TLR2-dependent eosinophil interactions with mycobacteria: role of alpha-defensins.

Peripheral blood and tissue eosinophilia are a prominent feature in allergic diseases and during helminth infections. Eosinophil recruitment also frequently occurs upon mycobacterial infections, particularly in lung granuloma. However, the mechanism by which eosinophils interact with mycobacteria remains largely unknown. Because eosinophils recently have been shown to be involved in innate immune responses, we investigated the direct interactions of eosinophils with Mycobacterium bovis BCG as a study model. We show that live BCG attracts human eosinophils and induces reactive oxygen species (ROS) synthesis, granule protein release, and tumor necrosis factor (TNF)-alpha secretion. Using anti-TLR2 neutralizing antibodies before exposure of eosinophils to BCG, we showed a critical role of TLR2 signaling in ROS and eosinophil peroxidase release. BCG-induced eosinophil activation is mediated through the p38 mitogen-activated protein (MAP) kinase and nuclear factor (NF)-kappaB pathways. In addition, a mycobacterial wall component, lipomannan, induced a TLR2-dependent eosinophil activation. In addition, we showed that eosinophils express and produce alpha-defensins upon stimulation with BCG and lipomannan and that alpha-defensins could inhibit mycobacterial growth in synergy with eosinophil cationic protein. These results suggest a role for human eosinophils as direct effectors in TLR2-mediated innate immunity against mycobacteria and confer to these cells potent cytotoxic functions through defensin and eosinophil cationic protein production.

[1]  Susanna Navarro,et al.  Eosinophil cationic protein high-affinity binding to bacteria-wall lipopolysaccharides and peptidoglycans. , 2008, Biochemistry.

[2]  R. Tapping,et al.  Microbial Products Stimulate Human Toll-like Receptor 2 Expression through Histone Modification Surrounding a Proximal NF-κB-binding Site* , 2007, Journal of Biological Chemistry.

[3]  A. Menendez,et al.  Defensins in the immunology of bacterial infections. , 2007, Current opinion in immunology.

[4]  C. Parish,et al.  Th2-mediated anti-tumour immunity: friend or foe? , 2007, Tissue antigens.

[5]  G. Rook.  Th2 cytokines in susceptibility to tuberculosis. , 2007, Current molecular medicine.

[6]  Chul Hee Choi,et al.  Intracellular signalling cascades regulating innate immune responses to Mycobacteria: branching out from Toll‐like receptors , 2007, Cellular microbiology.

[7]  B. Ryffel,et al.  Tumor necrosis factor is critical to control tuberculosis infection. , 2007, Microbes and infection.

[8]  C. Wong,et al.  Intracellular signaling mechanisms regulating toll-like receptor-mediated activation of eosinophils. , 2007, American journal of respiratory cell and molecular biology.

[9]  H. Castro-Faria-Neto,et al.  Toll-Like Receptor-2-Mediated C-C Chemokine Receptor 3 and Eotaxin-Driven Eosinophil Influx Induced by Mycobacterium bovis BCG Pleurisy , 2006, Infection and Immunity.

[10]  Z. Toossi,et al.  Intestinal helminth co‐infection has a negative impact on both anti‐Mycobacterium tuberculosis immunity and clinical response to tuberculosis therapy , 2006, Clinical and experimental immunology.

[11]  M. Yadav,et al.  The beta-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. , 2006, Blood.

[12]  H. Weighardt,et al.  Toll-like receptor 9 contributes to recognition of Mycobacterium bovis Bacillus Calmette-Guérin by Flt3-ligand generated dendritic cells. , 2006, Immunobiology.

[13]  I. Orme,et al.  Pulmonary Lymphatics Are Primary Sites of Mycobacterium tuberculosis Infection in Guinea Pigs Infected by Aerosol , 2006, Infection and Immunity.

[14]  L. O’Neill,et al.  How Toll-like receptors signal: what we know and what we don't know. , 2006, Current opinion in immunology.

[15]  B. Ryffel,et al.  Innate immunity to mycobacterial infection in mice: critical role for toll-like receptors. , 2005, Tuberculosis.

[16]  P. Salgame.  Host innate and Th1 responses and the bacterial factors that control Mycobacterium tuberculosis infection. , 2005, Current opinion in immunology.

[17]  C. Wennerås,et al.  Human eosinophils selectively recognize and become activated by bacteria belonging to different taxonomic groups. , 2005, Microbes and infection.

[18]  B. Ryffel,et al.  Toll-like receptor pathways in the immune responses to mycobacteria. , 2004, Microbes and infection.

[19]  G. Besra,et al.  Mycobacterial lipoarabinomannan and related lipoglycans: from biogenesis to modulation of the immune response , 2004, Molecular microbiology.

[20]  I. Orme,et al.  Rapid Accumulation of Eosinophils in Lung Lesions in Guinea Pigs Infected with Mycobacterium tuberculosis , 2004, Infection and Immunity.

[21]  K. Ohta,et al.  Expression and Function of Toll-Like Receptors in Eosinophils: Activation by Toll-Like Receptor 7 Ligand 1 , 2003, The Journal of Immunology.

[22]  Yun Feng,et al.  Mycobacterium bovis bacille Calmette-Guérin (BCG) enhances human beta-defensin-1 gene transcription in human pulmonary gland epithelial cells. , 2003, Acta pharmacologica Sinica.

