Superior olivary complex organization and cytoarchitecture may be correlated with function and catarrhine primate phylogeny

In the mammalian auditory system, the medial nucleus of the trapezoid body and the lateral superior olive (MNTB-LSO system) contribute to binaural intensity processing and lateralization. Localization precision varies with the sound frequencies. As recency of common ancestry with human beings increases, primates have improved low-frequency sensitivity and reduced sensitivity to higher frequencies. The medial part of the MNTB is devoted to higher frequency processing. Thus, its high-frequency-dependent function is nearly lost in humans and its role in binaural processing as part of the contralateral pathway to the LSO remains questionable. Here, Nissl-stained sections of the superior olivary complex of man (Homo sapiens), bonobo (Pan paniscus), chimpanzee (Pan troglodytes), gorilla (Gorilla gorilla), orangutan (Pongo pygmaeus), gibbon (Hylobates lar), and macaque (Macaca fascicularis) were compared to reveal differences and coincidences. From chimpanzees to humans, the size of the LSO decreased, and the MNTB as a compact nucleus nearly disappears. From chimpanzees to humans, the LSO/MNTB ratio increases dramatically too, whereas the LSO/MSO ratio remains 1.1; a finding that probably corresponds to the phylogenetic proximity between the species

Cholesterol Corrects Altered Conformation of MHC-II Protein in Leishmania donovani Infected Macrophages: Implication in Therapy

Previously we reported that Kala-azar patients show progressive decrease in serum cholesterol as a function of splenic parasite burden. Splenic macrophages (MΦ) of Leishmania donovani (LD) infected mice show decrease in membrane cholesterol, while LD infected macrophages (I-MΦ) show defective T cell stimulating ability that could be corrected by liposomal delivery of cholesterol. T helper cells recognize peptide antigen in the context of class II MHC molecule. It is known that the conformation of a large number of membrane proteins is dependent on membrane cholesterol. In this investigation we tried to understand the influence of decreased membrane cholesterol in I-MΦ on the conformation of MHC-II protein and peptide-MHC-II stability, and its bearing on the antigen specific T-cell activatio

Efficient Capture of Infected Neutrophils by Dendritic Cells in the Skin Inhibits the Early Anti-Leishmania Response

Neutrophils and dendritic cells (DCs) converge at localized sites of acute inflammation in the skin following pathogen deposition by the bites of arthropod vectors or by needle injection. Prior studies in mice have shown that neutrophils are the predominant recruited and infected cells during the earliest stage of Leishmania major infection in the skin, and that neutrophil depletion promotes host resistance to sand fly transmitted infection. How the massive influx of neutrophils aimed at wound repair and sterilization might modulate the function of DCs in the skin has not been previously addressed. The infected neutrophils recovered from the skin expressed elevated apoptotic markers compared to uninfected neutrophils, and were preferentially captured by dermal DCs when injected back into the mouse ear dermis. Following challenge with L. major directly, the majority of the infected DCs recovered from the skin at 24 hr stained positive for neutrophil markers, indicating that they acquired their parasites via uptake of infected neutrophils. When infected, dermal DCs were recovered from neutrophil depleted mice, their expression of activation markers was markedly enhanced, as was their capacity to present Leishmania antigens ex vivo. Neutrophil depletion also enhanced the priming of L. major specific CD4+ T cells in vivo. The findings suggest that following their rapid uptake by neutrophils in the skin, L. major exploits the immunosuppressive effects associated with the apoptotic cell clearance function of DCs to inhibit the development of acquired resistance until the acute neutrophilic response is resolved

Mechanisms of leukocyte lipid body formation and function in inflammation

An area of increasingly interest for the understanding of cell signaling are the spatio-temporal aspects of the different enzymes involved in lipid mediator generation (eicosanoid-forming enzymes, phospholipases and their regulatory kinases and phosphatases) and pools of lipid precursors. The compartmentalization of signaling components within discrete and dynamic sites in the cell is critical for specificity and efficiency of enzymatic reactions of phosphorilation, enzyme activation and function. We hypothesized that lipid bodies - inducible non-membrane bound cytoplasmic lipid domains - function as specialized intracellular sites of compartmentalization of signaling with major roles in lipid mediator formation within leukocytes engaged in inflammatory process. Over the past years substantial progresses have been made demonstrating that all enzymes involved in eicosanoid synthesis localize at lipid bodies and lipid bodies are distinct sites for eicosanoid generation. Here we will review our current knowledge on the mechanisms of formation and functions of lipid bodies pertinent to inflammation

