decrease lung lesions and apoptosis during the early stages of infection with H5N1 influenza virus [102] .

These are a large group of natural stabilizers, including luteolin, disometin, apigenin, kaempferol, fisetin, quercetin, morin, genistein, and epigallocatechin gallate [111] [112] [113] . Luteolin was reported to suppress the release of histamine, leukotrienes, prostaglandin 2, and granulocyte/monocyte colony-stimulating factor in vitro from human MCs [104] . Moreover, it hindered the production of TNF-α and IL-6 in murine MCs [103] . Examinations revealed that luteolin targeted virus entry into the host cells and could significantly hinder SARS-CoV activity in vitro [105] . Fisetin and quercetin diminished the expression of TNF-α, IL-1β, IL-6, and IL-8 by MCs [106, 112] . It was observed that quercetin and its derivatives were able to constrain SARS-CoV serine proteases, which are of importance in the infectivity of the virus [107] . Quercetin also downregulated the transcription of histidine decarboxylase in MCs, as an enzyme involved in histamine generation [108] . Genistein was indicated to dose-dependently inhibit the degranulation of MCs and phosphorylation of some cellular proteins that contribute to the signaling of activated MCs [109] . Epigallocatechin gallate, found in green tea, showed anti-allergic effects by decreasing degranulation and histamine release in rat MCs [110] .

Coumarins are another group of herbal agents that stabilize MCs. Scopletin, scaporone, and artekeiskeanol A decreased the secretion of TNF-α and IL-6 [113] . Also, artekeiskeanol A and selinidin had the potential to suppress the phosphorylation of some molecules involved in signaling events in MCs [114, 115] .

Terpenoid inhibits antigen-IgE-induced degranulation. Some terpenoids, namely parthenolide and dehydroleucodine have been noted as influential MC stabilizers during the recent decades [113, 116] .

Sinomenine and theanine were demonstrated to inhibit MC degranulation induced by antigens, diminish the synthesis of IL-4, IL-1, IL-6, and TNF-α, as well as preventing the phosphorylation of signaling molecules [113] . Furthermore, theanine is suggested to stabilize MCs by preventing the perturbation of the lipid bilayers of these cells [117] .

Xestospongin C prevents the increase in intracellular calcium ion levels, which is essential for MC exocytosis [118] .

The analgesic and anti-inflammatory actions of this molecule are attributed to the inhibitory influence on the release of histamine and TNF-α from MCs [119] . Moreover, adelmidrol, as a palmitoylethanolamide analogue, was capable of reducing MCs degranulation in a rat model of chronic inflammation [132] . A systemic review of randomized clinical trials on the usage of this medication for the common cold and influenza demonstrated protective potential against viral infections of the respiratory tract [133] .

Anti-inflammatory and MC-stabilizing effects have been shown for some antihistamine medicines, namely olopatadine [120, 121, 134] , rupatadine [16, 122, 135] , and ketotifen [136, 137] , which inhibit release of histamine or other MC mediators. Therefore, these antihistaminic MC stabilisers and mediator blockers could be considered in the treatment of SARS-CoV-2 infection. It was concluded in a review of 18 randomized clinical trials that antihistamines exert limited short-term positive effects on the severity of common cold symptoms [138] .

The inhibitors of tyrosine protein kinases, namely compound-13, R-112, and ER-27317 are among the synthetic stabilizers of MCs, which can prevent signal transduction in allergic reactions [113] . Furthermore, hypothemycin was shown to block the FcεRImediated activation of MCs and cytokine release through constraining kit kinase [139] . Thymoquinone is a phytochemical compound, which was indicated to inhibit degranulation in meningeal MCs [140] . In a study, C 70 -tetraglycolic acid [TGA], a water-soluble fullerence, dampened the degranulation of human skin MCs [141] . Orazipone [OR-1384] and its derivative OR-1958 are recent sulphydryl anti-inflammatory agents that can reduce TNF-α production by human MCs [142] .

