Mast Cells In Innate Immunity Research Articles

Comparative Analysis of Orthologous Mast Cell Chymases Active Sites Using Bioinformatics Tools

Mast cells, neutrophils, basophils, natural killer cells, and cytotoxic T cells are among the hematopoietic cell lines originating from immune cells. The importance of mammalian mast cells in innate immunity has piqued the scientific community's interest. cytoplasmic granules of mast cells. Histamine, proteoglycans, proteins, and cytokines are examples of compounds (mediators) that produce mast cell cytoplasmic granules. When external stimuli are received, these granules are released, causing degranulation. Mast cells generate a lot of proteases including chymase, tryptase, and type A carboxypeptidase, among other things. The structure of chymase cma1 was unknown in mice, but it shares 74 percent of its human sequence with chymase CMA1, which was used as a reference. The human CMA1 structure was used to establish and interpret the mouse cma1 structure. Significant residues from the active site, such as catalytic triads and binding residues, were examined. The position of a catalytic triad in human CMA1 chymase and mouse cma1 chymase has been discovered to be similar. Val 175 and Val 197, respectively, replaced two Ala 192 and Gly 214 residues in active site binding residues in target, according to active site residue analysis. We may deduce from this substitution that the cleavage specificity of mouse cma1 chymase varies from that of human CMA1 chymase.

Comparative Analysis of Orthologous Mast Cell Chymases Active Sites Using Bioinformatics Tools

Mast cells, neutrophils, basophils, natural killer cells, and cytotoxic T cells are among the hematopoietic cell lines originating from immune cells. The importance of mammalian mast cells in innate immunity has piqued the scientific community's interest. cytoplasmic granules of mast cells. Histamine, proteoglycans, proteins, and cytokines are examples of compounds (mediators) that produce mast cell cytoplasmic granules. When external stimuli are received, these granules are released, causing degranulation. Mast cells generate a lot of proteases including chymase, tryptase, and type A carboxypeptidase, among other things. The structure of chymase cma1 was unknown in mice, but it shares 74 percent of its human sequence with chymase CMA1, which was used as a reference. The human CMA1 structure was used to establish and interpret the mouse cma1 structure. Significant residues from the active site, such as catalytic triads and binding residues, were examined. The position of a catalytic triad in human CMA1 chymase and mouse cma1 chymase has been discovered to be similar. Val 175 and Val 197, respectively, replaced two Ala 192 and Gly 214 residues in active site binding residues in target, according to active site residue analysis. We may deduce from this substitution that the cleavage specificity of mouse cma1 chymase varies from that of human CMA1 chymase.

Mast Cells Are Crucial for Induction of Group 2 Innate Lymphoid Cells and Clearance of Helminth Infections

Mast cells are important for eradication of intestinal nematodes; however, their precise mechanisms of action have remained elusive, especially in the early phase of infection. We found that Spi-B-deficient mice had increased numbers of mast cells and rapidly expelled the Heligmosomoides polygyrus (Hp) nematode. This was accompanied by induction of interleukin-13 (IL-13)-producing group 2 innate lymphoid cells (ILC2) and goblet cell hyperplasia. Immediately after Hp infection, mast cells were rapidly activated to produce IL-33 in response to ATP released from apoptotic intestinal epithelial cells. Invivo inhibition of the P2X7 ATP receptor rendered the Spi-B-deficient mice susceptible to Hp, concomitant with elimination of mast cell activation and IL-13-producing ILC2 induction. These results uncover a previously unknown role for mast cells in innate immunity in that activation of mast cells by ATP orchestrates the development of a protective type 2 immune response, in part by producing IL-33, which contributes to ILC2 activation.

