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1.
Front Immunol ; 10: 417, 2019.
Article in English | MEDLINE | ID: mdl-30915076

ABSTRACT

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) is one of the most prevalent lung infections of humans and kills ~1.7 million people each year. TB pathophysiology is complex with a central role played by granuloma where a delicate balance takes place to both constrain bacilli and prevent excessive inflammation that may destroy lung functions. Neutrophils reach the lung in waves following first encounter with bacilli and contribute both to early Mtb elimination and late deleterious inflammation. The hypoxic milieu where cells and bacilli cohabit inside the granuloma favors metabolism changes and the impact on TB infection needs to be more thoroughly understood. At the cellular level while the key role of the alveolar macrophage has long been established, behavior of neutrophils in the hypoxic granuloma remains poorly explored. This review will bring to the front new questions that are now emerging regarding neutrophils activity in TB. Are different neutrophil subsets involved in Mtb infection and how? How do neutrophils and close relatives contribute to shaping the granuloma immune environment? What is the role of hypoxia and hypoxia induced factors inside granuloma on neutrophil fate and functions and TB pathophysiology? Addressing these questions is key to the development of innovative host-directed therapies to fight TB.


Subject(s)
Cell Hypoxia/immunology , Granuloma, Respiratory Tract/immunology , Granuloma, Respiratory Tract/microbiology , Mycobacterium tuberculosis/immunology , Neutrophils/immunology , Tuberculosis, Pulmonary/epidemiology , Tuberculosis, Pulmonary/immunology , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Host-Pathogen Interactions/immunology , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Molecular Targeted Therapy/methods , Prevalence , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/microbiology
2.
Vet Res ; 48(1): 73, 2017 11 07.
Article in English | MEDLINE | ID: mdl-29116026

ABSTRACT

Achieving the control of bovine tuberculosis (bTB) would require the discovery of an efficient combined immunodiagnostic and vaccine strategy. Since in vivo experiments on cattle are not ethically and economically acceptable there is a need for a cost-effective animal model capable of reproducing, as closely as possible, the physiopathology of bTB to (i) better characterize the cellular and molecular features of bTB immunopathogenesis and (ii) screen preclinical vaccine candidates. To develop such a model, we focused on the C3HeB/FeJ Kramnik's mouse forming hypoxic, encapsulated granulomas with a caseous necrotic center following Mycobacterium tuberculosis infection. Our work represents the first investigation on C3HeB/FeJ interaction with M. bovis, the main agent of bTB. Detailed histopathological analysis of C3HeB/FeJ lung lesions development following aerogenous M. bovis infection unraveled a bimodal evolution of the pathology. The C3HeB/FeJ recapitulated all the hallmarks of classical bovine lung granulomas but also developed, to some extend, lethal necrotic large lesions characterized by high mycobacterial and neutrophil load, and an inefficient collagen-driven lesion encapsulation. Interestingly these rapidly invasive pneumonia lesions, occurring in a constant percentage of the mice, shared all features with some exacerbated lung lesions that we and others have observed in lungs of cattle naturally or experimentally infected with M. bovis. Together, our findings demonstrate the relevance of the C3HeB/FeJ mouse as a comprehensive model to study bTB immunopathology that could be used for further vaccine therapies in the future.


Subject(s)
Lung/pathology , Mycobacterium bovis/physiology , Tuberculosis, Bovine/pathology , Animals , Cattle , Disease Models, Animal , Granuloma/microbiology , Granuloma/pathology , Lung/microbiology , Mice , Mice, Inbred Strains , Tuberculosis, Bovine/microbiology , Tuberculosis, Bovine/physiopathology
3.
PLoS One ; 11(2): e0149455, 2016.
Article in English | MEDLINE | ID: mdl-26871571

