Characterisation of Death Receptor 3 dependent aortic changes during inflammatory arthritis

Murine collagen‐induced arthritis (mCIA) is characterized by decreased vascular constriction responses and increased MMP‐9. Here, we describe additional histological alterations within the aorta and surrounding perivascular adipose tissue (PVAT), study the role of PVAT in constriction response, and investigate the potential involvement of death receptor 3 (DR3). mCIA was induced in wild‐type (WT) and DR3−/− mice with nonimmunized, age‐matched controls. Vascular function was determined in isolated aortic rings ±PVAT, using isometric tension myography, in response to cumulative serotonin concentrations. Cellular expression of F4/80 (macrophages), Ly6G (neutrophils), DR3, and MMP‐9 was determined using immunohistochemistry. In WTs, arthritis‐induced vascular dysfunction was associated with increased F4/80+ macrophages and increased DR3 expression in the aorta and PVAT. MMP‐9 was also up‐regulated in PVAT, but did not correlate with alterations of PVAT intact constriction. DR3−/− mice inherently showed increased leukocyte numbers and MMP‐9 expression in the PVAT, but retained the same nonarthritic constriction response as DR3WT mice ±PVAT. Arthritic DR3−/− mice had a worsened constriction response than DR3WT and showed an influx of neutrophils to the aorta and PVAT. Macrophage numbers were also up‐regulated in DR3−/− PVAT. Despite this influx, PVAT intact DR3−/− constriction responses were restored to the same level as DR3WT. Impaired vascular constriction in inflammatory arthritis occurs independently of total MMP‐9 levels, but correlates with macrophage and neutrophil ingress. Ablating DR3 worsens the associated vasculature dysfunction, however, DR3−/− PVAT is able to protect the aorta against aberrant vasoconstriction caused in this model

Age-dependent maintenance of motor controland corticostriatal innervation by death receptor 3

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 (DR3ko) mice showed that constitutive neuronal DR3 expression was required for stable motor control function in the aging adult. DR3ko 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 DR3ko 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

CD4+ T cells, human cytomegalovirus and end-stage renal disease

CD4+ T cells are activated through their T-cell receptors, which recognize foreign antigenic peptides in the context of Major Histocompatibility Complex (MHC) II molecules [1, 2]. They have classically been regarded as facilitators of acquired immunity, providing cytokine help that aids the development of either the cellular cytotoxic CD8+ T cell (Th1) or humoral B-cell responses (Th2). However, the rapid expansion of our knowledge of cytokines and their function has resulted in the definition of further unique CD4+ T-cell subsets associated with specific immune conditions and intracellular transcription factors that drive their differentiation. It is now accepted that Th1 and Th2 differentiation are driven by the transcription factors T-bet and GATA-3, respectively [3, 4]. Th17 cells are defined by the expression of RORγt (known as RORC in humans) and RORα, express IL-23R and CCR6, secrete the cytokines IL-17 and IL-22 and are considered essential for the development of inflammatory and autoimmune disease [5–8]. Regulatory T cells (Tregs) are identified by the transcription factor FoxP3 and provide a negative buffer to immune responses through the release of suppressive cytokines such as TGFβ and IL-10 [9–11]. More recently, Th9 cells have been identified that release IL-9 and IL-10, adoptive transfer of which results in colitis and neuritis [12, 13], while Th22 cells produce IL-22 and IL-13, are defined by the transcription factors RORγt and AHR, express skin-homing receptors and are believed important in skin and mucosal pathology [14]. A summary of the above list is provided in Figure 1, but it is by no means exhaustive and there are CD4+ cell types that do not fit into these categories. However, it serves to demonstrate the complexity and plasticit