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1.
Proc Natl Acad Sci U S A ; 119(15): e2121098119, 2022 04 12.
Article in English | MEDLINE | ID: mdl-35377803

ABSTRACT

The pathogenesis of lung fibrosis involves hyperactivation of innate and adaptive immune pathways that release inflammatory cytokines and growth factors such as tumor growth factor (TGF)ß1 and induce aberrant extracellular matrix protein production. During the genesis of pulmonary fibrosis, resident alveolar macrophages are replaced by a population of newly arrived monocyte-derived interstitial macrophages that subsequently transition into alveolar macrophages (Mo-AMs). These transitioning cells initiate fibrosis by releasing profibrotic cytokines and remodeling the matrix. Here, we describe a strategy for leveraging the up-regulation of the mannose receptor CD206 in interstitial macrophages and Mo-AM to treat lung fibrosis. We engineered mannosylated albumin nanoparticles, which were found to be internalized by fibrogenic CD206+ monocyte derived macrophages (Mo-Macs). Mannosylated albumin nanoparticles incorporating TGFß1 small-interfering RNA (siRNA) targeted the profibrotic subpopulation of CD206+ macrophages and prevented lung fibrosis. The findings point to the potential utility of mannosylated albumin nanoparticles in delivering TGFß-siRNA into CD206+ profibrotic macrophages as an antilung fibrosis strategy.


Subject(s)
Lymphotoxin-alpha , Macrophages, Alveolar , Nanoparticles , Pulmonary Fibrosis , RNA, Small Interfering , Animals , Bleomycin/pharmacology , Disease Models, Animal , Lymphotoxin-alpha/genetics , Macrophages, Alveolar/immunology , Mannose Receptor , Mice , Mice, Inbred C57BL , Nanoparticles/administration & dosage , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/immunology , Pulmonary Fibrosis/therapy , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics
2.
ACS Nano ; 16(3): 4084-4101, 2022 03 22.
Article in English | MEDLINE | ID: mdl-35230826

ABSTRACT

The complex involvement of neutrophils in inflammatory diseases makes them intriguing but challenging targets for therapeutic intervention. Here, we tested the hypothesis that varying endocytosis capacities would delineate functionally distinct neutrophil subpopulations that could be specifically targeted for therapeutic purposes. By using uniformly sized (∼120 nm in diameter) albumin nanoparticles (ANP) to characterize mouse neutrophils in vivo, we found two subsets of neutrophils, one that readily endocytosed ANP (ANPhigh neutrophils) and another that failed to endocytose ANP (ANPlow population). These ANPhigh and ANPlow subsets existed side by side simultaneously in bone marrow, peripheral blood, spleen, and lungs, both under basal conditions and after inflammatory challenge. Human peripheral blood neutrophils showed a similar duality. ANPhigh and ANPlow neutrophils had distinct cell surface marker expression and transcriptomic profiles, both in naive mice and in mice after endotoxemic challenge. ANPhigh and ANPlow neutrophils were functionally distinct in their capacities to kill bacteria and to produce inflammatory mediators. ANPhigh neutrophils produced inordinate amounts of reactive oxygen species and inflammatory chemokines and cytokines. Targeting this subset with ANP loaded with the drug piceatannol, a spleen tyrosine kinase (Syk) inhibitor, mitigated the effects of polymicrobial sepsis by reducing tissue inflammation while fully preserving neutrophilic host-defense function.


