ABSTRACT
During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.
Subject(s)
Atherosclerosis/etiology , Atherosclerosis/pathology , Myocardial Infarction/complications , Myocardial Infarction/pathology , Animals , Apolipoproteins E/genetics , Hematopoietic Stem Cells/cytology , Inflammation/complications , Mice , Mice, Inbred C57BL , Monocytes/cytology , Spleen/cytology , Stem Cells/cytologyABSTRACT
Recognition and clearance of a bacterial infection are a fundamental properties of innate immunity. Here, we describe an effector B cell population that protects against microbial sepsis. Innate response activator (IRA) B cells are phenotypically and functionally distinct, develop and diverge from B1a B cells, depend on pattern-recognition receptors, and produce granulocyte-macrophage colony-stimulating factor. Specific deletion of IRA B cell activity impairs bacterial clearance, elicits a cytokine storm, and precipitates septic shock. These observations enrich our understanding of innate immunity, position IRA B cells as gatekeepers of bacterial infection, and identify new treatment avenues for infectious diseases.
Subject(s)
B-Lymphocyte Subsets/immunology , Escherichia coli Infections/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Immunity, Innate , Peritonitis/immunology , Sepsis/immunology , Animals , B-Lymphocyte Subsets/metabolism , Cell Lineage , Cell Separation , Female , Flow Cytometry , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Immunoglobulin M/metabolism , Immunophenotyping , Integrin alpha4beta1/immunology , Integrin alpha4beta1/metabolism , Lipopolysaccharides , Lymphocyte Activation , Lymphocyte Function-Associated Antigen-1/immunology , Lymphocyte Function-Associated Antigen-1/metabolism , Mice , Mice, Inbred C57BL , Parabiosis , Shock, Septic/immunology , Spleen/immunology , Toll-Like Receptor 4/immunologyABSTRACT
The expression of CD127, the IL-7-binding subunit of the IL-7 R, is tightly regulated during the development and activation of T cells and is reduced during chronic viral infection. However, the molecular mechanism regulating the dynamic expression of CD127 is still poorly understood. In this study, we report that the transcription factor Ets-1 is required for maintaining the expression of CD127 in murine peripheral T cells. Ets-1 binds to and activates the CD127 promoter, and its absence leads to reduced CD127 expression, attenuated IL-7 signaling, and impaired IL-7-dependent homeostatic proliferation of T cells. The expression of CD127 and Ets-1 is strongly correlated in human T cells. Both CD127 and Ets-1 expression are decreased in CD8(+) T cells during HIV infection. In addition, HIV-associated loss of CD127 is only observed in Ets-1(low) effector memory and central memory but not in Ets-1(high) naive CD8(+) T cells. Taken together, our data identify Ets-1 as a critical regulator of CD127 expression in T cells.
