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James E. Pease - One of the best experts on this subject based on the ideXlab platform.
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Eotaxin-3 exerts innate host defense activities that are modulated by mast cell proteases
5.3 Allergy and Immunology, 2015Co-Authors: Anele Gela, James E. Pease, Gopinath Kasetty, Sandra Jovic, Maria Ekoff, Gunnar Nilsson, Sven Kjellström, Arne EgestenAbstract:During bacterial infections of the airways, a Th1-profiled inflammation promotes the production of several host defense proteins and peptides with antibacterial activities. These are downregulated by Th2 cytokines of the allergic response. Instead, the eosinophil-recruiting chemokines eotaxin-1/CCL11, eotaxin-2/CCL24, and eotaxin-3/CCL26 are expressed. This study set out to investigate whether these chemokines could serve as innate host defense molecules during allergic inflammation. Antibacterial activities of the eotaxins were investigated using viable count assays and methods assessing bacterial permeabilization. CCL11, CCL24, and CCL26 all showed potent bactericidal activity, mediated through membrane disruption, against the airway pathogens. CCL26 retained bactericidal activity in the presence of salt at physiologic concentrations, and the region holding the highest bactericidal activity was the cationic and amphipathic COOH-terminus. Proteolysis of CCL26 by chymase and tryptase, respectively, released distinct fragments of the COOH- and NH2-terminal regions. The COOH-terminal fragment retained antibacterial activity while the NH2-terminal had potent LPS-neutralizing properties in the order of CCL26 full-length protein. An identical fragment to NH2-terminal fragment generated by tryptase was obtained after incubation with supernatants from activated mast cells. Taken together, the findings show that the eotaxins can contribute to host defense against common airway pathogens and that their activities are modulated by mast cell proteases.
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Eotaxin-3 (CCL26) exerts innate host defense activities that are modulated by mast cell proteases.
Allergy, 2015Co-Authors: Anele Gela, Matthias Morgelin, James E. Pease, Gopinath Kasetty, Sandra Jovic, Maria Ekoff, Gunnar Nilsson, Sven Kjellström, Artur Schmidtchen, Arne EgestenAbstract:BackgroundDuring bacterial infections of the airways, a Th1-profiled inflammation promotes the production of several host defense proteins and peptides with antibacterial activities including -defensins, ELR-negative CXC chemokines, and the cathelicidin LL-37. These are downregulated by Th2 cytokines of the allergic response. Instead, the eosinophil-recruiting chemokines eotaxin-1/CCL11, eotaxin-2/CCL24, and eotaxin-3/CCL26 are expressed. This study set out to investigate whether these chemokines could serve as innate host defense molecules during allergic inflammation. MethodsAntibacterial activities of the eotaxins were investigated using viable count assays, electron microscopy, and methods assessing bacterial permeabilization. Fragments generated by mast cell proteases were characterized, and their potential antibacterial, receptor-activating, and lipopolysaccharide-neutralizing activities were investigated. ResultsCCL11, CCL24, and CCL26 all showed potent bactericidal activity, mediated through membrane disruption, against the airway pathogens Streptococcus pneumoniae, Staphylococcus aureus, Nontypeable Haemophilus influenzae, and Pseudomonas aeruginosa. CCL26 retained bactericidal activity in the presence of salt at physiologic concentrations, and the region holding the highest bactericidal activity was the cationic and amphipathic COOH-terminus. Proteolysis of CCL26 by chymase and tryptase, respectively, released distinct fragments of the COOH- and NH2-terminal regions. The COOH-terminal fragment retained antibacterial activity while the NH2-terminal had potent LPS-neutralizing properties in the order of CCL26 full-length protein. An identical fragment to NH2-terminal fragment generated by tryptase was obtained after incubation with supernatants from activated mast cells. None of the fragments activated the CCR3-receptor. ConclusionsTaken together, the findings show that the eotaxins can contribute to host defense against common airway pathogens and that their activities are modulated by mast cell proteases. (Less)
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Alanine scanning mutagenesis of the chemokine receptor CCR3 reveals distinct extracellular residues involved in recognition of the eotaxin family of chemokines.
