The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Peter F. Weller - One of the best experts on this subject based on the ideXlab platform.
-
Image_1_Schistosomal Lipids Activate Human Eosinophils via Toll-Like Receptor 2 and PGD2 Receptors: 15-LO Role in Cytokine Secretion.TIF
2019Co-Authors: Kelly G. Magalhães, Peter F. Weller, Tatiana Luna-gomes, Fabio Mesquita-santos, Rafael Corrêa, Leonardo Santos Assunção, Georgia Correa Atella, Christianne Bandeira-melo, Patricia T. BozzaAbstract:Parasite-derived lipids may play important roles in host-pathogen interactions and immune evasion mechanisms. Remarkable accumulation of Eosinophils is a characteristic feature of inflammation associated with parasitic disease, especially caused by helminthes. Infiltrating Eosinophils are implicated in the pathogenesis of helminth infection by virtue of their capacity to release an array of tissue-damaging and immunoregulatory mediators. However, the mechanisms involved in the activation of human Eosinophils by parasite-derived molecules are not clear. Here we investigated the effects and mechanisms of schistosomal lipids-induced activation of human Eosinophils. Our results showed that stimulation of human Eosinophils in vitro with total lipid extracts from adult worms of S. mansoni induced direct activation of human Eosinophils, eliciting lipid droplet biogenesis, synthesis of leukotriene (LT) C4 and eoxin (EX) C4 (14,15 LTC4) and secretion of eosinophil pre-formed TGFβ. We demonstrated that main eosinophil activating components within S. mansoni lipid extract are schistosomal-derived lysophosphatidylcholine (LPC) and prostaglandin (PG)D2. Moreover, TLR2 is up-regulated in human Eosinophils upon stimulation with schistosomal lipids and pre-treatment with anti-TLR2 inhibited both schistosomal lipids- and LPC-, but not PGD2-, induced lipid droplet biogenesis and EXC4 synthesis within Eosinophils, indicating that TLR2 mediates LPC-driven human eosinophil activation. By employing PGD2 receptor antagonists, we demonstrated that DP1 receptors are also involved in various parameters of human eosinophil activation induced by schistosomal lipids, but not by schistosomal LPC. In addition, schistosomal lipids and their active components PGD2 and LPC, triggered 15-LO dependent production of EXC4 and secretion of TGFβ. Taken together, our results showed that schistosomal lipids contain at least two components—LPC and PGD2—that are capable of direct activation of human Eosinophils acting on distinct eosinophil-expressed receptors, noticeably TLR2 as well as DP1, trigger human eosinophil activation characterized by production/secretion of pro-inflammatory and immunoregulatory mediators.
-
Schistosomal Lipids Activate Human Eosinophils via Toll-Like Receptor 2 and PGD2 Receptors: 15-LO Role in Cytokine Secretion
Frontiers Media S.A., 2019Co-Authors: Kelly G. Magalhães, Tatiana Luna-gomes, Fabio Mesquita-santos, Rafael Corrêa, Leonardo Santos Assunção, Georgia Correa Atella, Peter F. WellerAbstract:Parasite-derived lipids may play important roles in host-pathogen interactions and immune evasion mechanisms. Remarkable accumulation of Eosinophils is a characteristic feature of inflammation associated with parasitic disease, especially caused by helminthes. Infiltrating Eosinophils are implicated in the pathogenesis of helminth infection by virtue of their capacity to release an array of tissue-damaging and immunoregulatory mediators. However, the mechanisms involved in the activation of human Eosinophils by parasite-derived molecules are not clear. Here we investigated the effects and mechanisms of schistosomal lipids-induced activation of human Eosinophils. Our results showed that stimulation of human Eosinophils in vitro with total lipid extracts from adult worms of S. mansoni induced direct activation