Subject(s)
Nanoparticles , Neutrophils , Albumins/metabolism , Animals , Endocytosis , Inflammation/drug therapy , Inflammation/metabolism , Mice , Neutrophils/metabolism
3.
PLoS One ; 9(2): e89647, 2014.
Article in English | MEDLINE | ID: mdl-24586934

ABSTRACT

Myocarditis, often due to an aberrant immune response to infection, is a major cause of dilated cardiomyopathy. Microbial pattern recognition receptors, such as TLRs, orchestrate the cytokine and chemokine responses that augment or limit the severity of myocarditis. Using the mouse model of experimental autoimmune myocarditis (EAM), in which disease is induced by immunization with a heart-specific self peptide and the agonist to multiple TLRs, complete Freund's adjuvant, we found that increased serum concentrations of the chemokine CXCL1/KC correlated directly with decreased severity of myocarditis. To directly test whether CXCL1/KC caused the amelioration of myocarditis, we treated mice, after challenge with heart-specific self peptide, with exogenous recombinant CXCL1/KC. We found that the administration of recombinant mouse CXCL1/KC completely abrogated heart inflammatory infiltration and cardiomyocyte damage. Moreover, we show that TLR4 signaling is required to increase serum protein concentrations of CXCL1/KC in EAM, and we demonstrate that the administration of the TLR4 agonist LPS significantly decreased severity and prevalence of EAM and reduced the number of heart-specific self peptide reactive effector T cells. These findings reveal a novel function of CXCL1/KC in the context of organ-specific autoimmune disease that may prove useful for the treatment of inflammatory conditions that underlie human heart disease.


Subject(s)
Autoimmune Diseases/drug therapy , Chemokine CXCL1/administration & dosage , Myocarditis/drug therapy , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Disease Models, Animal , Female , Ligands , Mice , Mice, Knockout , Models, Biological , Myocarditis/genetics , Myocarditis/immunology , Myocarditis/pathology , Myosin Heavy Chains/chemistry , Myosin Heavy Chains/metabolism , Nitric Oxide Synthase Type II/metabolism , Recombinant Proteins , Signal Transduction , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Toll-Like Receptor 4/metabolism
4.
Nat Immunol ; 15(3): 239-47, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24487321

ABSTRACT

Here we found that the transcription repressor DREAM bound to the promoter of the gene encoding A20 to repress expression of this deubiquitinase that suppresses inflammatory NF-κB signaling. DREAM-deficient mice displayed persistent and unchecked A20 expression in response to endotoxin. DREAM functioned by transcriptionally repressing A20 through binding to downstream regulatory elements (DREs). In contrast, binding of the transcription factor USF1 to the DRE-associated E-box domain in the gene encoding A20 activated its expression in response to inflammatory stimuli. Our studies define the critical opposing functions of DREAM and USF1 in inhibiting and inducing A20 expression, respectively, and thereby the strength of NF-κB signaling. Targeting of DREAM to induce USF1-mediated A20 expression is therefore a potential anti-inflammatory strategy for the treatment of diseases associated with unconstrained NF-κB activity, such as acute lung injury.


Subject(s)
DNA-Binding Proteins/biosynthesis , Inflammation/metabolism , Intracellular Signaling Peptides and Proteins/biosynthesis , Kv Channel-Interacting Proteins/metabolism , Repressor Proteins/metabolism , Ubiquitin-Protein Ligases/biosynthesis , Upstream Stimulatory Factors/metabolism , Acute Lung Injury/genetics , Acute Lung Injury/metabolism , Animals , Chromatin Immunoprecipitation , Cysteine Endopeptidases , DNA-Binding Proteins/genetics , Disease Models, Animal , Gene Expression Regulation/immunology , Immunoblotting , Inflammation/genetics , Intracellular Signaling Peptides and Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/genetics , NF-kappa B/metabolism , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Tumor Necrosis Factor alpha-Induced Protein 3 , Ubiquitin-Protein Ligases/genetics
5.
PLoS One ; 7(2): e30742, 2012.
Article in English | MEDLINE | ID: mdl-22355325