Molecular immunology, 2005Co-Authors: Cécile E. Duchesnes, Timothy J. Williams, Philip M. Murphy, James E. PeaseAbstract:Despite considerable differences in primary structure, the chemokines eotaxin-1/CCL11, eotaxin-2/CCL24 and eotaxin-3/CCL26 signal via a single receptor, CCR3, but exhibit different potencies and efficacies. To examine receptor/ligand interactions in more detail, we performed alanine scanning mutagenesis of 21 charged residues within the extracellular loops (ECLs) of CCR3. Following transient expression in the L1.2 cell line, CCR3 mutants were assessed for their ability to be expressed at the cell surface, bind CCL11 and induce chemotactic responses to CCL11, CCL24 and CCL26. The majority of constructs were well expressed at the cell surface and bound CCL11 with low nanomolar affinity. Exceptions to this rule included the mutants E175A and E176A (ECL2) which were poorly expressed and responded weakly to all three ligands in chemotaxis assays. In contrast, the mutants K26 (amino-terminus) E179 and E180 (ECL2) responded in chemotaxis assays to CCL11 and CCL24, but not to CCL26. Mutation of residues in ECL3 was informative, with the D272A, K277A and D280A mutants exhibiting reduced chemotactic responses to two or more of the three ligands examined, despite being expressed on the cell surface at levels similar to WT CCR3. This suggests a major role for ECL3 in the recognition of all three eotaxins. In summary, distinct acidic and basic residues within CCR3 determine both receptor expression and activation by the eotaxins. Determining how these chemokines interact with their receptor at the molecular level should increase our understanding of the process of chemokine receptor activation.
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CCR3 functional responses are regulated by both CXCR3 and its ligands CXCL9, CXCL10 and CXCL11.
European journal of immunology, 2003Co-Authors: Georgina Xanthou, Timothy J. Williams, Cécile E. Duchesnes, James E. PeaseAbstract:The chemokine receptor CXCR3 is predominantly expressed on T lymphocytes, and its agonists CXCL9, CXCL10 and CXCL11 are IFN-gamma-inducible chemokines that promote Th1 responses. In contrast, the CCR3 agonists CCL11, CCL24 and CCL26 are involved in the recruitment of cells such as eosinophils and basophils during Th2 responses. Here, we report that although CCL11, CCL24 and CCL26 are neither agonists nor antagonists of CXCR3, CCL11 binds with high affinity to CXCR3. This suggests that, in vivo, CXCR3 may act as a decoy receptor, sequestering locally produced CCL11. We also demonstrate that the CXCR3 ligands inhibit CCR3-mediated functional responses of both human eosinophils and CCR3 transfectants induced by all three eotaxins, with CXCL11 being the most efficacious antagonist. The examination of CCR3-CCR1 chimeric constructs revealed that CCL11 and CXCL11 share overlapping binding sites contained within the CCR3 extracellular loops, a region that was previously shown to be essential for effective receptor-activation. Hence, eosinophil responses mediated by chemokines acting at CCR3 may be regulated by two distinct mechanisms: the antagonistic effects of CXCR3 ligands and the sequestration of CCL11 by CXCR3-expressing cells. Such interplay may serve to finely tune inflammatory responses in vivo.
Arne Egesten - One of the best experts on this subject based on the ideXlab platform.
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Eotaxin-3 exerts innate host defense activities that are modulated by mast cell proteases
5.3 Allergy and Immunology, 2015Co-Authors: Anele Gela, James E. Pease, Gopinath Kasetty, Sandra Jovic, Maria Ekoff, Gunnar Nilsson, Sven Kjellström, Arne EgestenAbstract:During bacterial infections of the airways, a Th1-profiled inflammation promotes the production of several host defense proteins and peptides with antibacterial activities. These are downregulated by Th2 cytokines of the allergic response. Instead, the eosinophil-recruiting chemokines eotaxin-1/CCL11, eotaxin-2/CCL24, and eotaxin-3/CCL26 are expressed. This study set out to investigate whether these chemokines could serve as innate host defense molecules during allergic inflammation. Antibacterial activities of the eotaxins were investigated using viable count assays and methods assessing bacterial permeabilization. CCL11, CCL24, and CCL26 all showed potent bactericidal activity, mediated through membrane disruption, against the airway pathogens. CCL26 retained bactericidal activity in the presence of salt at physiologic concentrations, and the region holding the highest bactericidal activity was the cationic and amphipathic COOH-terminus. Proteolysis of CCL26 by chymase and tryptase, respectively, released distinct fragments of the COOH- and NH2-terminal regions. The COOH-terminal fragment retained antibacterial activity while the NH2-terminal had potent LPS-neutralizing properties in the order of CCL26 full-length protein. An identical fragment to NH2-terminal fragment generated by tryptase was obtained after incubation with supernatants from activated mast cells. Taken together, the findings show that the eotaxins can contribute to host defense against common airway pathogens and that their activities are modulated by mast cell proteases.
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Eotaxin-3 (CCL26) exerts innate host defense activities that are modulated by mast cell proteases.
