ABSTRACT
The Death Receptor 3 (DR3)/Tumour Necrosis Factor-like cytokine 1A (TL1A) axis stimulates effector T cells and type 2 innate lymphocytes (ILC2) that trigger cytokine release and drive disease pathology in several inflammatory and autoimmune diseases, including murine models of acute allergic lung inflammation (ALI). The aim of this study was to elucidate the role of DR3 in chronic ALI compared to acute ALI, using mice genetically deficient in the DR3 gene (DR3ko). Results showed DR3 expression in the lungs of wild-type mice was up-regulated following induction of acute ALI and this increased expression was maintained in chronic disease. DR3ko mice were resistant to cellular accumulation within the alveolar passages in acute, but not chronic ALI. However, DR3ko mice displayed reduced immuno-histopathology and goblet cell hyperplasia; hallmarks of the asthmatic phenotype; in chronic, but not acute ALI. These data suggest DR3 is a potential therapeutic target, involved in temporally distinct aspects of ALI progression and pathogenesis.
Subject(s)
Goblet Cells/pathology , Hypersensitivity/immunology , Lung/immunology , Lymphocytes/immunology , Pneumonia/immunology , Receptors, Tumor Necrosis Factor, Member 25/metabolism , Acute Disease , Animals , Cells, Cultured , Chronic Disease , Disease Progression , Female , Hyperplasia , Hypersensitivity/physiopathology , Immunity, Innate , Mice , Mice, Inbred C57BL , Mice, Knockout , Pneumonia/physiopathology , Receptors, Tumor Necrosis Factor, Member 25/genetics , Th2 Cells/immunologyABSTRACT
Death receptor 3 is a proinflammatory member of the immunomodulatory tumor necrosis factor receptor superfamily, which has been implicated in several inflammatory diseases such as arthritis and inflammatory bowel disease. Intriguingly however, constitutive DR3 expression has been detected in the brains of mice, rats, and humans, although its neurological function remains unknown. By mapping the normal brain expression pattern of DR3, we found that DR3 is expressed specifically by cells of the neuron lineage in a developmentally regulated and region-specific pattern. Behavioral studies on DR3-deficient (DR3(ko)) mice showed that constitutive neuronal DR3 expression was required for stable motor control function in the aging adult. DR3(ko) mice progressively developed behavioral defects characterized by altered gait, dyskinesia, and hyperactivity, which were associated with elevated dopamine and lower serotonin levels in the striatum. Importantly, retrograde tracing showed that absence of DR3 expression led to the loss of corticostriatal innervation without significant neuronal loss in aged DR3(ko) mice. These studies indicate that DR3 plays a key nonredundant role in the retention of normal motor control function during aging in mice and implicate DR3 in progressive neurological disease.
Subject(s)
Aging/physiology , Cerebral Cortex/metabolism , Corpus Striatum/metabolism , Motor Skills/physiology , Receptors, Tumor Necrosis Factor, Member 25/physiology , Aging/genetics , Animals , Cell Communication/genetics , Cell Communication/physiology , Cerebral Cortex/growth & development , Cerebral Cortex/physiology , Corpus Striatum/growth & development , Corpus Striatum/physiology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurotransmitter Agents/deficiency , Neurotransmitter Agents/genetics , Neurotransmitter Agents/physiology , Receptors, Tumor Necrosis Factor, Member 25/deficiency , Receptors, Tumor Necrosis Factor, Member 25/geneticsABSTRACT
Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints that is associated with cartilage and bone destruction. Death Receptor 3 (DR3), a tumor necrosis factor (TNF) receptor superfamily member, has recently been associated with the pathogenesis of RA. We demonstrate that absence of DR3 confers resistance to the development of adverse bone pathology in experimental antigen-induced arthritis (AIA). DR3(ko) mice exhibited a reduction in all histopathological hallmarks of AIA but, in particular, failed to develop subchondral bone erosions and were completely protected from this characteristic of AIA. In contrast, TNF-like protein 1A (TL1A), the ligand for DR3, exacerbated disease in a dose- and DR3-dependent fashion. Analysis of osteoclast number within AIA joint revealed a reduction in areas susceptible to bone erosion in DR3(ko) mice, whereas in vitro osteoclastogenesis assays showed that TL1A could directly promote osteoclastogenesis in mouse and man. Treatment with antagonistic anti-TL1A mAb protected animals in a systemic model of RA disease collagen-induced arthritis. We therefore conclude that the DR3-TL1A pathway regulates joint destruction in two murine models of arthritis and represents a potential novel target for therapeutic intervention in inflammatory joint disease.