[23]  A. González-Arenas,et al.  Macrophage--Mycobacterium tuberculosis interactions: role of complement receptor 3. , 2003, Microbial pathogenesis.

[24]  L. Kremer,et al.  Lipomannans, But Not Lipoarabinomannans, Purified from Mycobacterium chelonae and Mycobacterium kansasii Induce TNF-α and IL-8 Secretion by a CD14-Toll-Like Receptor 2-Dependent Mechanism1 , 2003, The Journal of Immunology.

[25]  N. French,et al.  Eosinophilia and progression to active tuberculosis in HIV-1-infected Ugandans. , 2003, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[26]  E. Banfi,et al.  Human Eosinophil Peroxidase Induces Surface Alteration, Killing, and Lysis of Mycobacterium tuberculosis , 2003, Infection and Immunity.

[27]  I. Orme,et al.  Immunopathogenesis of Pulmonary Granulomas in the Guinea Pig after Infection with Mycobacterium tuberculosis , 2003, Infection and Immunity.

[28]  C. Locht,et al.  Structural study of lipomannan and lipoarabinomannan from Mycobacterium chelonae. Presence of unusual components with alpha 1,3-mannopyranose side chains. , 2002, The Journal of biological chemistry.

[29]  K. Kisich,et al.  Tumor Necrosis Factor Alpha Stimulates Killing of Mycobacterium tuberculosis by Human Neutrophils , 2002, Infection and Immunity.

[30]  S. Dower,et al.  Toll-Like Receptor (TLR)2 and TLR4 in Human Peripheral Blood Granulocytes: A Critical Role for Monocytes in Leukocyte Lipopolysaccharide Responses1 , 2002, The Journal of Immunology.

[31]  W. Busse,et al.  CD14(+) cells are necessary for increased survival of eosinophils in response to lipopolysaccharide. , 2000, American journal of respiratory cell and molecular biology.

[32]  Gilla Kaplan,et al.  Immunopathologic Effects of Tumor Necrosis Factor Alpha in Murine Mycobacterial Infection Are Dose Dependent , 2000, Infection and Immunity.

[33]  G. Khuller,et al.  Antibacterial activity of human neutrophil peptide-1 against Mycobacterium tuberculosis H37Rv: in vitro and ex vivo study. , 2000, The European respiratory journal.

[34]  B. Delahunt,et al.  Role of Eosinophils in the Pathogenesis ofMycobacterium bovis BCG Infection in Gamma Interferon Receptor-Deficient Mice , 2000, Infection and Immunity.

[35]  A. Capron,et al.  Expression of Cd28 and Cd86 by Human Eosinophils and Role in the Secretion of Type 1 Cytokines (Interleukin 2 and Interferon γ) , 1999, The Journal of experimental medicine.

[36]  E. Werneck-Barroso,et al.  Effects of inhibitors of inflammatory mediators and cytokines on eosinophil and neutrophil accumulation induced by Mycobacterium bovis bacillus Calmette‐Guérinin mouse pleurisy , 1997, Journal of leukocyte biology.

[37]  Kobayashi,et al.  The Immunopathogenesis of Granulomatous Inflammation Induced by Mycobacterium tuberculosis , 1996, Methods.

[38]  S. Durham,et al.  Kinetics of cell infiltration and cytokine messenger RNA expression after intradermal challenge with allergen and tuberculin in the same atopic individuals. , 1994, The Journal of allergy and clinical immunology.

[39]  L. Bermudez,et al.  Tumor necrosis factor alpha stimulates mycobactericidal/mycobacteriostatic activity in human macrophages by a protein kinase C-independent pathway. , 1992, Cellular immunology.

[40]  R. Prabhakar,et al.  Pulmonary eosinophilia in pulmonary tuberculosis. , 1992, Chest.

[41]  A. Águas,et al.  Live but not heat-killed mycobacteria cause rapid chemotaxis of large numbers of eosinophils in vivo and are ingested by the attracted granulocytes , 1991, Infection and immunity.

[42]  V. Kindler,et al.  The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection , 1989, Cell.

[43]  M. Yazdanbakhsh,et al.  Synergism between eosinophil cationic protein and oxygen metabolites in killing of schistosomula of Schistosoma mansoni. , 1987, Journal of immunology.

[44]  M. Capron,et al.  Innate immune function of eosinophils: from antiparasite to antitumor cells. , 2008, Methods in molecular biology.

[45]  M. Lotze,et al.  Eosinophilic granulocytes and damage-associated molecular pattern molecules (DAMPs): role in the inflammatory response within tumors. , 2007, Journal of immunotherapy.

[46]  E. Miranda,et al.  Mycobacterium bovis Bacillus Calmette-Guérin (BCG) stimulates human beta-defensin-2 gene transcription in human epithelial cells. , 2006, Cellular immunology.

[47]  J. Ring,et al.  The interaction of human peripheral blood eosinophils with bacterial lipopolysaccharide is CD14 dependent. , 2001, Blood.

[48]  D. Dombrowicz,et al.  IgE receptors on human eosinophils. , 2000, Chemical immunology.

[49]  G. Gleich,et al.  The eosinophilic leukocyte: structure and function. , 1986, Advances in immunology.

[50]  C. Aquirre,et al.  Late generalized tuberculosis and eosinophilia. , 1983, Archives of internal medicine.