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Background: Recent studies indicate that Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) signaling promote the development of high fat diet-induced atherosclerosis in hypercholesterolemic mice.Objectives: The authors investigated the role of TLR4/MyD88 signaling in hematopoietic and stromal cells in the development and infection-mediated acceleration of atherosclerosis.Methods: The authors generated bone marrow chimeras between wild-type and Tlr4-/- mice, as well as wild-type and Myd88-/- mice. All mice were on the Apoe-/- background and fed high fat diet. The authors infected the chimeric mice with C. pneumoniae (CP) and fed them high fat diet.Results: Aortic sinus plaques and lipid content were significantly reduced in Apoe-/- mice that received Tlr4-/-or Myd88-/- bone marrow compared with control animals despite similar cholesterol levels. Similarly, Tlr4 or Myd88 deficiency in stromal cells also led to a reduction in the lesion area and lipid in aortic sinus plaques. MyD88 expression only in CD11c+ dendritic cells (myeloid cells) in cells was sufficient in otherwise MyD88-deficient mice to induce CP infection-mediated acceleration of atherosclerosis, underlining the key role of MyD88 in CD11c+ dendritic cells (myeloid cells). Whereas CP infection markedly accelerated atherosclerosis in TLR4- or MyD88-positive chimeras, CP infection had a minimal effect on atherosclerosis in TLR4- or MyD88-deficient mice (either in the hematopoietic or stromal cell compartments).Conclusions: The authors show that both CP infection and metabolic stress associated with dyslipidemia use the same innate immune response pathway, utilizing TLR4/MyD88 signaling, with similar relative contributions in bone marrow-derived hematopoietic cells and in stromal cells. Further studies are required to understand this intricate and complex cross talk among innate and adaptive immune systems in various conditions to more effectively design dendritic cell-mediated atheroprotective vaccines and other therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Eukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2α) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2α phosphorylation is observed in mouse and human atheroma.Objectives: Potent ISR inhibitors that modulate neurodegenerative disorders have been identified. Here, the authors evaluated the potential benefits of intercepting ISR in a chronic metabolic and inflammatory disease, atherosclerosis.Methods: The authors investigated ISR's role in lipid-induced inflammasome activation and atherogenesis by taking advantage of 3 different small molecules and the ATP-analog sensitive kinase allele technology to intercept ISR at multiple molecular nodes.Results: The results show lipid-activated eIF2α signaling induces a mitochondrial protease, Lon protease 1 (LONP1), that degrades phosphatase and tensin-induced putative kinase 1 and blocks Parkin-mediated mitophagy, resulting in greater mitochondrial oxidative stress, inflammasome activation, and interleukin-1β secretion in macrophages. Furthermore, ISR inhibitors suppress hyperlipidemia-induced inflammasome activation and inflammation, and reduce atherosclerosis.Conclusions: These results reveal endoplasmic reticulum controls mitochondrial clearance by activating eIF2α-LONP1 signaling, contributing to an amplified oxidative stress response that triggers robust inflammasome activation and interleukin-1β secretion by dietary fats. These findings underscore the intricate exchange of information and coordination of both organelles' responses to lipids is important for metabolic health. Modulation of ISR to alleviate organelle stress can prevent inflammasome activation by dietary fats and may be a strategy to reduce lipid-induced inflammation and atherosclerosis. [ABSTRACT FROM AUTHOR]

Background T cells and macrophages are implicated in the pathogenesis of aortic aneurysm (AA) and atherosclerosis. We recently demonstrated that a vaccine using an apoB-100–related peptide p210 reduces atherosclerosis with favorable modulation of CD8 + T cells in apolipoprotein E–deficient (apoE −/− ) mice. Objectives This study hypothesized that a p210 vaccine could reduce AA formation in the angiotensin II (Ang II)–induced AA model. Methods Male apoE −/− mice were immunized with p210 vaccine and implanted with an Ang II–releasing pump for 4 weeks. Flow cytometry assessed T cell activation and phenotype. Interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) expression were assessed using reverse transcription polymerase chain reaction. We used ex vivo aortic explants to test monocyte adhesion and in vitro cocultures to evaluate CD8 + T cell function. Results The p210 vaccine activated CD8 + T cells and reduced AA formation and mortality due to AA rupture, which was attenuated by CD8 + T cell depletion. Vaccination decreased expression of IL-6 and MCP-1 and reduced macrophage infiltration in the aorta. Cytotoxic T-lymphocyte assay showed that CD8 + T cells from p210-immunized mice had higher lytic activity against Ang II–stimulated macrophages. The p210 vaccine decreased splenic Th17 cells, and in vitro coculture of CD4 + and CD8 + T cells showed that CD8 + T cells from p210-immunized mice inhibited the polarization of CD4 + T cells into Th17 cells. IL-17A −/− mice infused with a higher dose of Ang II did not develop AA rupture. Conclusions A p210 vaccine protected against Ang II–induced AA formation and mortality by reducing macrophage infiltration in the aorta and decreasing Th17 cell polarization. Our findings provide a potentially novel immunomodulating approach against AA. [ABSTRACT FROM AUTHOR]