of human Eosinophils, eliciting lipid droplet biogenesis, synthesis of leukotriene (LT) C4 and eoxin (EX) C4 (14,15 LTC4) and secretion of eosinophil pre-formed TGFβ. We demonstrated that main eosinophil activating components within S. mansoni lipid extract are schistosomal-derived lysophosphatidylcholine (LPC) and prostaglandin (PG)D2. Moreover, TLR2 is up-regulated in human Eosinophils upon stimulation with schistosomal lipids and pre-treatment with anti-TLR2 inhibited both schistosomal lipids- and LPC-, but not PGD2-, induced lipid droplet biogenesis and EXC4 synthesis within Eosinophils, indicating that TLR2 mediates LPC-driven human eosinophil activation. By employing PGD2 receptor antagonists, we demonstrated that DP1 receptors are also involved in various parameters of human eosinophil activation induced by schistosomal lipids, but not by schistosomal LPC. In addition, schistosomal lipids and their active components PGD2 and LPC, triggered 15-LO dependent production of EXC4 and secretion of TGFβ. Taken together, our results showed that schistosomal lipids contain at least two components—LPC and PGD2—that are capable of direct activation of human Eosinophils acting on distinct eosinophil-expressed receptors, noticeably TLR2 as well as DP1, trigger human eosinophil activation characterized by production/secretion of pro-inflammatory and immunoregulatory mediators
-
vesicle mediated secretion of human eosinophil granule derived major basic protein
Laboratory Investigation, 2009Co-Authors: Rossana C N Melo, Ann M. Dvorak, Lisa A Spencer, Sandra A C Perez, Josiane S Neves, Staci P Bafford, Ellen S Morgan, Peter F. WellerAbstract:Major basic protein (MBP), the predominant cationic protein of human eosinophil specific granules, is stored within crystalloid cores of these granules. Secretion of MBP contributes to the immunopathogenesis of varied diseases. Prior electron microscopy (EM) of Eosinophils in sites of inflammation noted losses of granule cores in the absence of granule exocytosis and suggested that eosinophil granule proteins might be released through piecemeal degranulation (PMD), a secretory process mediated by transport vesicles. Because release of eosinophil granule-derived MBP through PMD has not been studied, we evaluated secretion of this cationic protein by human Eosinophils. Intracellular localizations of MBP were studied within nonstimulated and eotaxin-stimulated human Eosinophils by both immunofluorescence and a pre-embedding immunonanogold EM method that enables optimal epitope preservation and antigen access to membrane microdomains. In parallel, quantification of transport vesicles was assessed in Eosinophils from a patient with hypereosinophilic syndrome (HES). Our data demonstrate vesicular trafficking of MBP within eotaxin-stimulated Eosinophils. Vesicular compartments, previously implicated in transport from granules to the plasma membrane, including large vesiculotubular carriers termed eosinophil sombrero vesicles (EoSVs), were found to contain MBP. These secretory compartments were significantly increased in numbers within HES Eosinophils. Moreover, in addition to granule-stored MBP, even unstimulated Eosinophils contained appreciable amounts of MBP within secretory vesicles, as evidenced by immunonanogold EM and immunofluorescent colocalizations of MBP and CD63. These data suggest that eosinophil MBP, with its multiple extracellular activities, can be mobilized from granules by PMD into secretory vesicles and both granule- and secretory vesicle-stored pools of MBP are available for agonist-elicited secretion of MBP from human Eosinophils. The recognition of PMD as a secretory process to release MBP is important to understand the pathological basis of allergic and other eosinophil-associated inflammatory diseases.
-
Activated human Eosinophils.
