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1.
J Immunol ; 199(7): 2236-2248, 2017 10 01.
Article in English | MEDLINE | ID: mdl-28801358

ABSTRACT

IL-4 and IL-13 have been defined as anti-inflammatory cytokines that can counter myelin-reactive T cells and modulate experimental allergic encephalomyelitis. However, it is not known whether endogenous IL-4 and IL-13 contribute to the maintenance of peripheral tolerance and whether their function is coordinated with T regulatory cells (Tregs). In this study, we used mice in which the common cytokine receptor for IL-4 and IL-13, namely the IL-4Rα/IL-13Rα1 (13R) heteroreceptor (HR), is compromised and determined whether the lack of signaling by endogenous IL-4 and IL-13 through the HR influences the function of effector Th1 and Th17 cells in a Treg-dependent fashion. The findings indicate that mice-deficient for the HR (13R-/-) are more susceptible to experimental allergic encephalomyelitis than mice sufficient for the HR (13R+/+) and develop early onset and more severe disease. Moreover, Th17 cells from 13R-/- mice had reduced ability to convert to Th1 cells and displayed reduced sensitivity to suppression by Tregs relative to Th17 effectors from 13R+/+ mice. These observations suggest that IL-4 and IL-13 likely operate through the HR and influence Th17 cells to convert to Th1 cells and to acquire increased sensitivity to suppression, leading to control of immune-mediated CNS inflammation. These previously unrecognized findings shed light on the intricacies underlying the contribution of cytokines to peripheral tolerance and control of autoimmunity.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/immunology , Interleukin-13 Receptor alpha1 Subunit/immunology , Receptors, Cell Surface/immunology , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology , Animals , Cytokines/biosynthesis , Cytokines/immunology , Disease Models, Animal , Immune Tolerance , Interleukin-13/biosynthesis , Interleukin-13/metabolism , Interleukin-13 Receptor alpha1 Subunit/deficiency , Interleukin-13 Receptor alpha1 Subunit/genetics , Interleukin-4/biosynthesis , Interleukin-4/metabolism , Mice , Mice, Inbred C57BL , Receptors, Cell Surface/deficiency , Receptors, Cell Surface/genetics , Signal Transduction , Th1 Cells/immunology
2.
J Immunol ; 199(3): 894-902, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28646042

ABSTRACT

Type 1 diabetes (T1D) manifests when the insulin-producing pancreatic ß cells are destroyed as a consequence of an inflammatory process initiated by lymphocytes of the immune system. The NOD mouse develops T1D spontaneously and serves as an animal model for human T1D. The IL-4Rα/IL-13Rα1 heteroreceptor (HR) serves both IL-4 and IL-13 cytokines, which are believed to function as anti-inflammatory cytokines in T1D. However, whether the HR provides a responsive element to environmental (i.e., physiologic) IL-4/IL-13 in the regulation of peripheral tolerance and the development of T1D has yet to be defined. In this study, NOD mice deficient for the HR have been generated by means of IL-13Rα1 gene disruption and used to determine whether such deficiency affects the development of T1D. Surprisingly, the findings indicate that NOD mice lacking the HR (13R-/-) display resistance to T1D as the rise in blood glucose level and islet inflammation were significantly delayed in these HR-deficient relative to HR-sufficient (13R+/+) mice. In fact, the frequency and spleen-to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R-/- mice. This is likely due to an increase in the frequency of mTGFß+Foxp3int regulatory T cells and the persistence of CD206+ macrophages in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R+/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D.


Subject(s)
Diabetes Mellitus, Type 1/immunology , Interleukin-13 Receptor alpha1 Subunit/metabolism , Receptors, Cell Surface/metabolism , Adoptive Transfer , Animals , Blood Glucose , Disease Models, Animal , Insulin-Secreting Cells/immunology , Interleukin-13/immunology , Interleukin-13 Receptor alpha1 Subunit/deficiency , Interleukin-13 Receptor alpha1 Subunit/genetics , Interleukin-13 Receptor alpha1 Subunit/immunology , Interleukin-4/immunology , Lectins, C-Type/immunology , Macrophages/immunology , Mannose Receptor , Mannose-Binding Lectins/immunology , Mice , Mice, Inbred NOD , Pancreas/cytology , Pancreas/immunology , Receptors, Cell Surface/genetics , Receptors, Cell Surface/immunology , T-Lymphocytes, Regulatory/immunology , Th1 Cells/immunology , Th17 Cells/immunology
3.
J Neuroinflammation ; 14(1): 88, 2017 04 21.
Article in English | MEDLINE | ID: mdl-28427412