ABSTRACT

The complement anaphylatoxin C5a has a pathogenetic role in endotoxin-induced lung inflammatory injury by regulating phagocytic cell migration and activation. Endotoxin and C5a activate the enzyme sphingosine kinase (Sphk) 1 to generate the signaling lipid sphingosine-1-phosphate (S1P), a critical regulator of phagocyte function. We assessed the function of Sphk1 and S1P in experimental lung inflammatory injury and determined their roles in anaphylatoxin receptor signaling and on the expression of the two C5a receptors, C5aR (CD88) and C5L2, on phagocytes. We report that Sphk1 gene deficient (Sphk1(-/-)) mice had augmented lung inflammatory response to endotoxin compared to wild type mice. Sphk1 was required for C5a-mediated reduction in cytokine and chemokine production by macrophages. Moreover, neutrophils from Sphk1(-/-) mice failed to upregulate the anaphylatoxin receptor C5L2 in response to LPS. Exogenous S1P restored C5L2 cell surface expression of Sphk1(-/-) mouse neutrophils to wild type levels but had no effect on cell surface expression of the other anaphylatoxin receptor, CD88. These results provide the first genetic evidence of the crucial role of Sphk1 in regulating the balance between expression of CD88 and C5L2 in phagocytes. S1P-mediated up-regulation of C5L2 is a novel therapeutic target for mitigating endotoxin-induced lung inflammatory injury.


Subject(s)
Lipopolysaccharides/toxicity , Lysophospholipids/pharmacology , Phosphotransferases (Alcohol Group Acceptor)/physiology , Pneumonia/metabolism , Receptor, Anaphylatoxin C5a/metabolism , Receptors, Chemokine/metabolism , Sphingosine/analogs & derivatives , Anaphylatoxins/pharmacology , Animals , Bone Marrow/drug effects , Bone Marrow/metabolism , Cytokines/metabolism , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Macrophages/cytology , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/cytology , Neutrophils/drug effects , Neutrophils/metabolism , Phosphorylation/drug effects , Pneumonia/chemically induced , Pneumonia/pathology , Sepsis/chemically induced , Sepsis/metabolism , Sepsis/pathology , Signal Transduction/drug effects , Sphingosine/pharmacology
6.
Am J Pathol ; 178(1): 313-24, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21224068

ABSTRACT

Human embryonic stem cells differentiated under mesoderm-inducing conditions have important therapeutic properties in sepsis-induced lung injury in mice. Single cell suspensions obtained from day 7 human embryoid bodies (d7EBs) injected i.v. 1 hour after cecal ligation and puncture significantly reduced lung inflammation and edema as well as production of tumor necrosis factor-α and interferon-γ in lungs compared with controls, whereas interleukin-10 production remained elevated. d7EB cell transplantation also reduced mortality to 50% from 90% in the control group. The protection was ascribed to d7EB cell interaction with lung resident CD11b+ cells, and was correlated with the ability of d7EB cells to reduce it also reduced production of proinflammatory cytokines by CD11+ cells, and to endothelial NO synthase-derived NO by d7EB cells, leading to inhibition of inducible macrophage-type NO synthase activation in CD11b+ cells. The protective progenitor cells were positive for the endothelial and hematopoietic lineage marker angiotensin converting enzyme (ACE). Only the ACE+ fraction modulated the proinflammatory profile of CD11b+ cells and reduced mortality in septic mice. In contrast to the nonprotective ACE-cell fraction, the ACE+ cell fraction also produced NO. These findings suggest that an ACE+ subset of human embryonic stem cell-derived progenitor cells has a highly specialized anti-inflammatory function that ameliorates sepsis-induced lung inflammation and reduces mortality.


Subject(s)
Cell Differentiation , Embryonic Stem Cells/cytology , Embryonic Stem Cells/transplantation , Pneumonia/surgery , Sepsis/complications , Animals , CD11b Antigen/analysis , Cell Separation , Cell Tracking , Disease Models, Animal , Embryonic Stem Cells/chemistry , Humans , Male , Mice , Mice, Inbred Strains , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Peptidyl-Dipeptidase A/metabolism , Pneumonia/etiology
7.
J Biol Chem ; 285(21): 15848-57, 2010 May 21.
Article in English | MEDLINE | ID: mdl-20299461