International archives of allergy and immunology, 2005Co-Authors: Rossana C N Melo, Peter F. Weller, Ann M. DvorakAbstract:Eosinophils are leukocytes which, when stimulated with cytokines or chemokines, become activated and release mediators stored in their dominant population of cytoplasmic granules (termed specific or secondary granules) [1]. The morphology of activated Eosinophils is quite distinct. In a range of inflammatory and allergic disorders or upon physiological stimulation, activated Eosinophils are generally seen as cells full of granules, but these structures are undergoing progressive losses of their contents with retention of granule outer membranes, a process known as ‘piecemeal degranulation’ [2, 3] (fig. 1a). As a result, a mixed population of intact (fig. 1a, asterisks) and enlarged, emptying (fig. 1a, arrows) granules is always visualized in cell sections [3]. Also, a decrease of specific granule numbers can occur [3]. A rare view of an activated eosinophil is shown in figure 1b taken from a hypereosinophilic subject. While a single specific granule (Gr) is seen in the cytoplasm in conjunction with an osmiophilic lipid body (LB), the cell surface shows elaborate projections indicative of activation. Vesiculotubular structures (fig. 1b, arrowheads), termed ‘eosinophil sombrero vesicles’ (EoSV) and recently associated with the eosinophil secretory pathway [4, 5] reside in the cytoplasm. This vesicle population is unique to Eosinophils and allows the prompt identification of these cells by electron microscopy when specific granules are not present [3]. Fig. 1 Different views of activated Eosinophils. a Eotaxin-stimulated Eosinophils show piecemeal degranulation (arrows). Intact granules are indicated by asterisks. b Eosinophil from a hypereosinophilic subject. Arrowheads indicate eosinophil sombrero vesicles. ... Shape changes are another hallmark of activated human Eosinophils. In parallel with the morphological alterations of specific granules, Eosinophils are able to change their morphology in response to different agonists. Figure 2 shows shape changes in Eosinophils stimulated by eotaxin, a potent eosinophil activator. Fig. 2 Shape changes in eotaxin-activated Eosinophils. a The eosinophil shows a narrow constriction at the midpoint of the cell. b The cell shows a broadened cytoplasmic area filled with granules and displaying broad surface processes. c Granule-free uropod ...
-
Human eosinophil-lymphocyte interactions.
Memorias Do Instituto Oswaldo Cruz, 1997Co-Authors: Peter F. Weller, Kaiser G. LimAbstract:While the eosinophil's effector functions clearly can contribute to the pathogenesis of allergic diseases, the evolutionary benefit to having Eosinophils as a distinct class of leukocyte is not clear, especially if one must reconsider the nominally beneficial role of Eosinophils in parasite host defense, Eosinophils are equipped to respond to lymphocytes and their cytokines (and not solely the eosinophil growth factor cytokines), but the functional consequences of such eosinophil responses need to be defined. Conversely, Eosinophils, as antigen-presenting cells (APCs) or sources of lymphocyte-active cytokines, may stimulate and affect lymphocyte functioning. Eosinophils share with CD4+ lymphocytes expression of a number of receptors, including CD4 and IL-2R, and specific alpha-4 integrins that may help in their common recruitment and activation. Further, elucidation of the interactions between lymphocytes and Eosinophils will contribute to a broader understanding of the functioning of Eosinophils in "normal" ongoing immune responses and in allergic disorders.
Marc E. Rothenberg - One of the best experts on this subject based on the ideXlab platform.
-
Eosinophil Knockout Humans: Uncovering the Role of Eosinophils Through Eosinophil-Directed Biological Therapies.