ABSTRACT

BACKGROUND: The majority of Parkinson's disease (PD) cases are sporadic and idiopathic suggesting that this neurodegenerative disorder is the result of both environmental and genetic factors. Stress and neuroinflammation are among the factors being investigated for their possible contributions to PD. Experiments in rodents showed that severe chronic stress can reduce the number of dopaminergic neurons in the substantia nigra pars compacta (SNc); the same cells that are lost in PD. These actions are at least in part mediated by increased oxidative stress. Here, we tested the hypothesis that the interleukin-13 receptor alpha 1 (IL-13Rα1), a cytokine receptor whose activation increases the vulnerability of dopaminergic neurons to oxidative damage, participates in the stress-dependent damage of these neurons. METHODS: Mice were subject to daily sessions of 8 h (acute) stress for 16 weeks (5 days a week), a procedure previously showed to induce loss of dopaminergic neurons in the SNc. The source and the kinetics of interleukin-13 (IL-13), the endogenous ligand of IL-13Rα1, were evaluated 0, 1, 3, 6, and 8 h and at 16 weeks of stress. Identification of IL-13 producing cell-type was performed by immunofluorescent and by in situ hybridization experiments. Markers of oxidative stress, microglia activation, and the number of dopaminergic neurons in IL-13Rα1 knock-out animals (Il13ra1 Y/ - ) and their wild-type littermates (Il13ra1 Y/+ ) were evaluated at 16 weeks of stress and at 20 weeks, following a 4 week non-stressed period and compared to non-stressed mice. RESULTS: IL-13 was expressed in microglial cells within the SN and in a fraction of the tyrosine hydroxylase-positive neurons in the SNc. IL-13 levels were elevated during daily stress and peaked at 6 h. 16 weeks of chronic restraint stress significantly reduced the number of SNc dopaminergic neurons in Il13ra1 Y/+ mice. Neuronal loss at 16 weeks was significantly lower in Il13ra1 Y/- mice. However, the loss of dopaminergic neurons measured at 20 weeks, after 4 weeks of non-stress following the 16 weeks of stress, was similar in Il13ra1 Y/+ and Il13ra1 Y/- mice. CONCLUSIONS: IL-13, a cytokine previously demonstrated to increase the susceptibility of SNc dopaminergic neurons to oxidative stress, is elevated in the SN by restraint stress. Lack of IL-13Rα1 did not prevent nor halted but delayed neuronal loss in the mouse model of chronic restraint stress. IL-13/IL-13Rα1 may represent a target to reduce the rate of DA neuronal loss that can occur during severe chronic restraint stress.


Subject(s)
Dopaminergic Neurons/metabolism , Interleukin-13 Receptor alpha1 Subunit/deficiency , Oxidative Stress/physiology , Stress, Psychological/metabolism , Animals , Cell Count/methods , Dopaminergic Neurons/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Stress, Psychological/pathology , Substantia Nigra/metabolism , Substantia Nigra/pathology
4.
Mucosal Immunol ; 9(1): 240-53, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26153764

ABSTRACT

Molecular mechanisms that regulate lung repair vs. progressive scarring in pulmonary fibrosis remain elusive. Interleukin (IL)-4 and IL-13 are pro-fibrotic cytokines that share common receptor chains including IL-13 receptor (R) α1 and are key pharmacological targets in fibrotic diseases. However, the roles of IL-13Rα1 in mediating lung injury/repair are unclear. We report dysregulated levels of IL-13 receptors in the lungs of bleomycin-treated mice and to some extent in idiopathic pulmonary fibrosis patients. Transcriptional profiling demonstrated an epithelial cell-associated gene signature that was homeostatically dependent on IL-13Rα1 expression. IL-13Rα1 regulated a striking array of genes in the lung following bleomycin administration and Il13ra1 deficiency resulted in exacerbated bleomycin-induced disease. Increased pathology in bleomycin-treated Il13ra1(-/-) mice was due to IL-13Rα1 expression in structural and hematopoietic cells but not due to increased responsiveness to IL-17, IL-4, IL-13, increased IL-13Rα2 or type 1 IL-4R signaling. These data highlight underappreciated protective roles for IL-13Rα1 in lung injury and homeostasis.


Subject(s)
Idiopathic Pulmonary Fibrosis/immunology , Interleukin-13 Receptor alpha1 Subunit/immunology , Interleukin-13/immunology , Lung Injury/immunology , Adult , Animals , Bleomycin , Case-Control Studies , Female , Gene Expression Regulation , Homeostasis/immunology , Humans , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/pathology , Interleukin-13/genetics , Interleukin-13 Receptor alpha1 Subunit/deficiency , Interleukin-13 Receptor alpha1 Subunit/genetics , Interleukin-17/genetics , Interleukin-17/immunology , Interleukin-4/genetics , Interleukin-4/immunology , Lung/immunology , Lung/pathology , Lung Injury/chemically induced , Lung Injury/genetics , Lung Injury/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Protein Isoforms/genetics , Protein Isoforms/immunology , Receptors, Interleukin-4/genetics , Receptors, Interleukin-4/immunology , Signal Transduction , Transcription, Genetic
5.
J Immunol ; 189(12): 5498-502, 2012 Dec 15.
Article in English | MEDLINE | ID: mdl-23169588