ABSTRACT

During chronic infection with Mycobacterium tuberculosis (Mtb), bacilli multiplication is constrained within lung granulomas until excessive inflammation destroys the lung. Neutrophils are recruited early and participate in granuloma formation, but excessive neutrophilia exacerbates the tuberculosis disease. Neutrophils thus appear as potential targets for therapeutic interventions, especially in patients for whom no antibiotic treatment is possible. Signals that regulate neutrophil recruitment to the lung during mycobacterial infection need to be better understood. We demonstrated here, in the mouse model, that neutrophils were recruited to the lung in two waves after intranasal infection with virulent Mtb or the live attenuated vaccine strain Bacillus Calmette Guérin (BCG). A first wave of neutrophils was swiftly recruited, followed by a subsequent adaptive wave that reached the lung together with IFN-γ- and IL-17A-producing T cells. Interestingly, the second neutrophil wave did not participate to mycobacteria control in the lung and established contacts with T cells. The adaptive wave was critically dependent on the expression of IL-17RA, the receptor for IL-17A, expressed in non-hematopoietic cells. In absence of this receptor, curtailed CXCL-1 and 5 production in the lung restrained neutrophil recruitment. CXCL-1 and 5 instillation reconstituted lung neutrophil recruitment in BCG-infected IL17RA-/- mice.


Subject(s)
BCG Vaccine/immunology , Chemokine CXCL1/immunology , Chemokine CXCL5/immunology , Mycobacterium tuberculosis/immunology , Neutrophil Infiltration , Receptors, Interleukin-17/immunology , Tuberculosis, Pulmonary/immunology , Animals , Humans , Lung/cytology , Lung/immunology , Lung/microbiology , Male , Mice , Mice, Inbred C57BL , Neutrophils/immunology , Neutrophils/microbiology , Tuberculosis, Pulmonary/microbiology , Tuberculosis, Pulmonary/prevention & control
4.
J Immunol ; 191(7): 3818-26, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23997221

ABSTRACT

Neutrophils participate in the control of mycobacterial infection both by directly eliminating bacilli and by interacting with macrophages and dendritic cells (DCs). Despite host defenses, slow-growing mycobacteria can persist in the host for decades, mostly inside macrophages and DCs, and eventually destroy tissues after exacerbated inflammation. IL-17A-driven neutrophil recruitment may participate in this process. We report that mouse bone marrow-derived DCs infected with live Mycobacterium bovis Bacillus Calmette-Guérin (BCG) produced large amounts of CXCL1 and CXCL2, and attracted neutrophils. After physical contact with DCs infected with live BCG, the neutrophils produced large quantities of the immunosuppressive cytokine IL-10 via the MyD88 and spleen tyrosine kinase pathways. The CD11b integrin was involved in this neutrophil-DC interaction and allowed IL-10 production. TCR OVA transgenic mice immunized with a BCG strain producing OVA mounted an OVA-specific Th17 and Th1 CD4 response. Interestingly, IL-10-producing neutrophils specifically shut down IL-17A production by Th17 CD4 cells, but not IFN-γ production by Th1 cells. This was due to Th17 CD4 cell-restricted expression of the receptor for IL-10. After neutrophil depletion, total mouse lung cells produced less IL-10 but more IL-17A; IFN-γ production was not affected. Therefore, we suggest that during mycobacterial infection, regulatory neutrophils are instructed by infected reservoir DCs to produce IL-10 that specifically targets IL-10Rα-expressing Th17 CD4 T cells. This could be important to control the otherwise exuberant Th17 response.


Subject(s)
Dendritic Cells/immunology , Dendritic Cells/metabolism , Interleukin-10/biosynthesis , Neutrophils/immunology , Receptors, Interleukin-10/metabolism , Th17 Cells/immunology , Th17 Cells/microbiology , Animals , CD11b Antigen/metabolism , Dendritic Cells/microbiology , Female , Interleukin-17/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Transgenic , Models, Immunological , Mycobacterium bovis/immunology , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Neutrophils/metabolism , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Syk Kinase , Tuberculosis/veterinary
5.
J Biol Chem ; 284(35): 23187-96, 2009 Aug 28.
Article in English | MEDLINE | ID: mdl-19561082