Annual review of immunology, 2021Co-Authors: Elizabeth A. Jacobsen, David J. Jackson, Enrico Heffler, Sameer K. Mathur, Albert J. Bredenoord, Ian D. Pavord, Praveen Akuthota, Florence Roufosse, Marc E. RothenbergAbstract:The enigmatic eosinophil has emerged as an exciting component of the immune system, involved in a plethora of homeostatic and inflammatory responses. Substantial progress has been achieved through experimental systems manipulating Eosinophils in vivo, initially in mice and more recently in humans. Eosinophil knockout mice have identified a contributory role for Eosinophils in basal and inflammatory processes and protective immunity. Primarily fueled by the purported proinflammatory role of Eosinophils in eosinophil-associated diseases, a series of anti-eosinophil therapeutics have emerged as a new class of drugs. These agents, which dramatically deplete Eosinophils, provide a valuable opportunity to characterize the consequences of eosinophil knockout humans. Herein, we comparatively describe mouse and human eosinophil knockouts. We put forth the view that human Eosinophils negatively contribute to a variety of diseases and, unlike mouse Eosinophils, do not yet have an identified role in physiological health; thus, clarifying all roles of Eosinophils remains an ongoing pursuit. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
-
targeting Eosinophils in allergy inflammation and beyond
Nature Reviews Drug Discovery, 2013Co-Authors: Patricia C. Fulkerson, Marc E. RothenbergAbstract:Eosinophils can regulate local immune and inflammatory responses, and their accumulation in the blood and tissue is associated with several inflammatory and infectious diseases. Thus, therapies that target Eosinophils may help control diverse diseases, including atopic disorders such as asthma and allergy, as well as diseases that are not primarily associated with Eosinophils, such as autoimmunity and malignancy. Eosinophil-targeted therapeutic agents that are aimed at blocking specific steps involved in eosinophil development, migration and activation have recently entered clinical testing and have produced encouraging results and insights into the role of Eosinophils. In this Review, we describe recent advances in the development of first-generation eosinophil-targeted therapies and highlight strategies for using personalized medicine to treat eosinophilic disorders.
-
Eosinophils biological properties and role in health and disease
Clinical & Experimental Allergy, 2008Co-Authors: Simon P. Hogan, Helene F Rosenberg, R Moqbel, Simon Phipps, Paul S Foster, Paige Lacy, Barry A Kay, Marc E. RothenbergAbstract:Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of diverse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, the biology of Eosinophils is summarized, focusing on transcriptional regulation of eosinophil differentiation, characterization of the growing properties of eosinophil granule proteins, surface proteins and pleiotropic mediators, and molecular mechanisms of eosinophil degranulation. New views on the role of Eosinophils in homeostatic function are examined, including developmental biology and innate and adaptive immunity (as well as their interaction with mast cells and T cells) and their proposed role in disease processes including infections, asthma, and gastrointestinal disorders. Finally, strategies for targeted therapeutic intervention in eosinophil-mediated mucosal diseases are conceptualized.
-
a central regulatory role for Eosinophils and the eotaxin ccr3 axis in chronic experimental allergic airway inflammation
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Patricia C. Fulkerson, Simon P. Hogan, Christine A Fischetti, Melissa Mcbride, Lynn M Hassman, Marc E. RothenbergAbstract:To clarify the role and regulation of Eosinophils, we subjected several key eosinophil-related genetically engineered mice to a chronic model of allergic airway inflammation aiming to identify results that were independent of the genetic targeting strategy. In particular, mice with defects in eosinophil development (Δdbl-GATA) and eosinophil recruitment [mice deficient in CCR3 (CCR3 knockout) and mice deficient in both eotaxin-1 and eotaxin-2 (eotaxin-1/2 double knockout)] were subjected to Aspergillus fumigatus-induced allergic airway inflammation. Allergen-induced eosinophil recruitment into the airway was abolished by 98%, 94%, and 99% in eotaxin-1/2 double knockout, CCR3 knockout, and Δdbl-GATA mice, respectively. Importantly, allergen-induced type II T helper lymphocyte cytokine production was impaired in the lungs of eosinophil- and CCR3-deficient mice. The absence of Eosinophils correlated with reduction in allergen-induced mucus production. Notably, by using global transcript expression profile analysis, a large subset (29%) of allergen-induced genes was eosinophil- and CCR3-dependent; pathways downstream from Eosinophils were identified, including in situ activation of coagulation in the lung. In summary, we present multiple lines of independent evidence that Eosinophils via CCR3 have a central role in chronic allergic airway disease.