Mechanisms of eosinophil cytokine release

Human eosinophils have been demonstrated to contain a multitude of cytokines and chemokines that exist pre-formed within these cells. This content of pre-formed cytokines, with diverse potential biologic activities, provides eosinophils with capabilities distinct from most other leukocytes. The localization of pre-formed cytokines within eosinophils is both within specific granules and associated with substantial numbers of morphologically distinct cytoplasmic vesicles. Stimulation for release of specific cytokines, such as IL-4, leads to a regulated signal transduction cascade, which is dependent on the formation of leukotriene C4 within eosinophils where it acts as an intracrine mediator. IL-4 release occurs selectively and is by means of vesicular transport. The capabilities of eosinophils not only to rapidly release pre-formed cytokines but also to differentially regulate which cytokines are released endow eosinophils with distinct abilities in innate and acquired immunity

Lipid Bodies in Inflammatory Cells: Structure, Function, and Current Imaging Techniques

Lipid bodies (LBs), also known as lipid droplets, have increasingly been recognized as functionally active organelles linked to diverse biological functions and human diseases. These organelles are actively formed in vivo within cells from the immune system, such as macrophages, neutrophils, and eosinophils, in response to different inflammatory conditions and are sites for synthesis and storage of inflammatory mediators. In this review, the authors discuss structural and functional aspects of LBs and current imaging techniques to visualize these organelles in cells engaged in inflammatory processes, including infectious diseases. The dynamic morphological aspects of LBs in leukocytes as inducible, newly formable organelles, elicitable in response to stimuli that lead to cellular activation, contribute to the evolving understanding of LBs as organelles that are critical regulators of different inflammatory diseases, key markers of leukocyte activation, and attractive targets for novel anti-inflammatory therapies

Allergen activates peripheral blood eosinophil nuclear factor-kappaB to generate granulocyte macrophage-colony stimulating factor, tumour necrosis factor-alpha and interleukin-8

Background Allergic inflammation is characterized by the influx and activation of eosinophils. Cytokines generated by both resident and infiltrating cells are responsible for the initiation and maintenance of this pathogenesis. This study focuses on allergen‐induced activation of eosinophil NF‐κB and generation of granulocyte macrophage‐colony stimulating factor (GM‐CSF), TNF‐α, and IL‐8.Methods Peripheral blood eosinophils were enriched to &gt;99.9% by Percoll gradient sedimentation and negative magnetic affinity chromatography. NF‐κB activation by 10 μg/mL house dust mite (HDM) extract was demonstrated immunocytochemically using a monoclonal antibody against the active form of NF‐κB (NF‐κBa). The authenticity of NF‐κB was confirmed by Western blot. Cytokine production was assessed both by immuno‐staining of eosinophils and by assay of cytokines in the cell supernatant.Results Activation of peripheral blood eosinophils from atopic, but not non‐atopic, donors induced activation of NF‐κB, which peaked at 4 h and was accompanied by a decline in IκB‐α. The activation of authentic NF‐κB was confirmed in gel shift assays. Supershift assays showed p65 to be the major subunit of eosinophil NF‐κB. Immunofluorescent confocal microscopy demonstrated localization of NF‐κBa to the nucleus. Following activation, cytokine immunoreactivity was seen in a fraction of the eosinophils and cytokines were released into the supernatant. The NF‐κB inhibitors, calpain inhibitor 1 (10 μm), pentoxifylline (0.5 mm), pyrrolidine dithiocarbamate (PDTC, 10 μm) or gliotoxin (1 pg/mL) reduced the generation of GM‐CSF, TNF‐α and IL‐8 in parallel with their inhibition of NF‐κB.Conclusions HDM allergen activates human eosinophil NF‐κB leading to the production of the cytokines GM‐CSF, TNF‐α and IL‐8. We speculate that a role for eosinophil NF‐κB‐dependent cytokines is to act as an autocrine loop augmenting the survival of eosinophils in vivo.</p