ABSTRACT

Mycobacterium tuberculosis modulates host immune responses through proteins and complex glycolipids. Here, we report that the glycosylphosphatidylinositol anchor phosphatidyl-myo-inositol hexamannosides PIM(6) or PIM(2) exert potent anti-inflammatory activities. PIM strongly inhibited the Toll-like receptor (TLR4) and myeloid differentiation protein 88 (MyD88)-mediated release of NO, cytokines, and chemokines, including tumor necrosis factor (TNF), interleukin 12 (IL-12) p40, IL-6, keratinocyte-derived chemokine, and also IL-10 by lipopolysaccharide (LPS)-activated macrophages. This effect was independent of the presence of TLR2. PIM also reduced the LPS-induced MyD88-independent, TIR domain-containing adaptor protein inducing interferon beta (TRIF)-mediated expression of co-stimulatory receptors. PIM inhibited LPS/TLR4-induced NFkappaB translocation. Synthetic PIM(1) and a PIM(2) mimetic recapitulated these in vitro activities and inhibited endotoxin-induced airway inflammation, TNF and keratinocyte-derived chemokine secretion, and neutrophil recruitment in vivo. Mannosyl, two acyl chains, and phosphatidyl residues are essential for PIM anti-inflammatory activity, whereas the inosityl moiety is dispensable. Therefore, PIM exert potent antiinflammatory effects both in vitro and in vivo that may contribute to the strategy developed by mycobacteria for repressing the host innate immunity, and synthetic PIM analogs represent powerful anti-inflammatory leads.


Subject(s)
Adaptor Proteins, Vesicular Transport/immunology , Cytokines/immunology , Down-Regulation , Myeloid Differentiation Factor 88/immunology , Phosphatidylinositols/immunology , Toll-Like Receptor 4/immunology , Tuberculosis/immunology , Adaptor Proteins, Vesicular Transport/genetics , Animals , Cells, Cultured , Cytokines/genetics , Gene Expression , Humans , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Macrophages/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium tuberculosis/immunology , Myeloid Differentiation Factor 88/genetics , Toll-Like Receptor 4/genetics , Tuberculosis/genetics , Tuberculosis/microbiology
6.
J Immunol ; 180(2): 1169-78, 2008 Jan 15.
Article in English | MEDLINE | ID: mdl-18178857

ABSTRACT

Acute cigarette smoke exposure of the airways (two cigarettes twice daily for three days) induces acute inflammation in mice. In this study, we show that airway inflammation is dependent on Toll-like receptor 4 and IL-1R1 signaling. Cigarette smoke induced a significant recruitment of neutrophils in the bronchoalveolar space and pulmonary parenchyma, which was reduced in TLR4-, MyD88-, and IL-1R1-deficient mice. Diminished neutrophil influx was associated with reduced IL-1, IL-6, and keratinocyte-derived chemokine levels and matrix metalloproteinase-9 activity in the bronchoalveolar space. Further, cigarette smoke condensate (CSC) induced a macrophage proinflammatory response in vitro, which was dependent on MyD88, IL-1R1, and TLR4 signaling, but not attributable to LPS. Heat shock protein 70, a known TLR4 agonist, was induced in the airways upon smoke exposure, which probably activates the innate immune system via TLR4/MyD88, resulting in airway inflammation. CSC-activated macrophages released mature IL-1beta only in presence of ATP, whereas CSC alone promoted the TLR4/MyD88 signaling dependent production of IL-1alpha and pro-IL-1beta implicating cooperation between TLRs and the inflammasome. In conclusion, acute cigarette exposure results in LPS-independent TLR4 activation, leading to IL-1 production and IL-1R1 signaling, which is crucial for cigarette smoke induced inflammation leading to chronic obstructive pulmonary disease with emphysema.


