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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)
Shinji Kagami - One of the best experts on this subject based on the ideXlab platform.
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association of nerve growth factor chemokine c c motif ligands and immunoglobulin e with pruritus in cutaneous t cell lymphoma
Acta Dermato-venereologica, 2013Co-Authors: Hiraku Suga, Hideki Fujita, Shinji Kagami, Makoto Sugaya, Tomomitsu Miyagaki, Hanako Ohmatsu, Yoshihide Asano, Yayoi Tada, Takafumi Kadono, Shinichi SatoAbstract:Many patients with cutaneous T-cell lymphoma (CTCL) experience severe pruritus. This study evaluated serum levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in patients with CTCL. Although serum NGF and BDNF levels in patients with CTCL were not significantly higher than in healthy controls, serum NGF levels in patients with Sezary syndrome were higher than in those with mycosis fungoides and in healthy controls. Enhanced NGF expression by keratinocytes and increased dermal nerve fibres were detected in lesional skin of subjects with Sezary syndrome. Correlations between pruritus in CTCL and serum levels of NGF, BDNF, chemokine (C-C motif) ligand 1 (CCL1), CCL17, CCL26, CCL27, lactate dehydrogenase (LDH), IgE, and soluble interleukin-2 receptor were analysed. Serum CCL1, CCL26, LDH, and IgE levels correlated with pruritus in patients with CTCL. NGF may be associated with increased dermal nerve fibres and pruritus in Sezary syndrome, and CCL1, CCL26, and IgE may be associated with pruritus in CTCL.
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CCL28 production in HaCaT cells was mediated by different signal pathways from CCL27
Experimental dermatology, 2006Co-Authors: Shinji Kagami, Mayumi Komine, Yuichiro Tsunemi, Hidehisa Saeki, Takashi Kakinuma, Koichiro Nakamura, K. Sasaki, Akihiko Asahina, Kunihiko TamakiAbstract:Both CCL27 and CCL28 are ligands for CCR10 and attract CCR10(+) lymphocytes. We previously demonstrated that CCL27 and CCL28 were strongly expressed in sera and lesional keratinocytes of patients with atopic dermatitis and psoriasis vulgaris. However, the regulation of CCL27 and CCL28 production in keratinocytes has not been well documented. In this study, we showed that CCL27 and CCL28 expression and production by a human keratinocyte cell line, HaCaT cells, were strongly induced by inflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta. CCL27 production was downregulated by inhibitors of p38 mitogen-activated protein kinase and nuclear factor-kappa B (NF-kappaB). By contrast, CCL28 production was downregulated by inhibitors of extracellular signal-regulated kinase and NF-kappaB. Our study results suggest that CCL28 produced by keratinocytes is mediated by different signal pathways from CCL27 and that both CCL27 and CCL28 are involved in the pathogenesis of inflammatory skin diseases.
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significant elevation of serum levels of eotaxin 3 CCL26 but not of eotaxin 2 ccl24 in patients with atopic dermatitis serum eotaxin 3 CCL26 levels reflect the disease activity of atopic dermatitis
Clinical and Experimental Immunology, 2003Co-Authors: Shinji Kagami, Yuichiro Tsunemi, Tomonori Takekoshi, Megumi Kishimoto, Hidehisa Saeki, Hiroshi Mitsui, Takashi Kakinuma, Hideki Fujita, Koichiro Nakamura, Hideshi ToriiAbstract:Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease characterized by the predominant infiltration of T cells, eosinophils and macrophages in lesional skin. Recently, eotaxin-2/CCL24 and eotaxin-3/CCL26 were identified as CC chemokines that signal exclusively via the CCR3 receptor and have eosinophil-selective chemoattractant activity, as does eotaxin/CCL11. We previously reported that serum levels of thymus and activation-regulated chemokine (TARC)/CCL17 and macrophage-derived chemokine (MDC)/CCL22 were correlated with the severity of AD. In this report, we investigated the participation of eotaxin-2/CCL24 and eotaxin-3/CCL26 in AD, first measuring the serum levels of eotaxin-2/CCL24 and eotaxin-3/CCL26 in 30 patients with AD, 20 patients with psoriasis vulgaris and 20 healthy controls. The serum levels of eotaxin-3/CCL26 (but not eotaxin-2/CCL24) were significantly higher in patients with AD than in either healthy controls or patients with psoriasis vulgaris; furthermore, the eotaxin-3/CCL26 levels in patients with moderate and severe AD were significantly higher than eotaxin-3/CCL26 levels in patients with mild AD. The serum eotaxin-3/CCL26 levels tended to decrease after treatment, but there was no significant difference between groups. Moreover, the serum eotaxin-3/CCL26 levels were significantly correlated with the serum TARC/CCL17 and MDC/CCL22 levels, eosinophil numbers in peripheral blood and the scoring AD (SCORAD) index. Our study strongly suggests that serum levels of eotaxin-3/CCL26, but not of eotaxin-2/CCL24, have a notable correlation with disease activity of AD and that eotaxin-3/CCL26, as well as TARC/CCL17 and MDC/CCL22, may be involved in the pathogenesis of AD.