Leukotrienes are molecules secreted from MCs, basophils, and eosinophils contribute remarkably to asthma pathogenesis. Cysteinyl leukotrienes (CysLTs) induce the contraction of smooth muscles, swelling, and edema in the airways. Leukotriene B4 acts as a chemoattractant and activates neutrophils and eosinophils [93] . Both synthesis and binding of leukotrienes to their receptors could be targeted. The synthesis inhibitors, such as zileuton, target the 5-lipoxygenase enzyme. The other group, including telukast, zafirlukast, and montelukast, blocks the CysLT1 receptor on the cells that CysLTs target [123] . It has been noted that montelukast may also have an antiviral impact through targeting SARS-Cov-2 3CL protease, which is one of the key proteases in coronaviruses [100] .

MCs produce different proteases, such as tryptase. Camostat mesylate, an inhibitor of tryptase, was observed to prevent the entry of SARS-CoV into cells by targeting TMPRSS2, leading to the blockade of virus spread and pathogenesis [143] . Also, SARS-CoV relies on TMPRSS2 for the priming of S proteins, which is needed for virus entry into cells lining the respiratory tract [124] .

In some people, SARS-CoV-2 can cause the uncontrolled production of cytokines and the development of cytokine storm syndrome. Evidence indicates that MCs can respond to SARS-CoV-2 and accumulate in the lungs of patients with COVID-19, where they correlate with pulmonary edema, inflammation, and thrombosis. MCs are foundational drivers of inflammation [144] that produce preformed inflammatory mediators and cytokines upon activation. Preventing the release of mast cell-derived mediators and impeding the impacts imposed by these mediators could blunt the severity of COVID-19. Additionally, MC activators could be considered for testing as adjuvants for COVID-19 vaccines. Further, the medications that target the performance of MCs could be potentially of value in the treatment of COVID-19. The recognition of the cytokine storm initiated by MCs is crucial for the proper treatment of COVID-19 in patients and could potentially lead to novel clinical approaches for many pathological conditions in which cytokine storm or cytokine release syndromes are life-threatening features. 

The authors declare no conflict of interest.

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Tocilizumab for the treatment of severe coronavirus disease 2019

Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact

TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib

SP and IL-33 together markedly enhance TNF synthesis and secretion from human mast cells mediated by the interaction of their receptors

Targeted Immunomodulatory Therapy: An Overview

Coronavirus disease 2019 in elderly patients: Characteristics and prognostic factors based on 4-week follow-up

Drugs supply and pharmaceutical care management practices at a designated hospital during the COVID-19 epidemic

Pharmaco-Immunomodulatory Therapy in COVID-19

Exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in COVID-19 patients

Substance P and IL-33 administered together stimulate a marked secretion of IL-1β from human mast cells, inhibited by methoxyluteolin

Interleukin-1 family cytokines and mast cells: Activation and inhibition

Anakinra Therapy for Non-cancer Inflammatory Diseases

Mast cells play a key role in host defense against herpes simplex virus infection through TNF-α and IL-6 production

Assessing the importance of interleukin-6 in COVID-19

Assessing the importance of interleukin-6 in COVID-19-Authors' reply

The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome

Lombardy Section Italian Society Infectious And Tropical Diseases. Vademecum for the treatment of people with COVID-19

Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support

The role of IL-6 and IL-6 blockade in COVID-19

Clazakizumab in late antibody-mediated rejection: Study protocol of a randomized controlled pilot trial

Sarilumab for the treatment of ankylosing spondylitis: Results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN)

IL-6 targeting compared to TNF targeting in rheumatoid arthritis: Studies of olokizumab, sarilumab and sirukumab

Role of common cytokine receptor gamma chain (gamma(c))-and Jak3-dependent signaling in the proliferation and survival of murine mast cells

Targeting Janus kinase 3 in mast cells prevents immediate hypersensitivity reactions and anaphylaxis

The JAK1/JAK2-inhibitor ruxolitinib inhibits mast cell degranulation and cytokine release

Tackling the cytokine storm in COVID-19, challenges and hopes

Dysregulation of Immune Response in Patients With Coronavirus

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

G-protein-coupled receptor 35 is a target of the asthma drugs cromolyn disodium and nedocromil sodium