ABSTRACT

The mechanism underlying the protective effect of sphingosine kinase 1 (SphK1) in inflammatory injury is not clear. We demonstrated using SphK1-null mice (SphK1(-/-)) the crucial role of SphK1 in suppressing lipopolysaccharide-induced neutrophil oxidant production and sequestration in lungs and mitigating lung inflammatory injury. This effect of SphK1 was independent of the production of sphingosine 1-phosphate, the product of SphK1 activity. The anti-inflammatory effect of SphK1 in the lipopolysaccharide model was mediated through SphK1 interaction with JNK. SphK1 stabilization of JNK in turn inhibited JNK binding to the JNK-interacting protein 3 (JIP3) and thus abrogated the activation of NADPH oxidase and oxidant generation and resultant NF-kappaB activation. Therefore, SphK1-mediated down-regulation of JNK activity serves to dampen inflammation and tissue injury.


Subject(s)
Lipopolysaccharides/toxicity , Lung/enzymology , MAP Kinase Kinase 4/metabolism , Neutrophils/enzymology , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Pneumonia/enzymology , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Down-Regulation/genetics , Down-Regulation/radiation effects , Enzyme Activation/drug effects , Enzyme Activation/genetics , Lysophospholipids/genetics , Lysophospholipids/metabolism , MAP Kinase Kinase 4/genetics , Mice , Mice, Knockout , NADPH Oxidases/genetics , NADPH Oxidases/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Oxidants/metabolism , Phosphotransferases (Alcohol Group Acceptor)/genetics , Pneumonia/chemically induced , Pneumonia/genetics , Sphingosine/analogs & derivatives , Sphingosine/genetics , Sphingosine/metabolism
8.
Physiol Genomics ; 38(1): 42-53, 2009 Jun 10.
Article in English | MEDLINE | ID: mdl-19351910

ABSTRACT

Activation of NF-kappaB is essential for protease-activated receptor-1 (PAR-1)-mediated ICAM-1 expression in endothelial cells. Here we show that PAR-1 activation induces binding of both p65/RelA and NFATc1 to the NF-kappaB binding site localized in intron-1 of the ICAM-1 gene to initiate transcription in endothelial cells. We discovered the presence of two NF-kappaB binding sites in intron-1 (+70, NF-kappaB site 1; +611, NF-kappaB site 2) of the human ICAM-1 gene. Chromatin immunoprecipitation results showed that thrombin induced binding of p65/RelA and of NFATc1 specifically to intronic NF-kappaB site 1 of the ICAM-1 gene. Electrophoretic mobility shift and supershift assays confirmed the binding of p65/RelA and NFATc1 to the intronic NF-kappaB site 1 in thrombin-stimulated cells. Thrombin increased the expression of ICAM-1-promoter-intron 1-reporter (-1,385 to +234) construct approximately 25-fold and mutation of intronic NF-kappaB site 1 markedly reduced thrombin-induced reporter expression. Moreover, inhibition of calcineurin, knockdown of either NFATc1 or p65/RelA with siRNA significantly reduced thrombin-induced ICAM-1 expression and polymorphonuclear leukocyte adhesion to endothelial cells. In contrast, NFATc1 knockdown had no effect on TNF-alpha-induced ICAM-1 expression. Thus these results suggest that p65/RelA and NFATc1 bind to the intronic NF-kappaB site 1 sequence to induce optimal transcription of the ICAM-1 gene in response to thrombin in endothelial cells.


Subject(s)
Gene Expression Regulation/physiology , Intercellular Adhesion Molecule-1/genetics , Introns , NF-kappa B/physiology , NFATC Transcription Factors/metabolism , Thrombin/physiology , Base Sequence , Cells, Cultured , Chromatin Immunoprecipitation , DNA Primers , Gene Knockdown Techniques , Humans , NFATC Transcription Factors/genetics , RNA, Small Interfering
9.
Nat Med ; 13(8): 920-6, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17618294