Subject(s)
Myeloid Differentiation Factor 88/genetics , Nicotiana/toxicity , Pneumonia/chemically induced , Pneumonia/genetics , Receptors, Interleukin-1 Type I/genetics , Smoke , Toll-Like Receptor 4/genetics , Animals , HSP70 Heat-Shock Proteins/metabolism , Immunity, Innate/drug effects , Immunity, Innate/genetics , Interleukin-1alpha/metabolism , Interleukin-1beta/metabolism , Macrophages/drug effects , Macrophages/immunology , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Mutant Strains , Neutrophils/drug effects , Neutrophils/immunology , Pneumonia/immunology , Signal Transduction/genetics
7.
Int J Exp Pathol ; 88(6): 387-91, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18039275

ABSTRACT

Recent studies on endotoxin/lipopolysaccharide (LPS)-induced acute inflammatory response in the lung are reviewed. The acute airway inflammatory response to inhaled endotoxin is mediated through Toll-like receptor 4 (TLR4) and CD14 signalling as mice deficient for TLR4 or CD14 are unresponsive to endotoxin. Acute bronchoconstriction, tumour necrosis factor (TNF), interleukin (IL)-12 and keratinocyte-derived chemokine (KC) production, protein leak and neutrophil recruitment in the lung are abrogated in mice deficient for the adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/Interleukin-1 receptor (TIR)-domain-containing adaptor protein (TIRAP), but independent of TIR-domain-containing adaptor-inducing interferon-beta (TRIF). In particular, LPS-induced TNF is required for bronchoconstriction, but dispensable for inflammatory cell recruitment. Lipopolysaccharide induces activation of the p38 mitogen-activated protein kinase (MAPK). Inhibition of pulmonary MAPK activity abrogates LPS-induced TNF production, bronchoconstriction, neutrophil recruitment into the lungs and broncho-alveolar space. In conclusion, TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin are dependent on TLR4/CD14/MD2 expression using the adapter proteins TIRAP and MyD88, while TRIF, IL-1R1 or IL-18R signalling pathways are dispensable. Further downstream in this axis of signalling, TNF blockade reduces only acute bronchoconstriction, while MAPK inhibition abrogates completely endotoxin-induced inflammation.


Subject(s)
Lung/immunology , MAP Kinase Signaling System , Pneumonia/immunology , Toll-Like Receptors/metabolism , Tumor Necrosis Factor-alpha/metabolism , Animals , Bronchoconstriction , Cytokines/immunology , Enzyme Activation , Humans , Lipopolysaccharides , Mice , Mice, Transgenic , Pneumonia/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
8.
J Immunol ; 179(2): 1178-89, 2007 Jul 15.
Article in English | MEDLINE | ID: mdl-17617611

ABSTRACT

MyD88, the common adapter involved in TLR, IL-1, and IL-18 receptor signaling, is essential for the control of acute Mycobacterium tuberculosis (MTB) infection. Although TLR2, TLR4, and TLR9 have been implicated in the response to mycobacteria, gene disruption for these TLRs impairs only the long-term control of MTB infection. Here, we addressed the respective role of IL-1 and IL-18 receptor pathways in the MyD88-dependent control of acute MTB infection. Mice deficient for IL-1R1, IL-18R, or Toll-IL-1R domain-containing adaptor protein (TIRAP) were compared with MyD88-deficient mice in an acute model of aerogenic MTB infection. Although primary MyD88-deficient macrophages and dendritic cells were defective in cytokine production in response to mycobacterial stimulation, IL-1R1-deficient macrophages exhibited only a reduced IL-12p40 secretion with unaffected TNF, IL-6, and NO production and up-regulation of costimulatory molecules CD40 and CD86. Aerogenic MTB infection of IL-1R1-deficient mice was lethal within 4 wk with 2-log higher bacterial load in the lung and necrotic pneumonia but efficient pulmonary CD4 and CD8 T cell responses, as seen in MyD88-deficient mice. Mice deficient for IL-18R or TIRAP controlled acute MTB infection. These data demonstrate that absence of IL-1R signal leads to a dramatic defect of early control of MTB infection similar to that seen in the absence of MyD88, whereas IL-18R and TIRAP are dispensable, and that IL-1, together with IL-1-induced innate response, might account for most of MyD88-dependent host response to control acute MTB infection.


