Estrogen regulates T helper 17 phenotype and localization in experimental autoimmune arthritis.

INTRODUCTION: The incidence and progression of many autoimmune diseases are sex-biased, which might be explained by the immunomodulating properties of endocrine hormones. Treatment with estradiol potently inhibits experimental autoimmune arthritis. Interleukin-17-producing T helper cells (Th17) are key players in several autoimmune diseases, particularly in rheumatoid arthritis. The aim of this study was to investigate the effects of estrogen on Th17 cells in experimental arthritis. METHODS: Ovariectomized DBA/1 mice treated with 17ß-estradiol (E2) or placebo were subjected to collagen-induced arthritis (CIA), and arthritis development was assessed. Th17 cells in joints and lymph nodes were studied by flow cytometry. Lymph node Th17 cells were also examined in ovariectomized estrogen receptor α-knockout mice (ERα-/-) and wild-type littermates, treated with E2 or placebo and subjected to antigen-induced arthritis. RESULTS: E2-treated mice with established CIA showed reduced severity of arthritis and fewer Th17 cells in joints compared with controls. Interestingly, E2-treated mice displayed increased Th17 cells in lymph nodes during the early phase of the disease, dependent on ERα. E2 increased the expression of C-C chemokine receptor 6 (CCR6) on lymph node Th17 cells as well as the expression of the corresponding C-C chemokine ligand 20 (CCL20) within lymph nodes. CONCLUSIONS: This is the first study in which the effects of E2 on Th17 cells have been characterized in experimental autoimmune arthritis. We report that E2 treatment results in an increase of Th17 cells in lymph nodes during the early phase of arthritis development, but leads to a decrease of Th17 in joints during established arthritis. Our data suggest that this may be caused by interference with the CCR6-CCL20 pathway, which is important for Th17 cell migration. This study contributes to the understanding of the role of estrogen in the development of autoimmune arthritis and opens up new fields for research concerning the sex bias in autoimmune disease.

TLR3 impairment in human newborns.

Newborns are highly susceptible to viral infections. We hypothesized that this susceptibility could be due to a dysregulated expression of innate virus-sensing receptors, i.e., TLR3, TLR7, TLR8, and TLR9 and the cytosolic receptors retinoic acid-inducible gene I, melanoma differentiation-associated protein 5, protein kinase R, and IFN-γ-inducible protein 16. Cord blood mononuclear cells (CBMCs) expressed mRNA for all these receptors except for TLR3. In peripheral blood mononuclear cells (PBMCs), TLR3 mRNA was preferentially expressed in cytotoxic cells, particularly CD56(dim) NK cells. Cord NK cells in contrast showed low TLR3 mRNA expression and lacked TLR3 protein expression. Cord NK cells did not produce IFN-γ in response to polyinosinic-polycytidylic acid [poly(I:C)], whereas strong IFN-γ production was observed in poly(I:C)-stimulated adult NK cells. Cord NK cells had poor cytotoxic function that was only marginally enhanced by exposure to the TLR3 ligand poly(I:C). Opposite to NK cells from adults, their cytotoxicity was not improved by herpes simplex virus (HSV) exposure and they were unable to kill HSV-infected cells. There were no differences in the TLR3 mRNA levels among men, women, and pregnant women, implying that TLR3 is not under sex hormone control. However, decidual NK cells expressed low levels of TLR3 mRNA, which was attributed to their CD56(bright) phenotype. Our data show that cord blood NK cells have deficient TLR3 expression associated with an inability to respond to poly(I:C) and HSV activation and to kill HSV-infected cells. This might explain why newborns are particularly sensitive to neonatal HSV infections.

Arachidonate 15-lipoxygenase type B knockdown leads to reduced lipid accumulation and inflammation in atherosclerosis.

Inflammation in the vascular wall is important for development of atherosclerosis. We have shown previously that arachidonate 15-lipoxygenase type B (ALOX15B) is more highly expressed in human atherosclerotic lesions than in healthy arteries. This enzyme oxidizes fatty acids to substances that promote local inflammation and is expressed in lipid-loaded macrophages (foam cells) present in the atherosclerotic lesions. Here, we investigated the role of ALOX15B in foam cell formation in human primary macrophages and found that silencing of human ALOX15B decreased cellular lipid accumulation as well as proinflammatory cytokine secretion from macrophages. To investigate the role of ALOX15B in promoting the development of atherosclerosis in vivo, we used lentiviral shRNA silencing and bone marrow transplantation to knockdown mouse Alox15b gene expression in LDL-receptor-deficient (Ldlr(-/-)) mice. Knockdown of mouse Alox15b in vivo decreased plaque lipid content and markers of inflammation. In summary, we have shown that ALOX15B influences progression of atherosclerosis, indicating that this enzyme has an active proatherogenic role.