-
quantity and distribution of Eosinophils in the gastrointestinal tract of children
Pediatric and Developmental Pathology, 2006Co-Authors: Charles W Debrosse, Justin W Case, Philip E Putnam, Margaret H Collins, Marc E. RothenbergAbstract:Abstract There are a lack of data on the quantity and location of Eosinophils in the gastrointestinal tract of healthy individuals. Accordingly, we examined gastrointestinal biopsies obtained during endoscopic evaluation of pediatric patients. Biopsies were previously interpreted as having no diagnostic abnormality. The presence of extracellular eosinophil constituents and the quantity of Eosinophils in atopic versus nonatopic individuals was determined. In the esophagus, Eosinophils were present in only 2.7% of high-power fields (hpf), with a mean value of 0.03 ± 0.10 Eosinophils/hpf (mean ± standard deviation) and a maximum of 1 eosinophil/hpf. Examination of the antrum and fundus revealed similar numbers of Eosinophils in the lamina propria (1.9 ± 1.3 and 2.1 ± 2.4 Eosinophils/hpf, respectively), with no Eosinophils observed in the surface epithelium. In the small intestine, there were 9.6 ± 5.3 (maximum, 26 Eosinophils/hpf) and 12.4 ± 5.4 Eosinophils/hpf (maximum, 28 Eosinophils/hpf) in the intercrypt...
Helene F Rosenberg - One of the best experts on this subject based on the ideXlab platform.
-
the cellular functions of Eosinophils collegium internationale allergologicum cia update 2020
International Archives of Allergy and Immunology, 2020Co-Authors: Hansuwe Simon, Shida Yousefi, Nina Germic, Isabelle C Arnold, Angela Franciska Haczku, A V Karaulov, Dagmar Simon, Helene F RosenbergAbstract:Eosinophils and their secretory mediators play an important role in the pathogenesis of infectious and inflammatory disorders. Although Eosinophils are largely evolutionally conserved, their physiologic functions are not well understood. Given the availability of new eosinophil-targeted depletion therapies, there has been a renewed interest in understanding eosinophil biology as these strategies may result in secondary disorders when applied over long periods of time. Recent data suggest that Eosinophils are not only involved in immunological effector functions but also carry out tissue protective and immunoregulatory functions that actively contribute to the maintenance of homeostasis. Prolonged eosinophil depletion may therefore result in the development of secondary disorders. Here, we review recent literature pointing to important roles for Eosinophils in promoting immune defense, antibody production, activation of adipose tissue, and tissue remodeling and fibrosis. We also reflect on patient data from clinical trials that feature anti-eosinophil therapeutics.
-
Eosinophils: changing perspectives in health and disease
Nature Reviews Immunology, 2013Co-Authors: Helene F Rosenberg, Kimberly D. Dyer, Paul S FosterAbstract:Eosinophils have been traditionally perceived as terminally differentiated cytotoxic effector cells. Recent studies have provided a more sophisticated understanding of eosinophil effector functions and a more nuanced view of their contributions to the pathogenesis of various diseases, including asthma and respiratory allergies, eosinophilic gastrointestinal diseases, hypereosinophilic syndromes and parasitic infection. Eosinophils are granulocytes that develop in the bone marrow from pluripotent progenitors in response to cytokines, such as interleukin-5 (IL-5), IL-3 and granulocyte–macrophage colony-stimulating factor (GM-CSF). Mature Eosinophils are released into the peripheral blood and enter tissues in response to cooperative signalling between IL-5 and eotaxin family chemokines. Eosinophils in peripheral blood and tissues are uniquely identified by their bilobed nuclei, their large specific granules that store cytokines, cationic proteins and enzymes, and their expression of the IL-5 receptor and CC-chemokine receptor 3 (CCR3). In addition, the receptors sialic acid-binding immunoglobulin-like lectin 8 (SIGLEC-8) and SIGLEC-F are expressed by human and mouse Eosinophils, respectively. IL-5 has a central and profound role in all aspects of eosinophil development, activation and survival. IL-5 is produced by T helper 2 (T_H2) cells, and more recently the contributions of the epithelium-derived innate cytokines thymic stromal lymphopoietin (TSLP), IL-25 and IL-33 in promoting eosinophilia via the induction of IL-5 have also been recognized. Although eosinophil responses are influenced by cytokines produced by T cells, Eosinophils in