Significance of Mast Cell Formed Extracellular Traps in Microbial Defense

Mast cells (MCs) are critically involved in microbial defense by releasing antimicrobial peptides (such as cathelicidin LL-37 and defensins) and phagocytosis of microbes. In past years, it has become evident that in addition MCs may eliminate invading pathogens by ejection of web-like structures of DNA strands embedded with proteins known together as extracellular traps (ETs). Upon stimulation of resting MCs with various microorganisms, their products (including superantigens and toxins), or synthetic chemicals, MCs become activated and enter into a multistage process that includes disintegration of the nuclear membrane, release of chromatin into the cytoplasm, adhesion of cytoplasmic granules on the emerging DNA web, and ejection of the complex into the extracellular space. This so-called ETosis is often associated with cell death of the producing MC, and the type of stimulus potentially determines the ratio of surviving vs. killed MCs. Comparison of different microorganisms with specific elimination characteristics such as S pyogenes (eliminated by MCs only through extracellular mechanisms), S aureus (removed by phagocytosis), fungi, and parasites has revealed important aspects of MC extracellular trap (MCET) biology. Molecular studies identified that the formation of MCET depends on NADPH oxidase-generated reactive oxygen species (ROS). In this review, we summarize the present state-of-the-art on the biological relevance of MCETosis, and its underlying molecular and cellular mechanisms. We also provide an overview over the techniques used to study the structure and function of MCETs, including electron microscopy and fluorescence microscopy using specific monoclonal antibodies (mAbs) to detect MCET-associated proteins such as tryptase and histones, and cell-impermeant DNA dyes for labeling of extracellular DNA. Comparing the type and biofunction of further MCET decorating proteins with ETs produced by other immune cells may help provide a better insight into MCET biology in the pathogenesis of autoimmune and inflammatory disorders as well as microbial defense

Investigation of Serum Levels and Activity of Matrix Metalloproteinases 2 and 9 (MMP2, 9) in Opioid and Methamphetamine-Dependent Patients

Matrix metalloproteinases (MMPs) are a group of zinc-dependent proteolytic enzymes that play a role in extracellular matrix (mainly collagen) degradation and remodeling. MMPs are not only causes of the increase rewarding effects of drugs, but also act as pro-addictive agents. In this research, 22 morphine and 20 methamphetamine-dependent patients included and their serum levels and activity of MMP2 and 9 were assessed by ELISA and gelatin zymography and compared with those of 23 healthy individuals as a control group. Our findings showed a significant increase in serum levels and activity of MMP-2 in opium and methamphetamine groups in comparison with the control group. Moreover, unlike MMP-2, serum levels and activity of MMP-9 in both case groups found to be decreased. This study showed that long-term abuse of opium and methamphetamine changes the activity and serum levels of MMP9 and MMP2. The effects of methamphetamines and opium are associated with an increase in extracellular dopamine levels in the brain, achieved by facilitating the release of dopamine from pre-synaptic nerves. Our findings showed that serum levels and activities of MMP-9 and MMP-2 could be considered as alternative valuable biomarkers from those investigated of pro-addictive or anti-addictive factors in dependent patients

How Infection and Vaccination Are Linked to Acute and Chronic Urticaria: A Special Focus on COVID-19

Since more than a century ago, there has been awareness of the connection between viral infections and the onset and exacerbation of urticaria. Our knowledge about the role of viral infection and vaccination in acute and chronic urticaria improved as a result of the COVID-19 pandemic but it has also highlighted knowledge gaps. Viral infections, especially respiratory tract infections like COVID-19, can trigger the onset of acute urticaria (AU) and the exacerbation of chronic urticaria (CU). Less frequently, vaccination against viruses including SARS-CoV-2 can also lead to new onset urticaria as well as worsening of CU in minority. Here, with a particular focus on COVID-19, we review what is known about the role of viral infections and vaccinations as triggers and causes of acute and chronic urticaria. We also discuss possible mechanistic pathways and outline the unmet needs in our knowledge. Although the underlying mechanisms are not clearly understood, it is believed that viral signals, medications, and stress can activate skin mast cells (MCs). Further studies are needed to fully understand the relevance of viral infections and vaccinations in acute and chronic urticaria and to better clarify causal pathways

