Cardiovascular disease (CVD) is the leading cause of mortality worldwide, accounting for 16.7 million deaths each year. The underlying cause of the majority of CVD is atherosclerosis. In the past, atherosclerosis was considered to be the result of passive lipid accumulation in the vessel wall. Today's picture is far more complex. Atherosclerosis is considered a chronic inflammatory disease that results in the formation of plaques in large and mid-sized arteries. Both cells of the innate and the adaptive immune system play a crucial role in its pathogenesis. By transforming immune cells into pro- and anti-inflammatory chemokine- and cytokine-producing units, and by guiding the interactions between the different immune cells, the immune system decisively influences the propensity of a given plaque to rupture and cause clinical symptoms like myocardial infarction and stroke. In this review, we give an overview on the newest insights in the role of different immune cells and subtypes in atherosclerosis.

Identifying pathways for b-cell generation is essential for cell therapy in diabetes. We investigated the potential of 17b-estradiol (E 2 ) and estrogen receptor (ER) signaling for stimulating b-cell generation during embryonic development and in the severely injured adult pancreas. E 2 concentration, ER activity, and number of ERa transcripts were enhanced in the pancreas injured by partial duct ligation (PDL) along with nuclear localization of ERa in b-cells. PDL-induced proliferation of b-cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and b-cell growth in PDL pancreas were impaired when ERa was turned off chemically or genetically (ERa 2/2 ), whereas in situ delivery of E 2 promoted b-cell formation. In the embryonic pancreas, b-cell replication, number of Ngn3 + progenitor cells, and expression of key transcription factors of the endocrine lineage were decreased by ERa inactivation. The current study reveals that E 2 and ERa signaling can drive b-cell replication and formation in mouse pancreas.Decreased functional b-cell mass is the major cause for hyperglycemia in diabetes. Restoration of the endogenous b-cell mass as a therapeutic strategy, however, requires a better understanding of signaling pathways that control b-cell growth and differentiation. Embryonic b-cells are generated by a developmental program executed through the timed action of a number of key transcription factors among which Neurogenin3 (Ngn3) is key for endocrine specification. Ngn3 + cells delaminate from pancreatic epithelium, are mitotically quiescent, and give rise to endocrine cells. Ngn3 cells appear maximally competent for driving b-cell formation at embryonic day (E) 14.5. Formed b-cells expand through self-replication, already evident at E18.5, and continue into early postnatal life (1). Also in adult mice with severely injured pancreas by partial duct ligation (PDL), Ngn3 + cells are generated near duct epithelium and can differentiate into b-cells (2). b-Cells are vastly generated through replication in PDL (3,4), but some derive from acinar (5) and duct (6) cells, apparently through an Ngn3 + stage (2,5) as in embryonic pancreas. How the numbers of Ngn3 + endocrine progenitors and replicating b-cells are controlled in the embryonic or mature pancreas is uncertain. Identifying factors that control these processes and manipulating them may be of therapeutic advantage. What is known is that 17b-estradiol (E 2 ) enhances b-cell survival and glycemic control in various animal models (7,8) by signaling through estrogen receptor (ER) a (8,9) and/or ERb (10).However, little is known about the importance of estrogen and ER signaling for b-cell proliferation and differentiation. So far, no in vivo effects on b-cell formation have been reported for the ER antagonist tamoxifen (TAM), although this compound is used to conditionally activate Cre recombinase activity (Cre ERT ) in genetic

Clinical complications of atherosclerosis are almost exclusively linked to destabilization of the atherosclerotic plaque. Batf3-dependent dendritic cells specialize in cross-presentation of necrotic tissue-derived epitopes to directly activate cytolytic CD8 Tcells. The mature plaque (necrotic, containing dendritic cells and CD8 Tcells) could offer the ideal environment for cross-presentation, resulting in cytotoxic immunity and plaque destabilization. Ldlr−/− mice were transplanted with batf3−/− or wt bone marrow and put on a western type diet. Hematopoietic batf3 deficiency sharply decreased CD8α+ DC numbers in spleen and lymph nodes (>80%; P < 0,001). Concordantly, batf3−/− chimeras had a 75% reduction in OT-I cross-priming capacity in vivo. Batf3−/− chimeric mice did not show lower Tcell or other leukocyte subset numbers. Despite dampened cross-presentation capacity, batf3−/− chimeras had equal atherosclerosis burden in aortic arch and root. Likewise, batf3−/− chimeras and wt mice revealed no differences in parameters of plaque stability: plaque Tcell infiltration, cell death, collagen composition, and macrophage and vascular smooth muscle cell content were unchanged. These results show that CD8α+ DC loss in hyperlipidemic mice profoundly reduces cross-priming ability, nevertheless it does not influence lesion development. Taken together, we clearly demonstrate that CD8α+ DC-mediated cross-presentation does not significantly contribute to atherosclerotic plaque formation and stability.

The costimulatory molecule CD40 is a major driver of atherosclerosis. It is expressed on a wide variety of cell types, including mature dendritic cells (DCs), and is required for optimal T-cell activation and expansion. It remains undetermined whether and how CD40 on DCs impacts the pathogenesis of atherosclerosis. Here, the effects of constitutively active CD40 in DCs on atherosclerosis were examined using low-density lipoprotein-deficient (Ldlr) bone marrow chimeras that express a transgene containing an engineered latent membrane protein 1 (LMP)/CD40 fusion protein conferring constitutive CD40 signaling under control of the DC-specific CD11c promoter (DC-LMP1/CD40). As expected, DC-LMP1/CD40/Ldlr chimeras (DC-LMP1/CD40) showed increased antigen-presenting capacity of DCs and increased T-cell numbers. However, the mice developed extensive neutrophilia compared to CD40wt/Ldlr (CD40wt) chimeras. Despite overt T-cell expansion and neutrophilia, a reduction in conventional DC frequency and a dramatic (approximately 80%) reduction in atherosclerosis was observed. Further analyses revealed that cholesterol and triglyceride levels had decreased by 37% and 60%, respectively, in DC-LMP1/CD40 chimeras. Moreover, DC-LMP1/CD40 chimeras developed inflammatory bowel disease characterized by massive transmural influx of leukocytes and lymphocytes, resulting in villous degeneration and lipid malabsorption. Constitutive activation of CD40 in DCs results in inflammation of the gastrointestinal tract, thereby impairing lipid uptake, which consequently results in attenuated atherosclerosis.

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