Allergy, 2015Co-Authors: Anele Gela, Matthias Morgelin, James E. Pease, Gopinath Kasetty, Sandra Jovic, Maria Ekoff, Gunnar Nilsson, Sven Kjellström, Artur Schmidtchen, Arne EgestenAbstract:BackgroundDuring bacterial infections of the airways, a Th1-profiled inflammation promotes the production of several host defense proteins and peptides with antibacterial activities including -defensins, ELR-negative CXC chemokines, and the cathelicidin LL-37. These are downregulated by Th2 cytokines of the allergic response. Instead, the eosinophil-recruiting chemokines eotaxin-1/CCL11, eotaxin-2/CCL24, and eotaxin-3/CCL26 are expressed. This study set out to investigate whether these chemokines could serve as innate host defense molecules during allergic inflammation. MethodsAntibacterial activities of the eotaxins were investigated using viable count assays, electron microscopy, and methods assessing bacterial permeabilization. Fragments generated by mast cell proteases were characterized, and their potential antibacterial, receptor-activating, and lipopolysaccharide-neutralizing activities were investigated. ResultsCCL11, CCL24, and CCL26 all showed potent bactericidal activity, mediated through membrane disruption, against the airway pathogens Streptococcus pneumoniae, Staphylococcus aureus, Nontypeable Haemophilus influenzae, and Pseudomonas aeruginosa. CCL26 retained bactericidal activity in the presence of salt at physiologic concentrations, and the region holding the highest bactericidal activity was the cationic and amphipathic COOH-terminus. Proteolysis of CCL26 by chymase and tryptase, respectively, released distinct fragments of the COOH- and NH2-terminal regions. The COOH-terminal fragment retained antibacterial activity while the NH2-terminal had potent LPS-neutralizing properties in the order of CCL26 full-length protein. An identical fragment to NH2-terminal fragment generated by tryptase was obtained after incubation with supernatants from activated mast cells. None of the fragments activated the CCR3-receptor. ConclusionsTaken together, the findings show that the eotaxins can contribute to host defense against common airway pathogens and that their activities are modulated by mast cell proteases. (Less)
Claire Loiseau - One of the best experts on this subject based on the ideXlab platform.
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th22 cells are efficiently recruited in the gut by ccl28 as an alternative to ccl20 but do not compensate for the loss of th17 cells in treated hiv 1 infected individuals
Mucosal Immunology, 2020Co-Authors: Manon Nayrac, Mary Requena, Claire Loiseau, Michelle Cazabat, Bertrand Suc, Nicolas Carrere, Karl Barange, Laurent Alric, Guillaume MartinblondelAbstract:Gut CD4+ T cells are incompletely restored in most HIV-1-infected individuals on antiretroviral therapy, notably Th17 cells, a key subset in mucosal homeostasis. By contrast, gut Th22 cells are usually restored at normal frequencies. Th22 cells display a CCR6+CCR10+ phenotype and could thus respond to CCL20- and CCL28-mediated chemotaxis, while Th17 cells, which express CCR6 but not CCR10, depend on CCL20. Herein, we found that CCL28 is normally expressed by duodenal enterocytes of treated HIV-1-infected individuals, while CCL20 expression is blunted. Ex vivo, we showed that Th22 cells contribute to the reduction of CCL20 production by enterocytes through an IL-22- and IL-18-dependent mechanism. Th22 cells preferentially migrate via CCL20- rather than CCL28-mediated chemotaxis when both chemokines are available in the microenvironment. However, when the CCL20/CCL28 ratio drops, as in treated HIV-1-infected individuals, Th22 cells can migrate via the CCR10–CCL28 axis, as an alternative to CCR6–CCL20. This could explain the better reconstitution of gut Th22 compared with Th17 cells on antiretroviral therapy. Lastly, we assessed the relationships between the frequencies of gut Th17 and Th22 cells and inflammatory markers related to microbial translocation, and showed that Th22 cells do not compensate for the loss of Th17 cells in treated HIV-1-infected individuals.