Significance of Mast Cell Formed Extracellular Traps in Microbial Defense

Mast cells (MCs) are critically involved in microbial defense by releasing antimicrobial peptides (such as cathelicidin LL-37 and defensins) and phagocytosis of microbes. In past years, it has become evident that in addition MCs may eliminate invading pathogens by ejection of web-like structures of DNA strands embedded with proteins known together as extracellular traps (ETs). Upon stimulation of resting MCs with various microorganisms, their products (including superantigens and toxins), or synthetic chemicals, MCs become activated and enter into a multistage process that includes disintegration of the nuclear membrane, release of chromatin into the cytoplasm, adhesion of cytoplasmic granules on the emerging DNA web, and ejection of the complex into the extracellular space. This so-called ETosis is often associated with cell death of the producing MC, and the type of stimulus potentially determines the ratio of surviving vs. killed MCs. Comparison of different microorganisms with specific elimination characteristics such as S pyogenes (eliminated by MCs only through extracellular mechanisms), S aureus (removed by phagocytosis), fungi, and parasites has revealed important aspects of MC extracellular trap (MCET) biology. Molecular studies identified that the formation of MCET depends on NADPH oxidase-generated reactive oxygen species (ROS). In this review, we summarize the present state-of-the-art on the biological relevance of MCETosis, and its underlying molecular and cellular mechanisms. We also provide an overview over the techniques used to study the structure and function of MCETs, including electron microscopy and fluorescence microscopy using specific monoclonal antibodies (mAbs) to detect MCET-associated proteins such as tryptase and histones, and cell-impermeant DNA dyes for labeling of extracellular DNA. Comparing the type and biofunction of further MCET decorating proteins with ETs produced by other immune cells may help provide a better insight into MCET biology in the pathogenesis of autoimmune and inflammatory disorders as well as microbial defense

Mast Cell-Mediated Orchestration of the Immune Responses in Human Allergic Asthma : Current Insights

Improving the lung function after experimental allergen challenge by blocking of mast cell (MC) mediators and the capability of MC mediators (including histamine, prostaglandin (PG) D2, and leukotriene (LT) C4) in induction of mucosal edema, bronchoconstriction, and mucus secretion provide evidence that MCs play a key role in pathophysiology of asthma. In asthma, the number of MCs increases in the airways and infiltration of MCs in a variety of anatomical sites including the epithelium, the submucosal glands, and the smooth muscle bundles occurs. MC localization within the ASM is accompanied with the hypertrophy and hyperplasia of the layer, and smooth muscle dysfunction that is mainly observed in forms of bronchial hyperresponsiveness, and variable airflow obstruction. Owing to the expression of a wide range of surface receptors and releasing various cytoplasmic mediators, MCs orchestrate the pathologic events of the disease. MC-released preformed mediators including chymase, tryptase, and histamine and de novo synthesized mediators such as PGD2, LTC4, and LTE4 in addition of cytokines mainly TGFβ1, TSLP, IL-33, IL-4, and IL-13 participate in pathogenesis of asthma. The release of MC mediators and MC/airway cell interactions during remodeling phase of asthma results in persistent cellular and structural changes in the airway wall mainly epithelial cell shedding, goblet cell hyperplasia, hypertrophy of ASM bundles, fibrosis in subepithelial region, abnormal deposition of extracellular matrix (ECM), increased tissue vascularity, and basement membrane thickening. We will review the current knowledge regarding the participation of MCs in each stage of asthma pathophysiology including the releasing mediators and their mechanism of action, expression of receptors by which they respond to stimuli, and finally the pharmaceutical products designed based on the strategy of blocking MC activation and mediator release

Role of Mast Cells in Shaping the Tumor Microenvironment

Early mast cell (MC) infiltration has been reported in a wide range of human and animal tumors particularly malignant melanoma and breast and colorectal cancer. The consequences of their presence in the tumor microenvironment (TME) or at their margins still remain unclear as it is associated with a good or poor prognosis based on the type and anatomical site of the tumor. Within the tumor, MC interactions occur with infiltrated immune cells, tumor cells, and extracellular matrix (ECM) through direct cell-to-cell interactions or release of a broad range of mediators capable of remodeling the TME. MCs actively contribute to angiogenesis and induce neovascularization by releasing the classical proangiogenic factors including VEGF, FGF-2, PDGF, and IL-6, and nonclassical proangiogenic factors mainly proteases including tryptase and chymase. MCs support tumor invasiveness by releasing a broad range of matrix metalloproteinases (MMPs). MC presence within the tumor gained additional significance when it was assumed that controlling its activation by tyrosine kinase inhibitors (imatinib and masitinib) and tryptase inhibitors (gabexate and nafamostat mesylate) or controlling their interactions with other cell types may have therapeutic benefit