turn modulate the functions of B and T cells. Eosinophils also communicate with a range of innate immune cells (such as mast cells, dendritic cells, macrophages and neutrophils). Eosinophils serve to bridge innate and adaptive immunity by regulating the production of chemoattractants and cytokines (including CC-chemokine ligand 17 (CCL17), CCL22, a proliferation-inducing ligand (APRIL) and IL-6) and via antigen presentation. Both successful and unsuccessful attempts to target Eosinophils have yielded remarkable insights into their contribution to disease pathogenesis. Many eosinophil-associated inflammatory conditions have been shown to be heterogeneous in nature. As such, successful therapeutic strategies will depend on the correlation of disease activity with dysregulated eosinophil function as well as the identification of the crucial molecules that regulate eosinophil accumulation in the affected tissues. This Review describes the unique biology of the eosinophil. The authors explain how Eosinophils interact with other leukocyte populations to promote protective immunity following infection. They also discuss the pathological roles of Eosinophils in allergic-type diseases, such as asthma and the hypereosinophilic syndromes. Eosinophils have been traditionally perceived as terminally differentiated cytotoxic effector cells. Recent studies have profoundly altered this simplistic view of Eosinophils and their function. New insights into the molecular pathways that control the development, trafficking and degranulation of Eosinophils have improved our understanding of the immunomodulatory functions of these cells and their roles in promoting homeostasis. Likewise, recent developments have generated a more sophisticated view of how Eosinophils contribute to the pathogenesis of different diseases, including asthma and primary hypereosinophilic syndromes, and have also provided us with a more complete appreciation of the activities of these cells during parasitic infection.
-
Eosinophils biological properties and role in health and disease
Clinical & Experimental Allergy, 2008Co-Authors: Simon P. Hogan, Helene F Rosenberg, R Moqbel, Simon Phipps, Paul S Foster, Paige Lacy, Barry A Kay, Marc E. RothenbergAbstract:Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of diverse inflammatory responses, as well as modulators of innate and adaptive immunity. In this review, the biology of Eosinophils is summarized, focusing on transcriptional regulation of eosinophil differentiation, characterization of the growing properties of eosinophil granule proteins, surface proteins and pleiotropic mediators, and molecular mechanisms of eosinophil degranulation. New views on the role of Eosinophils in homeostatic function are examined, including developmental biology and innate and adaptive immunity (as well as their interaction with mast cells and T cells) and their proposed role in disease processes including infections, asthma, and gastrointestinal disorders. Finally, strategies for targeted therapeutic intervention in eosinophil-mediated mucosal diseases are conceptualized.
-
Eosinophils eosinophil ribonucleases and their role in host defense against respiratory virus pathogens
Journal of Leukocyte Biology, 2001Co-Authors: Helene F Rosenberg, Joseph B DomachowskeAbstract:Eosinophils remain among the most enigmatic of cells, as our appreciation of their detrimental activities--e.g., asthma and allergic disease--far outweighs our understanding of their beneficial effects. Among the major secretory effector proteins of Eosinophils are the ribonucleases eosinophil-derived neurotoxin (EDN) and eosinophil cationic protein (ECP) in primates and their orthologs, the eosinophil-associated ribonucleases (EARs) in rodents. The rapid diversification observed among these ribonucleases suggested that the ultimate target(s) might be similarly efficient at generating sequence diversity while maintaining an unalterable susceptibility to ribonucleolytic cleavage. This has prompted us to consider a role for these proteins and by extension, for Eosinophils, in host defense against single-stranded RNA virus pathogens. We detail our studies of the antiviral activity of Eosinophils and eosinophil ribonucleases against respiratory syncytial virus (RSV) in vitro and the related, natural rodent pathogen, pneumonia virus of mice (PVM), in vivo, and consider the possibility that antiviral host defense and the dysregulated responses leading to asthma represent opposing sides of an eosinophil-mediated double-edged sword.