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increased cxcr3 t cells impairs recruitment of t helper type 17 cells via interferon γ and interleukin 18 in the small intestine mucosa during treated hiv 1 infection
The Journal of Infectious Diseases, 2019Co-Authors: Manon Nayrac, Mary Requena, Claire Loiseau, Michelle Cazabat, Nicolas Carrere, Laurent Alric, Maud Mavigner, A L Iscache, Jacques IzopetAbstract:The restoration of CD4+ T cells, especially T-helper type 17 (Th17) cells, remains incomplete in the gut mucosa of most human immunodeficiency virus type 1 (HIV-1)–infected individuals despite sustained antiretroviral therapy (ART). Herein, we report an increase in the absolute number of CXCR3+ T cells in the duodenal mucosa during ART. The frequencies of Th1 and CXCR3+ CD8+ T cells were increased and negatively correlated with CCL20 and CCL25 expression in the mucosa. In ex vivo analyses, we showed that interferon γ, the main cytokine produced by Th1 and effector CD8+ T cells, downregulates the expression of CCL20 and CCL25 by small intestine enterocytes, while it increases the expression of CXCL9/10/11, the ligands of CXCR3. Interleukin 18, a pro-Th1 cytokine produced by enterocytes, also contributes to the downregulation of CCL20 expression and increases interferon γ production by Th1 cells. This could perpetuate an amplification loop for CXCR3-driven Th1 and effector CD8+ T cells recruitment to the gut, while impairing Th17 cells homing through the CCR6-CCL20 axis in treated HIV-1–infected individuals.
Satoshi Kimura - One of the best experts on this subject based on the ideXlab platform.
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CCL22 macrophage derived chemokine expression in apolipoprotein e deficient mice and effects of histamine in the setting of atherosclerosis
Journal of Atherosclerosis and Thrombosis, 2015Co-Authors: Satoshi Kimura, Ke-yong Wang, Xin Guo, Sohsuke Yamada, Atsunori Nabeshima, Hirotsugu Noguchi, Takeshi Watanabe, Masaru Harada, Yasuyuki SasaguriAbstract:Aim Macrophage-derived chemokine (CCL22) is a member of the CC-family of chemokines synthesized by monocyte-derived macrophages. Previous studies have reported a relationship between CCL22 and atherosclerosis and the role of histamine in this pathway. Histamine ncreases the CCL22 expression in human monocytes via the H2 receptor. In this study, we investigated the effects of CCL22 and the role of histamine in mouse monocytes with respect to atherosclerosis. Methods and results The expression of CCL22 was investigated in apolipoprotein E (apoE)-deficient mice. The mice had high serum concentrations of CCL22 and their atherosclerotic lesions contained abundant levels of CCL22. In addition, when the mouse monocyte cell line (J774A.1 cells) differentiated into macrophage-like cells, the cells showed a similar expression of CCL22 and reduced expression of H2 receptors. Histamine is synthesized from l-histidine by histidine decarboxylase (HDC) in a single enzymatic step. HDC knockout mice were compared with apoE/HDC double knockout mice. The findings indicated that the expression of CCL22 in atherosclerosis models is under the influence of histamine. In addition, in vitro studies using J774A.1 cells and an in vivo study using histamine receptor knockout mice showed that histamine stimulates the CCL22 expression via the histamine H2 receptor. Conclusions The current results support our previous CCL22 studies in the setting of human atherosclerosis and suggest that this molecule is involved in the atherogenic processes in a mouse model of atherosclerosis.
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Abstract 153: CCL22/ Macrophage-derived Chemokine Expression in the Setting of Atherosclerosis
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Satoshi Kimura, Ke-yong Wang, Sohsuke Yamada, Toshiyuki Nakayama, Yutaka OtsujiAbstract:Introduction: CCL22 (macrophage-derived chemokine) is a member of the CC-family of chemokines. The functional role of CCL22 as a chemokine involves migration/ recruitment of monocytes and the stimulation of platelet activity. In this study, we investigated the relationship between CCL22 and atherosclerosis in monocytes/ macrophages of mice and humans with respect to atherosclerosis. Hypothesis: We assessed the hypothesis that CCL22 is involved in the process of atherosclerosis and can be a biological marker for progression of atherosclerosis and atherosclerotic disease. Methods: Apolipoprotein E deficient (apoE-/-) mice as atherosclerotic models were used for this study. Male apoE-/- mice were weaned at 8 weeks of age onto a high-cholesterol diet consisting of 1.25% cholesterol and were maintained on this diet for 12 weeks or 24 weeks. Another group of apoE-/- mice was maintained for 30 weeks on a normal chow diet. Serum CCL22 concentrations were measured by ELISA and expression of CCL22 mRNA in the atheroma were evaluated by real-time PCR. Furthermore immunohistochemical staining was performed. In vitro, the expressions of CCL22 in the mouse monocytes and macrophages were examined and discussed. The expression of CCL22 human monocytes/ macrophages and human atherosclerotic lesions were similarly investigated. Results: ApoE-/- mice had predominately high concentrations of CCL22 compared with wild-type (C57BL/6J) mice. ApoE-/- mice developed atherosclerotic lesions with aging and this was influenced by a high-cholesterol diet. CCL22 concentrations increased with aging and a high-cholesterol diet. Their atherosclerotic lesions, especially in macrophages contained abundant levels of CCL22. When the mouse monocyte differentiated into macrophage, the cells showed similar expression of CCL22. Similarly, human macrophages also expressed abundant levels of CCL22 more than monocytes. In addition, immunohistochemical analysis of human atherosclerotic lesions and coronary stenotic lesion revealed that macrophages express CCL22. Conclusion: In conclusion, these results suggested that this molecule is involved in the atherogenic processes and CCL22 may represent an attractive molecular marker for progression of atherosclerosis.