ABSTRACT

The E3 ubiquitin ligase Cblb has a crucial role in the prevention of chronic inflammation and autoimmunity. Here we show that Cblb also has an unexpected function in acute lung inflammation. Cblb attenuates the sequestration of inflammatory cells in the lungs after administration of lipopolysaccharide (LPS). In a model of polymicrobial sepsis in which acute lung inflammation depends on the LPS receptor (Toll-like receptor 4, TLR-4), the loss of Cblb expression accentuates acute lung inflammation and reduces survival. Loss of Cblb significantly increases sepsis-induced release of inflammatory cytokines and chemokines. Cblb controls the association between TLR4 and the intracellular adaptor MyD88. Expression of wild-type Cblb, but not expression of a Cblb mutant that lacks E3 ubiquitin ligase function, prevents the activity of a reporter gene for the transcription factor nuclear factor-kappaB (NF-kappaB) in monocytes that have been challenged with LPS. The downregulation of TLR4 expression on the cell surface of neutrophils is impaired in the absence of Cblb. Our data reveal that Cblb regulates the TLR4-mediated acute inflammatory response that is induced by sepsis.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Lung/enzymology , Lung/pathology , Pneumonia/enzymology , Pneumonia/pathology , Proto-Oncogene Proteins c-cbl/metabolism , Acute Disease , Adaptor Proteins, Signal Transducing/deficiency , Adaptor Proteins, Signal Transducing/genetics , Animals , Cytokines/biosynthesis , Gene Deletion , Gene Expression Regulation, Enzymologic , Lipopolysaccharides/pharmacology , Lung/drug effects , Lung Injury , Mice , Mice, Inbred BALB C , Mice, Knockout , Myeloid Differentiation Factor 88/metabolism , NF-kappa B/metabolism , Phenotype , Pneumonia/chemically induced , Pneumonia/genetics , Protein Binding , Protein Transport , Proto-Oncogene Proteins c-cbl/deficiency , Proto-Oncogene Proteins c-cbl/genetics , Signal Transduction , Survival Rate , Toll-Like Receptor 4/metabolism
10.
J Immunol ; 174(3): 1472-8, 2005 Feb 01.
Article in English | MEDLINE | ID: mdl-15661906

ABSTRACT

The E3 ubiquitin ligase Casitas B cell lymphoma-b (Cbl-b) plays a critical role in the development of autoimmunity and sets the threshold for T cell activation. In the absence of Cbl-b, T cells stimulated via the TCR respond similarly to those that have received a CD28-mediated costimulatory signal, suggesting that the absence of Cbl-b substitutes for CD28-mediated costimulation. In this study, we show that loss of Cbl-b restores Ig class switching and germinal center formation in Vav1 mutant mice in response to an in vivo viral challenge. Genetic inactivation of Cbl-b also rescues impaired antiviral IgG production in CD28-mutant mice. Moreover, loss of CD28 results in disorganization of follicular dendritic cell clusters, which is also rescued by the Cbl-b mutation. Intriguingly, despite restored antiviral in vivo immunity and follicular dendritic cell clusters, loss of Cbl-b did not rescue germinal center formation in CD28-deficient mice. Mechanistically, in vivo vesicular stomatitis virus-induced IL-4 and IFN-gamma production and up-regulation of the inducible costimulatory molecule ICOS were dependent on CD28, and could not be rescued by the loss of Cbl-b. These data provide genetic evidence that CD28-dependent in vivo immune responses and Ig class switching can be genetically uncoupled from germinal center formation and ICOS induction by Cbl-b-Vav1-regulated signaling pathways.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Autoimmune Diseases/immunology , CD28 Antigens/physiology , Cell Cycle Proteins/physiology , Proto-Oncogene Proteins/physiology , Ubiquitin-Protein Ligases/physiology , Adaptor Proteins, Signal Transducing/deficiency , Adaptor Proteins, Signal Transducing/genetics , Animals , Antibodies, Viral/biosynthesis , Antigens, Differentiation, T-Lymphocyte/biosynthesis , Autoimmune Diseases/genetics , Autoimmune Diseases/pathology , CD28 Antigens/genetics , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/pathology , Cell Aggregation/genetics , Cell Aggregation/immunology , Cell Cycle Proteins/genetics , Cytokines/antagonists & inhibitors , Cytokines/biosynthesis , Dendritic Cells, Follicular/pathology , Germinal Center/immunology , Germinal Center/metabolism , Germinal Center/pathology , Immunoglobulin Class Switching/genetics , Immunoglobulin G/biosynthesis , Inducible T-Cell Co-Stimulator Protein , Mice , Mice, Knockout , Peanut Agglutinin/biosynthesis , Phenotype , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-cbl , Proto-Oncogene Proteins c-vav , Rhabdoviridae Infections/genetics , Rhabdoviridae Infections/immunology , Rhabdoviridae Infections/pathology , Ubiquitin-Protein Ligases/deficiency , Ubiquitin-Protein Ligases/genetics , Up-Regulation/genetics , Vesicular stomatitis Indiana virus/immunology
11.
Immunity ; 21(2): 167-77, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15308098