ABSTRACT

Inflammation and its mediators, including cytokines and reactive oxygen species, are thought to contribute to neurodegeneration. In the mouse brain, we found that IL-13Rα1 was expressed in the dopaminergic (DA) neurons of the substantia nigra pars compacta, which are preferentially lost in human Parkinson's disease. Mice deficient for Il13ra1 exhibited resistance to loss of DA neurons in a model of chronic peripheral inflammation using bacterial LPS. IL-13, as well as IL-4, potentiated the cytotoxic effects of t-butyl hydroperoxide and hydrogen peroxide on mouse DA MN9D cells. Collectively, our data indicate that expression of IL-13Rα1 on DA neurons can increase their susceptibility to oxidative stress-mediated damage, thereby contributing to their preferential loss. In humans, Il13ra1 lies on the X chromosome within the PARK12 locus of susceptibility to Parkinson's disease, suggesting that IL-13Rα1 may have a role in the pathogenesis of this neurodegenerative disease.


Subject(s)
Dopaminergic Neurons/immunology , Dopaminergic Neurons/metabolism , Interleukin-13 Receptor alpha1 Subunit/biosynthesis , Lipopolysaccharides/toxicity , Oxidative Stress/immunology , Animals , Cell Death/genetics , Cell Death/immunology , Chronic Disease , Disease Models, Animal , Dopaminergic Neurons/pathology , Genetic Diseases, X-Linked/genetics , Genetic Predisposition to Disease/etiology , Humans , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Interleukin-13 Receptor alpha1 Subunit/deficiency , Interleukin-13 Receptor alpha1 Subunit/genetics , Lipopolysaccharides/administration & dosage , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxidative Stress/genetics , Parkinson Disease/genetics , Parkinson Disease/metabolism , Parkinson Disease/pathology
6.
J Immunol ; 188(7): 3208-16, 2012 Apr 01.
Article in English | MEDLINE | ID: mdl-22351937

ABSTRACT

The earliest thymic progenitors (ETPs) were recently shown to give rise to both lymphoid and myeloid cells. Whereas the majority of ETPs are derived from IL-7Rα-positive cells and give rise exclusively to T cells, the origin of the myeloid cells remains undefined. In this study, we show both in vitro and in vivo that IL-13Rα1(+) ETPs yield myeloid cells with no potential for maturation into T cells, whereas IL-13Rα1(-) ETPs lack myeloid potential. Moreover, transfer of lineage-negative IL-13Rα1(+) bone marrow stem cells into IL-13Rα1-deficient mice reconstituted thymic IL-13Rα1(+) myeloid ETPs. Myeloid cells or macrophages in the thymus are regarded as phagocytic cells whose function is to clear apoptotic debris generated during T cell development. However, the myeloid cells derived from IL-13Rα1(+) ETPs were found to perform Ag-presenting functions. Thus, IL-13Rα1 defines a new class of myeloid restricted ETPs yielding APCs that could contribute to development of T cells and the control of immunity and autoimmunity.


Subject(s)
Antigen-Presenting Cells/cytology , Antigens, Differentiation/analysis , Bone Marrow Cells/classification , Granulocyte-Macrophage Progenitor Cells/cytology , Interleukin-13 Receptor alpha1 Subunit/analysis , Myelopoiesis , Thymus Gland/cytology , Animals , Antigen-Presenting Cells/chemistry , Antigen-Presenting Cells/drug effects , Antigen-Presenting Cells/immunology , Bone Marrow Cells/chemistry , Cell Lineage , Cell Movement , Cells, Cultured , Female , Gene Knock-In Techniques , Granulocyte-Macrophage Progenitor Cells/chemistry , Granulocyte-Macrophage Progenitor Cells/drug effects , Granulocyte-Macrophage Progenitor Cells/immunology , Interleukin-13/pharmacology , Interleukin-13 Receptor alpha1 Subunit/deficiency , Interleukin-13 Receptor alpha1 Subunit/genetics , Lymphocytes, Null/cytology , Lymphopoiesis , Male , Mice , Mice, Congenic , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Sequence Deletion , T-Lymphocytes/cytology
7.
J Immunol ; 187(9): 4873-80, 2011 Nov 01.
Article in English | MEDLINE | ID: mdl-21957151