Anele Gela - One of the best experts on this subject based on the ideXlab platform.
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Eotaxin-3 exerts innate host defense activities that are modulated by mast cell proteases
5.3 Allergy and Immunology, 2015Co-Authors: Anele Gela, James E. Pease, Gopinath Kasetty, Sandra Jovic, Maria Ekoff, Gunnar Nilsson, Sven Kjellström, Arne EgestenAbstract:During bacterial infections of the airways, a Th1-profiled inflammation promotes the production of several host defense proteins and peptides with antibacterial activities. These are downregulated by Th2 cytokines of the allergic response. Instead, the eosinophil-recruiting chemokines eotaxin-1/CCL11, eotaxin-2/CCL24, and eotaxin-3/CCL26 are expressed. This study set out to investigate whether these chemokines could serve as innate host defense molecules during allergic inflammation. Antibacterial activities of the eotaxins were investigated using viable count assays and methods assessing bacterial permeabilization. CCL11, CCL24, and CCL26 all showed potent bactericidal activity, mediated through membrane disruption, against the airway pathogens. CCL26 retained bactericidal activity in the presence of salt at physiologic concentrations, and the region holding the highest bactericidal activity was the cationic and amphipathic COOH-terminus. Proteolysis of CCL26 by chymase and tryptase, respectively, released distinct fragments of the COOH- and NH2-terminal regions. The COOH-terminal fragment retained antibacterial activity while the NH2-terminal had potent LPS-neutralizing properties in the order of CCL26 full-length protein. An identical fragment to NH2-terminal fragment generated by tryptase was obtained after incubation with supernatants from activated mast cells. Taken together, the findings show that the eotaxins can contribute to host defense against common airway pathogens and that their activities are modulated by mast cell proteases.
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Eotaxin-3 (CCL26) exerts innate host defense activities that are modulated by mast cell proteases.
Allergy, 2015Co-Authors: Anele Gela, Matthias Morgelin, James E. Pease, Gopinath Kasetty, Sandra Jovic, Maria Ekoff, Gunnar Nilsson, Sven Kjellström, Artur Schmidtchen, Arne EgestenAbstract:BackgroundDuring bacterial infections of the airways, a Th1-profiled inflammation promotes the production of several host defense proteins and peptides with antibacterial activities including -defensins, ELR-negative CXC chemokines, and the cathelicidin LL-37. These are downregulated by Th2 cytokines of the allergic response. Instead, the eosinophil-recruiting chemokines eotaxin-1/CCL11, eotaxin-2/CCL24, and eotaxin-3/CCL26 are expressed. This study set out to investigate whether these chemokines could serve as innate host defense molecules during allergic inflammation. MethodsAntibacterial activities of the eotaxins were investigated using viable count assays, electron microscopy, and methods assessing bacterial permeabilization. Fragments generated by mast cell proteases were characterized, and their potential antibacterial, receptor-activating, and lipopolysaccharide-neutralizing activities were investigated. ResultsCCL11, CCL24, and CCL26 all showed potent bactericidal activity, mediated through membrane disruption, against the airway pathogens Streptococcus pneumoniae, Staphylococcus aureus, Nontypeable Haemophilus influenzae, and Pseudomonas aeruginosa. CCL26 retained bactericidal activity in the presence of salt at physiologic concentrations, and the region holding the highest bactericidal activity was the cationic and amphipathic COOH-terminus. Proteolysis of CCL26 by chymase and tryptase, respectively, released distinct fragments of the COOH- and NH2-terminal regions. The COOH-terminal fragment retained antibacterial activity while the NH2-terminal had potent LPS-neutralizing properties in the order of CCL26 full-length protein. An identical fragment to NH2-terminal fragment generated by tryptase was obtained after incubation with supernatants from activated mast cells. None of the fragments activated the CCR3-receptor. ConclusionsTaken together, the findings show that the eotaxins can contribute to host defense against common airway pathogens and that their activities are modulated by mast cell proteases. (Less)