Mast cells are permissive for rhinovirus replication: potential implications for asthma exacerbations

SummaryBackgroundHuman rhinoviruses (HRVs) are a major trigger of asthma exacerbations, with the bronchial epithelium being the major site of HRV infection and replication. Mast cells (MCs) play a key role in asthma where their numbers are increased in the bronchial epithelium with increasing disease severity.ObjectiveIn view of the emerging role of MCs in innate immunity and increased localization to the asthmatic bronchial epithelium, we investigated whether HRV infection of MCs generated innate immune responses which were protective against infection.MethodsThe LAD2 MC line or primary human cord blood‐derived MCs (CBMCs) were infected with HRV or UV‐irradiated HRV at increasing multiplicities of infection (MOI) without or with IFN‐β or IFN‐λ. After 24 h, innate immune responses were assessed by RT‐qPCR and IFN protein release by ELISA. Viral replication was determined by RT‐qPCR and virion release by TCID 50 assay.Results HRV infection of LAD2 MCs induced expression of IFN‐β, IFN‐λ and IFN‐stimulated genes. However, LAD2 MCs were permissive for HRV replication and release of infectious HRV particles. Similar findings were observed with CBMCs. Neutralization of the type I IFN receptor had minimal effects on viral shedding, suggesting that endogenous type I IFN signalling offered limited protection against HRV. However, augmentation of these responses by exogenous IFN‐β, but not IFN‐λ, protected MCs against HRV infection.Conclusion and Clinical Relevance MCs are permissive for the replication and release of HRV, which is prevented by exogenous IFN‐β treatment. Taken together, these findings suggest a novel mechanism whereby MCs may contribute to HRV‐induced asthma exacerbations.

Modulation of Mast Cell and Basophil Functions by Benzene Metabolites

Benzene is a carcinogenic compound used in industrial manufacturing and a common environmental pollutant mostly derived from vehicle emissions and cigarette smoke. Benzene exposure is associated with a variety of clinical conditions ranging from hematologic diseases to chronic lung disorders. Beside its direct toxicity, benzene exerts multiple effects after being converted to reactive metabolites such as hydroquinone and benzoquinone. Mast cells and basophils are primary effector cells involved in the development of respiratory allergies such as rhinitis and bronchial asthma and they play an important role in innate immunity. Benzene and its metabolites can influence mast cell and basophil responses either directly or by interfering with other cells, such as T cells, macrophages and monocytes, which are functionally connected to mast cells and basophils. Hydroquinone and benzoquinone inhibit the release of preformed mediators, leukotriene synthesis and cytokine production in human basophils stimulated by IgE- and non IgE-mediated agonists. Furthermore, these metabolites reduce IgE-mediated degranulation of mast cells and the development of allergic lung inflammation in rats. Both in vitro and in vivo studies indicate that benzene metabolites alter biochemical and functional activities of other immunocompetent cells and may impair immune responses in the lung. These inhibitory effects of benzene metabolites are primarily mediated by interference with early transduction signals such as PI3 kinase. Together, currently available studies indicate that benzene metabolites interfere by multiple mechanisms with the role of basophils and mast cells in innate immunity and in chronic inflammation in the lung.

Adoptive transfer of mast cells does not enhance the impaired survival of KitW/ KitW−v mice in a model of low dose intraperitoneal infection with bioluminescent Salmonella typhimurium

Mast cells are important effector cells in IgE-associated immune responses, but also can contribute to host defense in certain examples of bacterial infection. We found that genetically mast cell-deficient WBB6F1- Kit W / Kit W−v mice exhibited more bacterial CFUs per spleen by 6 days after intraperitoneal injection of bioluminescent Salmonella typhimurium, and died more rapidly after infection, than did the congenic WBB6F1- Kit +/+ wild type mice. Adoptive transfer of bone marrow-derived cultured mast cells of Kit +/+ origin to the peritoneal cavity of Kit W / Kit W−v mice resulted in engraftment of mast cells in the peritoneal cavity and mesentery of the recipient mice, and the development of large numbers of mast cells in the spleen. However, such mast cell-engrafted Kit W / Kit W−v mice appeared sicker after intraperitoneal injection with S. typhimurium than did mast cell-deficient Kit W / Kit W−v mice, and exhibited numbers of CFUs of bacteria per spleen, and a survival curve, that were not significantly different than those of Kit W / Kit W−v mice. These results, when taken together with prior studies investigating the roles of mast cells in innate immunity, strongly suggest that whether mast cells can be shown to have a significant role in enhancing survival during bacterial infections may depend critically on the details of the particular experimental systems examined.

