No abstract

Recruitment of CCR2+Ly6Chigh monocytes to sites of infection is essential for efficient clearance of microbial pathogens. Although CCR2-mediated signals promote monocyte emigration from bone marrow, the contribution of CCR2 to later stages of monocyte recruitment remains unresolved. In this article, we show that CCR2 deficiency markedly worsens hepatic Listeria monocytogenes infection because Ly6Chigh monocytes are retained in the bone marrow. Intravenously transferred, CCR2-deficient Ly6Chigh monocytes traffic normally to hepatic foci of infection and contribute to bacterial clearance. Pertussis toxin treatment of adoptively transferred monocytes does not impair their intrahepatic trafficking, suggesting that chemokine signaling, once CCR2+Ly6Chigh monocytes emigrate from the bone marrow, is not required for monocyte localization to sites of bacterial infection in the liver. Expression of ICAM-1 is induced in close proximity to foci of bacterial infection in the liver, including on CD31+ endothelial cells, and blockade of CD11b and CD44 diminishes monocyte localization to these hepatic foci. Our studies demonstrated that Ly6Chigh monocyte recruitment from the bloodstream to the L. monocytogenes-infected liver does not require chemokine receptor-mediated signals but instead is principally dependent on integrin- and extracellular matrix-mediated monocyte adhesion.

The amyloidogenic peptide ␤-amyloid has previously been shown to bind to neurons in the form of fibrillar clusters on the cell surface, which induces neurodegeneration and activates a program of cell death characteristic of apoptosis. To further investigate the mechanism of A␤ neurotoxicity, we synthesized the all-D-and all-Lstereoisomers of the neurotoxic truncated form of A␤ (A␤ [25][26][27][28][29][30][31][32][33][34][35] ) and the full-length peptide (A␤ 1-42 ) and compared their physical and biological properties. We report that the purified peptides exhibit nearly identical structural and assembly characteristics as assessed by high performance liquid chromatography, electron microscopy, circular dichroism, and sedimentation analysis. In addition, both enantiomers induce similar levels of toxicity in cultured hippocampal neurons. These data suggest that the neurotoxic actions of A␤ result not from stereoisomer-specific ligand-receptor interactions but rather from A␤ cellular interactions in which fibril features of the amyloidogenic peptide are a critical feature. The promiscuous nature of these ␤-sheet-containing fibrils suggests that the accumulation of amyloidogenic peptides in vivo as extracellular deposits represents a site of bioactive peptides with the ability to provide inappropriate signals to cells leading to cellular degeneration and disease.Alzheimer's disease (AD), 1 vascular dementia, and hereditary cerebral hemorrhage with the Dutch type are diseases that share an invariant pathological feature, the accumulation of an amyloidogenic peptide into insoluble fibrillar extracellular deposits. In all three cases, the major component of the extracellular debris is the ␤-amyloid peptide (A␤) that is derived from the proteolytic processing of the large membraneanchored amyloid precursor protein (APP) encoded by a single gene located on chromosome 21 (1). However, the biological significance of these amyloid deposits has been extensively debated as to whether they are a causative factor of each disease or merely a metabolically inert end product lacking in biological activity. Evidence in support of a causative role for A␤ in neuropathology comes from genetic analysis of the APP gene where several autosomal dominant mutations have been linked with AD and hereditary cerebral hemorrhage with the Dutch type (2, 3). In a recent in vitro study, the ␤-APP 717 mutation consistently caused a significant increase in the percentage of the longer and more amyloidogenic A␤ 1-42 over the shorter A␤ 1-40 (4). Incorporation of this same mutation into a transgenic mouse model yields A␤ deposition and neuropathology that closely parallels that observed in AD (5). Additional in vivo evidence suggesting that the A␤ peptide itself may be biologically active comes from a transgenic model overexpressing A␤ , in which A␤ transgene expression was detected in a variety of peripheral tissues but histopathological changes were restricted to the brain. Moreover, the neurodegeneration was largely limited to the cerebral cortex, ...