Kelly G. Magalhães - One of the best experts on this subject based on the ideXlab platform.
-
Image_1_Schistosomal Lipids Activate Human Eosinophils via Toll-Like Receptor 2 and PGD2 Receptors: 15-LO Role in Cytokine Secretion.TIF
2019Co-Authors: Kelly G. Magalhães, Peter F. Weller, Tatiana Luna-gomes, Fabio Mesquita-santos, Rafael Corrêa, Leonardo Santos Assunção, Georgia Correa Atella, Christianne Bandeira-melo, Patricia T. BozzaAbstract:Parasite-derived lipids may play important roles in host-pathogen interactions and immune evasion mechanisms. Remarkable accumulation of Eosinophils is a characteristic feature of inflammation associated with parasitic disease, especially caused by helminthes. Infiltrating Eosinophils are implicated in the pathogenesis of helminth infection by virtue of their capacity to release an array of tissue-damaging and immunoregulatory mediators. However, the mechanisms involved in the activation of human Eosinophils by parasite-derived molecules are not clear. Here we investigated the effects and mechanisms of schistosomal lipids-induced activation of human Eosinophils. Our results showed that stimulation of human Eosinophils in vitro with total lipid extracts from adult worms of S. mansoni induced direct activation of human Eosinophils, eliciting lipid droplet biogenesis, synthesis of leukotriene (LT) C4 and eoxin (EX) C4 (14,15 LTC4) and secretion of eosinophil pre-formed TGFβ. We demonstrated that main eosinophil activating components within S. mansoni lipid extract are schistosomal-derived lysophosphatidylcholine (LPC) and prostaglandin (PG)D2. Moreover, TLR2 is up-regulated in human Eosinophils upon stimulation with schistosomal lipids and pre-treatment with anti-TLR2 inhibited both schistosomal lipids- and LPC-, but not PGD2-, induced lipid droplet biogenesis and EXC4 synthesis within Eosinophils, indicating that TLR2 mediates LPC-driven human eosinophil activation. By employing PGD2 receptor antagonists, we demonstrated that DP1 receptors are also involved in various parameters of human eosinophil activation induced by schistosomal lipids, but not by schistosomal LPC. In addition, schistosomal lipids and their active components PGD2 and LPC, triggered 15-LO dependent production of EXC4 and secretion of TGFβ. Taken together, our results showed that schistosomal lipids contain at least two components—LPC and PGD2—that are capable of direct activation of human Eosinophils acting on distinct eosinophil-expressed receptors, noticeably TLR2 as well as DP1, trigger human eosinophil activation characterized by production/secretion of pro-inflammatory and immunoregulatory mediators.