Mast cells in innate immunity

Mast cells have been most extensively studied in their traditional role as an early effector cell of allergic disease. However, in the majority of individuals, it might be the role of this cell as a sentinel in host defense that is most important. Mast cells have been repeatedly demonstrated to play a critical role in defense against bacterial infections, and evidence for their involvement in early responses to viral and fungal pathogens is growing. Mast cells are activated during innate immune responses by multiple mechanisms, including well-established responses to complement components. In addition, novel mechanisms have emerged as a result of the explosion of knowledge in our understanding of pattern-recognition receptors. The mast cell shares many features with other innate immune effector cells, such as neutrophils and macrophages. However, a unique role for mast cells is defined not only by their extensive mediator profile but also by their ability to interact with the vasculature, to expedite selective cell recruitment, and to set the stage for an appropriate acquired response.

The role of mast cells in asthma

While the role of mast cells in allergic reactions is unequivocal, their precise functions in asthma remain controversial. Mast cells uniquely populate all vascularized organs and tissues, including the upper and lower respiratory tree, even in healthy individuals. Histologic evidence suggests that asthma is accompanied by a mast cell hyperplasia in the inflamed mucosal epithelium and the adjacent smooth muscle. The mechanisms responsible for constitutive mast cell development have been partly elucidated. Moreover, both in vitro studies and in vivo disease models indicate that mast cells have a remarkably flexible program of gene expression, and this program can be drastically altered by the T-cell-derived Th2 cytokines relevant to asthma. Moreover, the role of mast cells in innate immunity is now firmly established, and the capacity for numerous microbial pathogens to initiate their activation in vitro and in vivo suggest mechanisms by which microbes could initiate disease exacerbations.

Moraxella catarrhalis induces mast cell activation and nuclear factor kappa B-dependent cytokine synthesis.

Human mast cells are often found perivascularly and at mucosal sites and may play crucial roles in the inflammatory response. Recent studies have suggested a prominent role for mast cells in host defense. In this study, we analyzed the effects of a common airway pathogen, Moraxella catarrhalis and a commensal bacterium, Neiserria cinerea, on activation of human mast cells. Human mast cell leukemia cells (HMC-1) were activated with either phorbol myristate acetate (PMA) and calcium ionophore or with varying concentrations of heat-killed suspensions of bacteria. Supernatants were assayed for the cytokines interleukin-4 (IL-4), granulocyte macrophage colony stimulating factor (GM-CSF), IL-6, IL-8, IL-13 and monocyte chemotactic protein-1 (MCP-1). Nuclear proteins were isolated and assayed by electrophoretic mobility shift assay (EMSA) for nuclear factor kappaB (NF-kappaB) nuclear binding activity. In some experiments, NF-kappaB inhibitor, Bay-11 was added to determine functional significance. Both M. catarrhalis and N. cinerea induced mast cell activation and selective secretion of two key inflammatory cytokines, IL-6 and MCP-1. This was accompanied by NF-kappaB activation. Neither spun bacterial supernatants nor bacterial lipopolysaccharide induced cytokine secretion, suggesting need for direct bacterial contact with mast cells. Scanning electron microscopy revealed active aggregation of bacteria over mast cell surfaces. The NF-kappaB inhibitor, Bay-11, inhibited expression of MCP-1. These findings suggest the possibility of direct interactions between human mast cells and common bacteria and provide evidence for a novel role for human mast cells in innate immunity.

Mast cells in innate immunity.

Mast cells are known to be the main effector cells in the elicitation of the IgE-mediated allergic response. The specific location of mast cells within tissues that interface the external environment, and the extent of their functional capacity, including the ability to phagocytose and to produce and secrete a wide spectrum of mediators, have led investigators to propose a potential role for mast cells in innate immune responses. Certain microorganisms have been found to interact either directly or indirectly with mast cells. This interaction results in mast cell activation and mediator release which elicit an inflammatory response or direct killing leading to bacterial clearance. The in vivo relevance of these in vitro observations has been demonstrated by the use of complement-deficient and/or mast cell-deficient and mast cell-reconstituted mice. In thus has been shown that both C3 and mast cell- and tumor necrosis factor-alpha-dependent recruitment of circulating leukocytes with bactericidal properties are crucial to a full response in certain models of acute infection. Modulation of mast cell numbers in vivo was also found to affect the host response against bacterial infection. Thus, mast cells do have a role in innate immunity in defined animal models of bacterial infection. Whether mast cells participate in innate immune responses in the protection of the human host against bacteria remains to be determined.