Mast cells: Therapeutic targets for <scp>COVID</scp>‐19 and beyond

Lam, Hiu Yan; Tergaonkar, Vinay; Kumar, Alan Prem; Ahn, Kwang Seok

doi:10.1002/iub.2552

Cited by 13 publications

(16 citation statements)

References 133 publications

(305 reference statements)

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“…There are many mechanisms of MCs activation in a pathological process, and in the case of lung damage in COVID-19 patients, this question remains open. MCs are activated by allergens, but they can also be caused by molecular pathogens through the activation of Toll-like receptors (TLR) [ 7 , 19 ]. Viruses can activate MCs through TLR [ 14 ] with a subsequent increase in expression of inflammatory mediators.…”

Section: Discussionmentioning

confidence: 99%

Role of mast cells in the pathogenesis of severe lung damage in COVID-19 patients

et al. 2022

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Background There is still insufficient knowledge with regard to the potential involvement of mast cells (MCs) and their mediators in the pathology of coronavirus disease-2019 (COVID-19). Therefore, our study aimed to investigate the role of MCs, their activation and protease profiles in the pathogenesis of early and late lung damage in COVID-19 patients. Methods Formalin-fixed and paraffin embedded lung specimens from 30 patients who died from COVID-19 and 9 controls were used for histological detection of MCs and their proteases (tryptase, chymase) followed by morphometric quantification. Results Our results demonstrated increased numbers of MCs at early stage and further augmentation of MCs number during the late stage of alveolar damage in COVID-19 patients, as compared to the control group. Importantly, the percentage of degranulated (activated) MCs was higher during both stages of alveolar lesions in comparison to the controls. While there was no prominent alteration in the profile of tryptase-positive MCs, our data revealed a significant elevation in the number of chymase-positive MCs in the lungs of COVID-19 patients, compared to the controls. Conclusions MCs are characterized by dysregulated accumulation and increased activation in the lungs of patients suffering from COVID-19. However, future profound studies are needed for precise analysis of the role of these immune cells in the context of novel coronavirus disease.

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Section: Discussionmentioning

confidence: 99%

Role of mast cells in the pathogenesis of severe lung damage in COVID-19 patients

et al. 2022

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“…Mast cells have been hypothesized to drive severe COVID-19 (Malone, et al 2020 ; Lam et al 2021 ) and LPS activates mast cells to release key pro-inflammatory mediators, including IL-6 (Leal-Berumen et al 1994 ). To clarify whether mast cells contribute to famotidine’s anti-inflammatory effect, mast cell deficient Kit W−sh /Kit W−sh sash mice were employed.…”

Section: Resultsmentioning

confidence: 99%

“…Famotidine has been implicated as an inhibitor of histamine-induced toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infected cells in vitro (Mukherjee et al 2021 ). Famotidine may also act through other on-target histaminergic mechanisms via gastric acid reduction (Malone, et al 2020 ; Aguila and Cua 2020 ) or immune cell generation of pro-inflammatory mediators (Malone, et al 2020 ; Lam et al 2021 ; Ennis and Tiligada 2020 ). Additionally, potentially relevant off-target effects of famotidine include scavenging reactive oxygen radicals, especially the hydroxyl ion (Ahmadi et al 2011 ; Ching et al 1994 , 1993 ; Lapenna et al 1994 ; Zyl et al 1993 ), which may reduce secondary inflammation and damage.…”

Section: Introductionmentioning

confidence: 99%

Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm

Yang

George

Thompson

et al. 2022

Mol Med

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Background Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm. Methods The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes. Results Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine’s mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages. Conclusions These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.

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“…COVID-19 manifestations, including pulmonary microthrombosis and inflammation, are mediated via PAF receptor [ 140 ] MRGPRX2 is a novel, low-affinity and low-selectivity receptor, to activate MCs in an IgE-independent manner [ 141 ]. This receptor has been cited as a therapeutic target for COVID-19 [ 142 ] MCs respond to TLR ligands by secreting cytokines, chemokines, and lipid mediators, and some studies have found that TLR ligands can also cause degranulation, although this finding is contentious [ 143 ] Several clinical investigations revealed that chemokines are directly involved in the different stages of SARS-CoV-2 infection [ 144 ]. At least nine chemokine receptors (CXCR1, CXCR2, CXCR3, CXCR4, CX3CR1, CCR1, CCR3, CCR4, and CCR5) have been described to be expressed by human MCs of different origins [ 145 ] Tryptase released from MCs can activate PAR-2 in an autocrine or paracrine manner [ 146 ].…”

Section: Secretory Activity Of Mcs: Main Categories Of the Mediators ...mentioning

confidence: 99%

“…MRGPRX2 is a novel, low-affinity and low-selectivity receptor, to activate MCs in an IgE-independent manner [ 141 ]. This receptor has been cited as a therapeutic target for COVID-19 [ 142 ]…”

Section: Secretory Activity Of Mcs: Main Categories Of the Mediators ...mentioning

confidence: 99%

Mast Cell Activation Syndrome in COVID-19 and Female Reproductive Function: Theoretical Background vs. Accumulating Clinical Evidence

Szukiewicz

Wątroba

Szewczyk

2022

Journal of Immunology Research

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Coronavirus disease 2019 (COVID-19), a pandemic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, can affect almost all systems and organs of the human body, including those responsible for reproductive function in women. The multisystem inflammatory response in COVID-19 shows many analogies with mast cell activation syndrome (MCAS), and MCAS may be an important component in the course of COVID-19. Of note, the female sex hormones estradiol (E2) and progesterone (P4) significantly influence mast cell (MC) behavior. This review presents the importance of MCs and the mediators from their granules in the female reproductive system, including pregnancy, and discusses the mechanism of potential disorders related to MCAS. Then, the available data on COVID-19 in the context of hormonal disorders, the course of endometriosis, female fertility, and the course of pregnancy were compiled to verify intuitively predicted threats. Surprisingly, although COVID-19 hyperinflammation and post-COVID-19 illness may be rooted in MCAS, the available clinical data do not provide grounds for treating this mechanism as significantly increasing the risk of abnormal female reproductive function, including pregnancy. Further studies in the context of post COVID-19 condition (long COVID), where inflammation and a procoagulative state resemble many aspects of MCAS, are needed.

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Mast cells: Therapeutic targets for COVID‐19 and beyond

Abstract: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 13 publications

References 133 publications

Role of mast cells in the pathogenesis of severe lung damage in COVID-19 patients

Role of mast cells in the pathogenesis of severe lung damage in COVID-19 patients

Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm

Mast Cell Activation Syndrome in COVID-19 and Female Reproductive Function: Theoretical Background vs. Accumulating Clinical Evidence

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