Mast cells and complement system: Ancient interactions between components of innate immunity

Abstract The emergence and evolution of the complement system and mast cells (MCs) can be traced back to sea urchins and the ascidian Styela plicata, respectively. Acting as a cascade of enzymatic reactions, complement is activated through the classical (CP), the alternative (AP), and the lectin pathway (LP) based on the recognized molecules. The system's main biological functions include lysis, opsonization, and recruitment of phagocytes. MCs, beyond their classic role as master cells of allergic reactions, play a role in other settings, as well. Thus, MCs are considered as extrahepatic producers of complement proteins. They express various complement receptors, including those for C3a and C5a. C3a and C5a not only activate the C3aR and C5aR expressing MCs but also act as chemoattractants for MCs derived from different anatomic sites, such as from the bone marrow, human umbilical cord blood, or skin in vitro. Cross talk between MCs and complement is facilitated by the production of complement proteins by MCs and their activation by the MC tryptase. The coordinated activity between MCs and the complement system plays a key role, for example, in a number of allergic, cutaneous, and vascular diseases. At a molecular level, MCs and complement system interactions are based on the production of several complement zymogens by MCs and their activation by MC-released proteases. Additionally, at a cellular level, MCs act as potent effector cells of complement activation by expressing receptors for C3a and C5a through which their chemoattraction and activation are mediated by anaphylatoxins in a paracrine and autocrine fashion.Peer reviewe

Mastocytosis : from a Molecular Point of View

Mast cells (MCs) are physiologically activated by binding of stem cell factor (SCF) to the extracellular domains of the Kit receptor. This binding increases the proliferation and prolongs the survival of normal mature MCs, as well as intensifies the release of mediators. In mastocytosis, somatic mutations of the coding Kit gene cause autocrine dysregulation and lead to constitutive KIT activation even in the absence of its ligand SCF. Clinical symptoms are caused by MC-mediator release and/or infiltration of MCs into tissues. Aberrant KIT activation may result in increased production of MCs in the skin and extracutaneous organs. Depending on the affected organ(s), the disease can be divided into cutaneous mastocytosis (CM), systemic mastocytosis (SM), and localized MC tumors. The updated classification of WHO discriminates between several distinct subvariants of CM and SM. While the prognosis in CM and indolent SM (ISM) is excellent with (almost) normal life expectancy, the prognosis in aggressive SM (ASM) and MC leukemia (MCL) is dismal. The symptoms may comprise urticaria, angioedema, flush, pruritus, abdominal pain, diarrhea, hypotension, syncope, and musculoskeletal pain and are the results of MC infiltration and mediator release into target organs, i.e., the skin, gastrointestinal tract, liver, spleen, lymph nodes, and bone marrow. Mastocytosis differs from a lot of other hematological disorders because its pathology is not only based on the lack of normal function of a specific pathway or of a specific cell type but additionally is a proliferative disease. Currently available treatments of mastocytosis include symptomatic, antimediator and cytoreductive targeted therapies.(VLID)358951

Role of Mast Cells in Shaping the Tumor Microenvironment

Early mast cell (MC) infiltration has been reported in a wide range of human and animal tumors particularly malignant melanoma and breast and colorectal cancer. The consequences of their presence in the tumor microenvironment (TME) or at their margins still remain unclear as it is associated with a good or poor prognosis based on the type and anatomical site of the tumor. Within the tumor, MC interactions occur with infiltrated immune cells, tumor cells, and extracellular matrix (ECM) through direct cell-to-cell interactions or release of a broad range of mediators capable of remodeling the TME. MCs actively contribute to angiogenesis and induce neovascularization by releasing the classical proangiogenic factors including VEGF, FGF-2, PDGF, and IL-6, and nonclassical proangiogenic factors mainly proteases including tryptase and chymase. MCs support tumor invasiveness by releasing a broad range of matrix metalloproteinases (MMPs). MC presence within the tumor gained additional significance when it was assumed that controlling its activation by tyrosine kinase inhibitors (imatinib and masitinib) and tryptase inhibitors (gabexate and nafamostat mesylate) or controlling their interactions with other cell types may have therapeutic benefit