XBP1 is a key regulator of the unfolded protein response (UPR), which is involved in a wide range of physiological and pathological processes. XBP1 ablation in liver causes profound hypolipidemia in mice, highlighting its critical role in lipid metabolism. XBP1 deficiency triggers feedback activation of its upstream enzyme IRE1α, instigating regulated IRE1-dependent decay (RIDD) of cytosolic mRNAs. Here, we identify RIDD as a crucial control mechanism of lipid homeostasis. Suppression of RIDD by RNA interference or genetic ablation of IRE1α reversed hypolipidemia in XBP1 deficient mice. Comprehensive microarray analysis of XBP1 and/or IRE1α deficient liver identified genes involved in lipogenesis and lipoprotein metabolism as RIDD substrates, which might contribute to the suppression of plasma lipid levels by activated IRE1α. Ablation of XBP1 ameliorated hepatosteatosis, liver damage and hypercholesterolemia in dyslipidemic animal models, suggesting that direct targeting of either IRE1α or XBP1 might be a feasible strategy to treat dyslipidemias.

Interleukin 17A (IL-17) is the signature cytokine produced by TH17 cells and has been implicated in host defense against infection and the pathophysiology of autoimmunity and cardiovascular disease. Little is known, however, about the influence of IL-17 on endothelial activation and leukocyte influx to sites of inflammation. We hypothesized that IL-17 would induce a distinct pattern of endothelial activation and leukocyte recruitment when compared to the TH1 cytokine, IFNγ. We found that IL-17 alone had minimal activating effects on cultured endothelium, while the combination of TNFα and IL-17 produced a synergistic increase in the expression of both P-selectin and E-selectin. Using intravital microscopy of the mouse cremaster muscle, we found that TNFα and IL-17 also led to a synergistic increase in E-selectin dependent leukocyte rolling on microvascular endothelium in vivo. In addition, TNFα and IL-17 enhanced endothelial expression of the neutrophilic chemokines CXCL1, CXCL2, and CXCL5, and led to a functional increase in leukocyte transmigration in vivo and CXCR2-dependent neutrophil but not T-cell transmigration in a parallel-plate flow chamber system. By contrast, endothelial activation with TNFα and IFNγ preferentially induced the expression of the integrin-ligands ICAM1 and VCAM1, as well as the T-cell chemokines CXCL9, CXCL10, and CCL5. These effects were further associated with a functional increase in T-cell but not neutrophil transmigration under laminar shear flow. Overall, these data show that IL-17 and TNFα act in a synergistic manner to induce a distinct pattern of endothelial activation that sustains and enhances neutrophil influx to sites of inflammation.

PD-1, a member of the CD28 family of immune regulatory molecules, is expressed on activated T cells, interacts with its ligands, PD-L1/B7-H1 and PD-L2/B7-DC, on other cells, and delivers inhibitory signals to the T cell. We studied the role of this pathway in modulating autoreactive T cell responses in two models of myocarditis. In a CD8+ T cell-mediated adoptive transfer model, we found that compared with Pd1+/+ CD8+ T cells, Pd1−/− CD8+ T cells cause enhanced disease, with increased inflammatory infiltrate, particularly rich in neutrophils. Additionally, we show enhanced proliferation in vivo and enhanced cytotoxic activity of PD-1–deficient T lymphocytes against myocardial endothelial cells in vitro. In experimental autoimmune myocarditis, a disease model dependent on CD4+ T cells, we show that mice lacking PD-1 develop enhanced disease compared with wild-type mice. PD-1–deficient mice displayed increased inflammation, enhanced serum markers of myocardial damage, and an increased infiltration of inflammatory cells, including CD8+ T cells. Together, these studies show that PD-1 plays an important role in limiting T cell responses in the heart.

OBJECTIVE Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. We studied the contribution of PD-1 pathway in regulating T cells that promote atherosclerotic lesion formation and inflammation. METHODS AND RESULTS We show that compared to Ldlr−/− control mice, Pd1−/−Ldlr−/− mice developed larger lesions with more abundant CD4+ and CD8+ T cells and macrophages, accompanied by higher levels of serum TNF-α. Iliac lymph node T cells from Pd1−/−Ldlr−/− mice proliferated more to αCD3 or oxidized LDL stimulation compared to controls. CD8+ T cells from Pd1−/−Ldlr−/− mice display more cytotoxic activity, compared to controls in vivo and in vitro. Administration of a blocking anti-PD-1 antibody increased lesional inflammation in hypercholesterolemic Ldlr−/− mice with more lesional T cells, and more activated T cells in paraaortic lymph nodes. The changes in lesional T cell content when PD-1 was absent or blocked were also observed in bone marrow chimeric Ldlr−/− mice lacking PD-L1 and PD-L2 on hematopoietic cells. CONCLUSIONS PD-1 has an important role in down-regulating proatherogenic T cell responses, and blockade of this molecule for treatment of viral infections or cancer may increase risk for cardiovascular complications.