ABSTRACT

Antigen-specific immunotolerance limits the expansion of self-reactive T cells involved in autoimmune diseases. Here, we show that the E3 ubiquitin ligase Cbl-b is upregulated in T cells after tolerizing signals. Loss of Cbl-b in mice results in impaired induction of T cell tolerance both in vitro and in vivo. Importantly, rechallenge of Cbl-b mutant mice with the tolerizing antigen results in massive lethality. Moreover, ablation of Cbl-b resulted in exacerbated autoimmunity. Mechanistically, loss of Cbl-b rescues reduced calcium mobilization of anergic T cells, which was attributed to Cbl-b-mediated regulation of PLCgamma-1 phosphorylation. Our results show a critical role for Cbl-b in the regulation of peripheral tolerance and anergy of T cells.


Subject(s)
Adaptor Proteins, Signal Transducing , Clonal Anergy/immunology , T-Lymphocytes/metabolism , Ubiquitin-Protein Ligases/metabolism , Adoptive Transfer , Animals , Antigens/immunology , Clonal Anergy/physiology , Enterotoxins/immunology , In Vitro Techniques , Mice , Phospholipase C gamma , Proto-Oncogene Proteins c-cbl , T-Lymphocytes/immunology , Type C Phospholipases/metabolism , Ubiquitin-Protein Ligases/immunology
12.
Nat Cell Biol ; 6(3): 215-26, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15039780

ABSTRACT

During the development of multicellular organisms, concerted actions of molecular signalling networks determine whether cells undergo proliferation, differentiation, death or ageing. Here we show that genetic inactivation of the stress signalling kinase, MKK7, a direct activator of JNKs in mice, results in embryonic lethality and impaired proliferation of hepatocytes. Beginning at passage 4-5, mkk7(-/-) mouse embryonic fibroblasts (MEFs) display impaired proliferation, premature senescence and G2/M cell cycle arrest. Similarly, loss of c-Jun or expression of a c-JunAA mutant in which the JNK phosphorylation sites were replaced with alanine results in a G2/M cell-cycle block. The G2/M cell-cycle kinase CDC2 was identified as a target for the MKK7-JNK-c-Jun pathway. These data show that the MKK7-JNK-c-Jun signalling pathway couples developmental and environmental cues to CDC2 expression, G2/M cell cycle progression and cellular senescence in fibroblasts.


Subject(s)
Cellular Senescence/genetics , G2 Phase/genetics , Hepatocytes/enzymology , Mitogen-Activated Protein Kinase Kinases/deficiency , Mitosis/genetics , Stress, Physiological/enzymology , Animals , CDC2 Protein Kinase/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cells, Cultured , Fetus , Fibroblasts/cytology , Fibroblasts/enzymology , Genes, Lethal/genetics , Hepatocytes/cytology , JNK Mitogen-Activated Protein Kinases , Liver/abnormalities , Liver/pathology , MAP Kinase Kinase 7 , MAP Kinase Signaling System/genetics , Mice , Mitogen-Activated Protein Kinase Kinases/genetics , Mitogen-Activated Protein Kinases/metabolism , Mutation/genetics , Phosphorylation , Proto-Oncogene Proteins c-jun/deficiency , Proto-Oncogene Proteins c-jun/genetics , Stress, Physiological/genetics
13.
Nat Med ; 9(12): 1484-90, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14625544

