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Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To [...]

Abstract Background Progressive airway inflammation and susceptibility to the airway colonisation and infection are characteristic for the pathophysiology of chronic obstructive pulmonary disease (COPD). Antimicrobial peptides (AMPs) are central to the function of the innate host immune response against microbial pathogens and are regulators of inflammation and immunity. S100A7/psoriasin, a recently described AMP, is an essential component of the human epithelia against invading pathogens and acts as an effector molecule of the host innate defence in the skin. We hypothesized that S100A7/psoriasin is involved in the airway mucosal immunity and differently regulated and expressed in the lung during progression of COPD. Methods S100A7/psoriasin gene expression was assessed in bronchial biopsies and bronchoalveolar lavage (BAL) fluid cells of healthy controls and COPD patients. Using confocal microscopy and immunohistochemistry, the protein expression of S100A7/psoriasin was investigated. Results Here, we report that S100A7/psoriasin, the major antimicrobial peptide of the human skin, is constitutively expressed in perinuclear granules of human bronchial epithelial cells and alveolar macrophages. Whereas typical activators of the innate immune response like TLR ligands and cytokines induced the upregulation of CXCL-8 mRNA and release of CXCL-8 by epithelial cells, S100A7/psoriasin mRNA expression was not modulated. To investigate a potential association of S100A7/psoriasin with COPD, S100A7/psoriasin mRNA expression was assessed in bronchial biopsies and BAL fluid cells of patients at different stages of COPD and controls. Overall, 10 healthy individuals and 34 COPD patients were enrolled in this study. We found an association of S100A7/psoriasin mRNA expression with bacterial detection in the tracheobronchial system (p = 0.0304), which was the strongest in individuals positive for with S. aureus (p = 0.0005). However, S100A7/psoriasin mRNA expression was not altered during the progression of COPD. Conclusions S100A7/psoriasin gene expression is unchanged in the airways during COPD. The newly identified association of S100A7/psoriasin with S. aureus may provide new insights into the antimicrobial defence response of the human airways, leading to the induction of S100A7/psoriasin upon microbial challenge.

Abstract: Objective: To modulate atherosclerosis by combining subcutaneous immunization with heat shock protein 65 (hsp65) in alum adjuvant and anti-CD45RB monoclonal antibodies (mAb). Methods: 8 week old Apoe −/− mice on normal chow were treated for 12 weeks: group A received hsp65-alum immunization combined with anti-CD45RB mAb, group B hsp65-alum immunization combined with isotype control antibody, and group C mock vaccine combined with isotype control antibody. Results: Unexpectedly, atherosclerotic lesions in the aortic root were significantly reduced in both hsp65-alum immunization groups (A and B) compared with the control group (C). Significantly elevated antibody titers against hsp65 were detected in both groups along with a significant increase in MHC class II expression on B cells. Body weight, total cholesterol and triglyceride levels were not different between groups. Treatment with anti-CD45RB antibody mediated a shift on CD4+ T cells from the CD45RBhigh to CD45RBlow isoform with a relative increase in CD4+Foxp3+ regulatory T cells (Treg) in an overall reduced T cell pool. Furthermore, anti-CD45RB treatment mediated a transient reduction of peripheral leukocytes and increased IFN-γ and IL-17A plasma levels. Conclusions: Subcutaneous immunization with hsp65-alum protects Apoe −/− mice against progression of early atherosclerosis. Administration of anti-CD45RB antibody provided no incremental benefit to the athero-protective effects of hsp65-alum treatment alone. [Copyright &y& Elsevier]

Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific Foxp3 promoter, allowing for specific ablation of FOXP3+ Tregs. Lethally irradiated, atherosclerosis-prone, low-den-sity lipoprotein receptor-deficient (Ldlr-/-) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3+ Tregs. Depletion of Tregs caused a 2.1-fold increase in atherosclerosis without a concomi-tant increase in vascular inflammation. These mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron rem-nants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. These results demonstrate that FOXP3+ Tregs inhibit atherosclerosis by modulating lipoprotein metabolism. [ABSTRACT FROM AUTHOR]