Vito Pistoia - One of the best experts on this subject based on the ideXlab platform.
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chemotaxis of human tonsil b lymphocytes to cc chemokine receptor ccr 1 ccr2 and ccr4 ligands is restricted to non germinal center cells
International Immunology, 2002Co-Authors: Anna Corcione, Giuseppe Tortolina, Nicoletta Battilana, Franco Dallegri, Luciano Ottonello, Raffaella Bonecchi, Fabio Malavasi, Silvano Sozzani, Giuseppe Taborelli, Vito PistoiaAbstract:We have investigated the effects of nine CC chemokines, i.e. macrophage inflammatory protein (MIP)-1a/CCL3, MIP-1b/CCL4, MIP-3a/CCL20, MIP-5/CCL15, monocyte chemotactic protein (MCP)1/CCL2, MCP-2/CCL8, MCP-3/CCL7, eotaxin/CCL11 and macrophage-derived chemokine (MDC)/ CCL22 on the locomotion of human tonsil B lymphocytes and their subsets. Upon isolation, B cells were poorly responsive, but, following short-term culture, they displayed statistically significant chemotactic responses (P < 0.001) to MIP-1a, MIP-5, MCP-1, MCP-2, MCP-3 and MDC. CC chemokine receptor (CCR) 1 to CCR6 were up-regulated after culture. MIP-1b, MIP-3a and eotaxin did not stimulate B cell migration. Scattered information is available on B cell subset responses to chemokines. Therefore, we investigated the effects of MIP-1a, MIP-5, MCP1, MCP-2, MCP-3 and MDC on the in vitro locomotion of non-germinal center (GC) (CD38 ‐ ) and GC (CD38 + ) B cells. All chemokines enhanced significantly (P < 0.001) the migration of the former, but not of the latter, cells. CCR1, CCR2 and CCR4 were detected by flow cytometry on non-GC (i.e. naive and memory) B cells, whereas they were absent (CCR1 and CCR2) or poorly expressed (CCR4) on GC B cells.
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chemotaxis of human tonsil b lymphocytes to cc chemokine receptor ccr 1 ccr2 and ccr4 ligands is restricted to non germinal center cells
International Immunology, 2002Co-Authors: Anna Corcione, Giuseppe Tortolina, Nicoletta Battilana, Franco Dallegri, Luciano Ottonello, Raffaella Bonecchi, Fabio Malavasi, Silvano Sozzani, Giuseppe Taborelli, Vito PistoiaAbstract:We have investigated the effects of nine CC chemokines, i.e. macrophage inflammatory protein (MIP)-1alpha/CCL3, MIP-1beta/CCL4, MIP-3alpha/CCL20, MIP-5/CCL15, monocyte chemotactic protein (MCP)-1/CCL2, MCP-2/CCL8, MCP-3/CCL7, eotaxin/CCL11 and macrophage-derived chemokine (MDC)/CCL22 on the locomotion of human tonsil B lymphocytes and their subsets. Upon isolation, B cells were poorly responsive, but, following short-term culture, they displayed statistically significant chemotactic responses (P < 0.001) to MIP-1alpha, MIP-5, MCP-1, MCP-2, MCP-3 and MDC. CC chemokine receptor (CCR) 1 to CCR6 were up-regulated after culture. MIP-1beta, MIP-3alpha and eotaxin did not stimulate B cell migration. Scattered information is available on B cell subset responses to chemokines. Therefore, we investigated the effects of MIP-1alpha, MIP-5, MCP-1, MCP-2, MCP-3 and MDC on the in vitro locomotion of non-germinal center (GC) (CD38(-)) and GC (CD38(+)) B cells. All chemokines enhanced significantly (P < 0.001) the migration of the former, but not of the latter, cells. CCR1, CCR2 and CCR4 were detected by flow cytometry on non-GC (i.e. naive and memory) B cells, whereas they were absent (CCR1 and CCR2) or poorly expressed (CCR4) on GC B cells.
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.