Cromolyn sodium: Fitting an old friend into current asthma treatment

The Anti-allergic Cromones: Past, Present, and Future

The therapeutic effects of sodium cromoglycate against influenza A virus H5N1 in mice. Influenza Other Respir Viruses

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

Mast cell stabilisers

Mast cell-induced lung injury in mice infected with H5N1 influenza virus

Effects of luteolin and other flavonoids on IgE-mediated allergic reactions

Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells

Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells

Anti-inflammatory activity of fisetin in human mast cells (HMC-1)

Binding interaction of quercetin-3-beta-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): Structure-activity relationship studies reveal salient pharmacophore features

Inhibitory effect of quercetin on tryptase and interleukin-6 release, and histidine decarboxylase mRNA transcription by human mast cell-1 cell line

Early and late events in Fc epsilon RI signal transduction in human cultured mast cells

Inhibitory effects of epigallocatechin gallate on compound 48/80-induced mast cell activation and passive cutaneous anaphylaxis

The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells

Regulation of IL-1-induced selective IL-6 release from human mast cells and inhibition by quercetin

Twenty-first century mast cell stabilizers

Anti-allergic effects of scoparone on mast cell-mediated allergy model

Suppression of the antigen-stimulated RBL-2H3 mast cell activation by Artekeiskeanol A

Inhibitory effects of parthenolide on antigen-induced microtubule formation and degranulation in mast cells

A novel imidazo[1,5-b]isoquinolinone derivative, U63A05, inhibits Syk activation in mast cells to suppress IgE-mediated anaphylaxis in mice

Xestospongin C, a novel blocker of IP3 receptor, attenuates the increase in cytosolic calcium level and degranulation that is induced by antigen in RBL-2H3 mast cells

Effects of palmitoylethanolamide on immunologically induced histamine, PGD2 and TNFalpha release from canine skin mast cells

Olopatadine: A drug for allergic conjunctivitis targeting the mast cell

Mast cell stabilization and anti-histamine effects of olopatadine ophthalmic solution: A review of pre-clinical and clinical research

Rupatadine inhibits proinflammatory mediator secretion from human mast cells triggered by different stimuli

Leukotriene synthesis inhibitors versus antagonists: The pros and cons

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Mast Cell Stabilizers as a Supportive Therapy Can Contribute to Alleviate Fatal Inflammatory Responses and Severity of Pulmonary Complications in COVID-19 Infection

Design of potential pharmaceutical-based metal complexes derived from cromolyn a mast cell stabilizer

Evidence questioning cromolyn's effectiveness and selectivity as a 'mast cell stabilizer' in mice

Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans

Chloride transport and the actions of nedocromil sodium and cromolyn sodium in asthma

Repurposing existing drugs for the treatment of COVID-19/SARS-CoV-2 infection: A review describing drug mechanisms of action

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms

Adelmidrol, a palmitoylethanolamide analogue, reduces chronic inflammation in a carrageenin-granuloma model in rats

A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold

Olopatadine inhibits exocytosis in rat peritoneal mast cells by counteracting membrane surface deformation

Rupatadine inhibits inflammatory mediator release from human laboratory of allergic diseases 2 cultured mast cells stimulated by plateletactivating factor

Ketotifen in the management of chronic urticaria: Resurrection of an old drug

Comparison of the modulatory effect of ketotifen, sodium cromoglycate, procaterol and salbutamol in human skin, lung and tonsil mast cells

Antihistamines for the common cold

Concurrent inhibition of kit-and FcepsilonRI-mediated signaling: Coordinated suppression of mast cell activation

Thymoquinone Inhibits Neurogenic Inflammation Underlying Migraine Through Modulation of Calcitonin Gene-Related Peptide Release and Stabilization of Meningeal Mast Cells in Glyceryltrinitrate-Induced Migraine Model in Rats

A new class of human mast cell and peripheral blood basophil stabilizers that differentially control allergic mediator release

Novel sulfhydryl-reactive compounds orazipone and OR-1958 inhibit cytokine production and histamine release in rat and human mast cells

Protease inhibitors targeting coronavirus and filovirus entry

Mast Cells in Inflammation and Disease: Recent Progress and Ongoing Concerns