Subject(s)
Immunity, Innate , Myeloid Differentiation Factor 88/immunology , Receptors, Interleukin-1/immunology , Signal Transduction/immunology , Tuberculosis/immunology , Animals , Cells, Cultured , Flow Cytometry , Immunohistochemistry , Membrane Glycoproteins/immunology , Membrane Glycoproteins/metabolism , Mice , Microscopy, Confocal , Mycobacterium tuberculosis/immunology , Myeloid Differentiation Factor 88/metabolism , Receptors, Interleukin-1/metabolism , Receptors, Interleukin-18/immunology , Receptors, Interleukin-18/metabolism
9.
J Biol Chem ; 282(36): 26014-25, 2007 Sep 07.
Article in English | MEDLINE | ID: mdl-17617634

ABSTRACT

Mycobacterium tuberculosis lipomannans (LMs) modulate the host innate immune response. The total fraction of Mycobacterium bovis BCG LM was shown both to induce macrophage activation and pro-inflammatory cytokines through Toll-like receptor 2 (TLR2) and to inhibit pro-inflammatory cytokine production by lipopolysaccharide (LPS)-activated macrophages through a TLR2-independent pathway. The pro-inflammatory activity was attributed to tri- and tetra-acylated forms of BCG LM but not the mono- and di-acylated ones. Here, we further characterize the negative activities of M. bovis BCG LM on primary murine macrophage activation. We show that di-acylated LMs exhibit a potent inhibitory effect on cytokine and NO secretion by LPS-activated macrophages. The inhibitory activity of mycobacterial mannose-capped lipoarabino-mannans on human phagocytes was previously attributed to their binding to the C-type lectins mannose receptor or specific intracellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN). However, we found that di-acylated LM inhibition of LPS-induced tumor necrosis factor secretion by murine macrophages was independent of TLR2, mannose receptor, or the murine ortholog SIGNR1. We further determined that tri-acyl-LM, an agonist of TLR2/TLR1, promoted interleukin-12 p40 and NO secretion through the adaptor proteins MyD88 and TIRAP, whereas the fraction containing tetra-acylated LM activated macrophages in a MyD88-dependent fashion, mostly through TLR4. TLR4-dependent pro-inflammatory activity was also seen with M. tuberculosis LM, composed mostly of tri-acylated LM, suggesting that acylation degree per se might not be sufficient to determine TLR2 versus TLR4 usage. Therefore, LM acylation pattern determines the anti-inflammatory versus pro-inflammatory effects of LM through different pattern recognition receptors or signaling pathways and may represent an additional mean of regulating the host innate immunity by mycobacteria.


Subject(s)
Cell Adhesion Molecules/immunology , Immunity, Innate , Interleukin-12 Subunit p40/immunology , Lectins, C-Type/immunology , Lipopolysaccharides/immunology , Macrophages/immunology , Mannose-Binding Lectins/immunology , Mycobacterium bovis/immunology , Receptors, Cell Surface/immunology , Toll-Like Receptor 2/immunology , Tumor Necrosis Factor-alpha/immunology , Acylation , Animals , Cell Adhesion Molecules/metabolism , Cell Line , Humans , Immunity, Innate/drug effects , Inflammation/immunology , Inflammation/metabolism , Lectins, C-Type/metabolism , Lipopolysaccharides/metabolism , Lipopolysaccharides/pharmacology , Macrophage Activation/drug effects , Macrophage Activation/immunology , Macrophages/metabolism , Mannose Receptor , Mannose-Binding Lectins/metabolism , Membrane Glycoproteins/immunology , Membrane Glycoproteins/metabolism , Mice , Mice, Knockout , Mycobacterium tuberculosis/immunology , Myeloid Differentiation Factor 88/immunology , Myeloid Differentiation Factor 88/metabolism , Nitric Oxide/immunology , Nitric Oxide/metabolism , Receptors, Cell Surface/metabolism , Receptors, Interleukin-1/immunology , Receptors, Interleukin-1/metabolism , Signal Transduction/drug effects , Signal Transduction/immunology , Toll-Like Receptor 1/agonists , Toll-Like Receptor 1/immunology , Toll-Like Receptor 2/agonists , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 4/agonists , Toll-Like Receptor 4/immunology , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/metabolism
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