ABSTRACT

IL-13 and IL-4 are hallmark cytokines of Th2-associated diseases including asthma. Recent studies revealed that IL-13Rα1 regulates asthma pathogenesis by mediating both IL-4- and IL-13-mediated responses. Nonetheless, the relative contribution of each cytokine in response to aeroallergen challenge and the degree of functional dichotomy between IL-4 and IL-13 in asthma remains unclear. Consistent with prior publications, we demonstrate that IL-13Rα1 regulates aeroallergen-induced airway resistance and mucus production but not IgE and Th2 cytokine production. We demonstrate that aeroallergen-induced eosinophil recruitment and chemokine production were largely dependent on IL-13Rα1 after Aspergillus but not house dust mite (HDM) challenges. Notably, Aspergillus-challenged mice displayed increased IL-13Rα1-dependent accumulation of dendritic cell subsets into lung-draining lymph nodes in comparison with HDM-challenged mice. Comparison of IL-4 and IL-13 levels in the different experimental models revealed increased IL-4/IL-13 ratios after HDM challenge, likely explaining the IL-13Rα1-independent eosinophilia and chemokine production. Consistently, eosinophil adoptive transfer experiments revealed near ablation of lung eosinophilia in response to Aspergillus in Il13ra1(-/-) mice, suggesting that Aspergillus-induced lung eosinophil recruitment is regulated by IL-13-induced chemokine production rather than altered IL-13 signaling in eosinophils. Furthermore, the near complete protection observed in Il13ra1(-/-) mice in response to Aspergillus challenge was dependent on mucosal sensitization, as alum/Aspergillus-sensitized mice that were rechallenged with Aspergillus developed IL-13Rα1-independent eosinophilia although other asthma parameters remained IL-13Rα1 dependent. These results establish that IL-13Rα1 is required for aeroallergen-induced airway resistance and that allergen-induced chemokine production and consequent eosinophilia is dictated by the balance between IL-4 and IL-13 production in situ.


Subject(s)
Air Pollutants/toxicity , Allergens/administration & dosage , Interleukin-13 Receptor alpha1 Subunit/physiology , Lung/immunology , Lung/metabolism , Respiratory Hypersensitivity/immunology , Respiratory Hypersensitivity/metabolism , Allergens/toxicity , Animals , Bronchial Hyperreactivity/genetics , Bronchial Hyperreactivity/immunology , Bronchial Hyperreactivity/metabolism , Interleukin-13 Receptor alpha1 Subunit/deficiency , Interleukin-13 Receptor alpha1 Subunit/genetics , Lung/pathology , Mice , Mice, Inbred BALB C , Mice, Knockout , Mucus/immunology , Mucus/metabolism , Respiratory Hypersensitivity/genetics , Transforming Growth Factor beta/biosynthesis
8.
J Immunol ; 180(4): 2376-84, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-18250447

ABSTRACT

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in children. Children previously vaccinated with a formalin-inactivated RSV vaccine experienced enhanced morbidity and mortality upon natural RSV infection. Histological analysis revealed the presence of eosinophils in the pulmonary infiltrate of the vaccinated children. Eosinophils are characteristic of Th2 responses, and Th2 cells are known to be necessary to induce pulmonary eosinophilia in RSV-infected BALB/c mice previously immunized with a recombinant vaccinia virus (vv) expressing the RSV G protein (vvG). Using IL-13-deficient mice, we find that IL-13 is necessary for eosinophils to reach the lung parenchyma and airways of vvG-immunized mice undergoing RSV challenge infection. IL-13 acts specifically on eosinophils as the magnitude of pulmonary inflammation, RSV G protein-specific CD4 T cell responses, and virus clearance were not altered in IL-13-deficient mice. After RSV challenge, eosinophils were readily detectable in the blood and bone marrow of vvG-immunized IL-13-deficient mice, suggesting that IL-13 is required for eosinophils to transit from the blood into the lung. Pulmonary levels of CCL11 and CCL22 protein were significantly reduced in IL-13-deficient mice indicating that IL-13 mediates the recruitment of eosinophils into the lungs by inducing the production of chemokines important in Th2 cell and eosinophil chemotaxis.


Subject(s)
Chemotaxis, Leukocyte/immunology , Eosinophils/cytology , Interleukin-13/physiology , Lung/immunology , Pulmonary Eosinophilia/immunology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Vaccines/administration & dosage , Animals , Eosinophils/virology , Female , Interleukin-13/biosynthesis , Interleukin-13 Receptor alpha1 Subunit/deficiency , Interleukin-13 Receptor alpha1 Subunit/genetics , Lung/pathology , Lung/virology , Mice , Mice, Inbred BALB C , Mice, Knockout , Pulmonary Eosinophilia/pathology , Pulmonary Eosinophilia/virology , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus Vaccines/immunology , Respiratory Syncytial Viruses/immunology , Vaccinia virus/immunology , Viral Envelope Proteins/administration & dosage , Viral Envelope Proteins/immunology
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