ABSTRACT

Genetic susceptibility and autoimmunity triggered by microbial infections are factors implicated in the pathogenesis of dilated cardiomyopathy, the most common cause of heart failure in young patients. Here we show that dendritic cells (DCs) loaded with a heart-specific self peptide induce CD4+ T-cell-mediated myocarditis in nontransgenic mice. Toll-like receptor (TLR) stimulation, in concert with CD40 triggering of self peptide-loaded dendritic cells, was shown to be required for disease induction. After resolution of acute myocarditis, DC-immunized mice developed heart failure, and TLR stimulation of these mice resulted in relapse of inflammatory infiltrates. Injection of damaged, syngeneic cardiomyocytes also induced myocarditis in mice if TLRs were activated in vivo. DC-induced myocarditis provides a unifying theory as to how tissue damage and activation of TLRs during infection can induce autoimmunity, relapses and cardiomyopathy.


Subject(s)
Autoimmunity , Cardiomyopathy, Dilated/etiology , Cardiomyopathy, Dilated/immunology , Dendritic Cells/immunology , Adaptation, Physiological , Animals , Autoantigens/administration & dosage , CD4-Positive T-Lymphocytes/immunology , CD40 Antigens/metabolism , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/pathology , Humans , Immunity, Innate , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, SCID , Models, Immunological , Peptide Fragments/immunology , Receptors, Cell Surface/metabolism , Toll-Like Receptors , Ventricular Myosins/immunology
14.
J Exp Med ; 197(3): 323-31, 2003 Feb 03.
Article in English | MEDLINE | ID: mdl-12566416

ABSTRACT

Dilated cardiomyopathy, resulting from myocarditis, is the most common cause of heart failure in young patients. We here show that interleukin (IL)-1 receptor type 1-deficient (IL-1R1(-/-)) mice are protected from development of autoimmune myocarditis after immunization with alpha-myosin-peptide(614-629). CD4(+) T cells from immunized IL-1R1(-/-) mice proliferated poorly and failed to transfer disease after injection into naive severe combined immunodeficiency (SCID) mice. In vitro stimulation experiments suggested that the function of IL-1R1(-/-)CD4(+) T cells was not intrinsically defect, but their activation by dendritic cells was impaired in IL-1R1(-/-) mice. Accordingly, production of tumor necrosis factor (TNF)-alpha, IL-1, IL-6, and IL-12p70 was reduced in dendritic cells lacking the IL-1 receptor type 1. In fact, injection of immature, antigen-loaded IL-1R1(+/+) but not IL-1R1(-/-) dendritic cells into IL-1R1(-/-) mice fully restored disease susceptibility by rendering IL-1R1(-/-) CD4(+) T cells pathogenic. Thus, IL-1R1 triggering is required for efficient activation of dendritic cells, which is in turn a prerequisite for induction of autoreactive CD4(+) T cells and autoimmunity.


Subject(s)
Autoimmune Diseases/etiology , Dendritic Cells/immunology , Myocarditis/etiology , Receptors, Interleukin-1/metabolism , Adoptive Transfer , Amino Acid Sequence , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Autoimmunity , CD4-Positive T-Lymphocytes/immunology , Cardiomyopathy, Dilated/etiology , Cardiomyopathy, Dilated/immunology , Cytokines/biosynthesis , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, SCID , Molecular Sequence Data , Myocarditis/immunology , Myocarditis/pathology , Peptide Fragments/genetics , Peptide Fragments/immunology , Receptors, Interleukin-1/deficiency , Receptors, Interleukin-1/genetics , Receptors, Interleukin-1 Type I , Ventricular Myosins/genetics , Ventricular Myosins/immunology
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