-
Schistosomal Lipids Activate Human Eosinophils via Toll-Like Receptor 2 and PGD2 Receptors: 15-LO Role in Cytokine Secretion
Frontiers Media S.A., 2019Co-Authors: Kelly G. Magalhães, Tatiana Luna-gomes, Fabio Mesquita-santos, Rafael Corrêa, Leonardo Santos Assunção, Georgia Correa Atella, Peter F. WellerAbstract:Parasite-derived lipids may play important roles in host-pathogen interactions and immune evasion mechanisms. Remarkable accumulation of Eosinophils is a characteristic feature of inflammation associated with parasitic disease, especially caused by helminthes. Infiltrating Eosinophils are implicated in the pathogenesis of helminth infection by virtue of their capacity to release an array of tissue-damaging and immunoregulatory mediators. However, the mechanisms involved in the activation of human Eosinophils by parasite-derived molecules are not clear. Here we investigated the effects and mechanisms of schistosomal lipids-induced activation of human Eosinophils. Our results showed that stimulation of human Eosinophils in vitro with total lipid extracts from adult worms of S. mansoni induced direct activation of human Eosinophils, eliciting lipid droplet biogenesis, synthesis of leukotriene (LT) C4 and eoxin (EX) C4 (14,15 LTC4) and secretion of eosinophil pre-formed TGFβ. We demonstrated that main eosinophil activating components within S. mansoni lipid extract are schistosomal-derived lysophosphatidylcholine (LPC) and prostaglandin (PG)D2. Moreover, TLR2 is up-regulated in human Eosinophils upon stimulation with schistosomal lipids and pre-treatment with anti-TLR2 inhibited both schistosomal lipids- and LPC-, but not PGD2-, induced lipid droplet biogenesis and EXC4 synthesis within Eosinophils, indicating that TLR2 mediates LPC-driven human eosinophil activation. By employing PGD2 receptor antagonists, we demonstrated that DP1 receptors are also involved in various parameters of human eosinophil activation induced by schistosomal lipids, but not by schistosomal LPC. In addition, schistosomal lipids and their active components PGD2 and LPC, triggered 15-LO dependent production of EXC4 and secretion of TGFβ. Taken together, our results showed that schistosomal lipids contain at least two components—LPC and PGD2—that are capable of direct activation of human Eosinophils acting on distinct eosinophil-expressed receptors, noticeably TLR2 as well as DP1, trigger human eosinophil activation characterized by production/secretion of pro-inflammatory and immunoregulatory mediators
Shigeharu Ueki - One of the best experts on this subject based on the ideXlab platform.
-
eosinophil extracellular trap cell death derived dna traps their presence in secretions and functional attributes
The Journal of Allergy and Clinical Immunology, 2016Co-Authors: Shigeharu Ueki, Yasunori Konno, Masahide Takeda, Yuki Moritoki, Makoto Hirokawa, Yoshinori Matsuwaki, Kohei Honda, Nobuo Ohta, Shiori YamamotoAbstract:Background Activated human Eosinophils, as well as neutrophils, can release extracellular chromatin to form DNA traps through cytolytic extracellular trap cell death (ETosis). Although formations of neutrophil DNA traps are recognized in patients with various inflammatory conditions, neither the presence of ETosis-derived eosinophil DNA traps in human allergic diseases nor the characteristics of these DNA traps have been studied. Objective We investigated the presence of ETosis-derived DNA traps in eosinophil-rich sinus and ear secretions and the functional attributes of ETosis DNA traps. Methods Eosinophil-rich secretions obtained from patients with eosinophilic chronic rhinosinusitis and eosinophilic otitis media were studied microscopically. In vitro studies of ETosis and DNA trap formation used blood-derived Eosinophils and neutrophils, and studies of the binding capacities of DNA traps used labeled bacteria and fluorescent microbeads. Stabilities of DNA traps were evaluated by using fluorescence microscopy. Results Abundant nuclear histone H1–bearing DNA traps formed in vivo in the eosinophilic secretions and contributed to their increased viscosity. In vitro , after brief shear flow, eosinophil ETosis-elicited DNA traps assembled to form stable aggregates. Eosinophil DNA traps entrapped bacteria and fungi and, through hydrophobic interactions, microbeads. In comparison with neutrophil-derived DNA traps, eosinophil DNA traps ultrastructurally exhibited thicker fibers with globular structures and were less susceptible to leukocyte-derived proteolytic degradation, likely because of the lesser protease activities of Eosinophils. Conclusions In human allergic diseases local cytolysis of Eosinophils not only releases free eosinophil granules but also generates nuclear-derived DNA traps that are major extracellular structural components within eosinophil-rich secretions.