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Thread: Late Neutrophil Surrounded - Platelets, Platelet Satellitism picture - blood histology atlas

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    Default Late Neutrophil Surrounded - Platelets, Platelet Satellitism picture - blood histology atlas

    Monocytes interact and cross-talk with platelets in many settings including inflammation, hemostasis, or vascular disorders. These interactions are important for the regulation of life span of both cell types. In this review the complex mechanism and interactions regulating life span of monocytes and thrombocytes are described in detail. Also we depict the apoptosis of platelets and Mphi in special consideration of phagocytosis.

    The mononuclear phagocyte system
    The mononuclear phagocyte system or monocyte-macrophage system constitutes the whole ensemble of CD34+ myeloid progenitor mononuclear cells sharing endocytic, morphologic, and antigenic characteristics Environment and prevalent or emerging systemic and local conditions (e.g., inflammation) induce activation, adherence, margination, and maturation of circulating peripheral blood mononuclear cells (PBMC). Approximately 2-9% of the peripheral human blood leukocytes are PBMC (about 5-10% of peripheral human blood leukocytes are mature monocytes) , but in average only about 40% of the available monocytes circulate while the rest migrate . The term PBMC itself is a collective term for heterogeneous monocytic subsets characterized by a high potential for differentiation Lately, particular populations even acting as pluripotent stem cells, were identified . The classical understanding of differentiation comprises the maturation of immature circulating PBMC into specialized and tissue typical resident macrophages and antigen presenting cells (APC) derived from bone marrow progenitors. Three origins have been identified: macrophages can originate from the yolk sac, the fetal liver and the bone marrow during different developmental stages . Directly related to their differentiation state is their functional capacity to play specific roles in immunoregulation during pathogen recognition, malignancy or tissue repair and morphogenetic remodelling . Independently of their origin all MPS act as professional phagocytosis and antigen presenting cells .

    Phagocytosis, the uptake of particles larger than 0.5 μm, is one of the strategies of cells to internalize particles and solutes. Professional phagocytes are characterized by their professional phagocytic receptors which are able to ingest particles even when expressed in non-phagocytic cells.

    Regulation of phagocytosis
    Phagocytosis can be divided in type I, involving the engulfment of particles via pseudopodia, and type II, referring to complement-dependant invagination of the plasma membrane After incorporation and lysis, distinct products of the degradation process are presented via major histocompatibility complex II (MHC-II) receptors. But to some extent, professional APC can break the rule presenting exogenous antigens on MHC class I molecules (cross-presentation).

    Mphi express a broad spectrum of specific membrane receptors enabling rapid and efficient phagocytosis. Important receptors are the scavenger receptors type A and B, comprising a group of receptors (CD204, MARCO, CD36, CD68 etc.) which recognize modified oxidized LDL and have been implicated in host defence Receptor occupancy activates the monocyte and can lead to internalization of (opsonized) pathogens. Phagosomes are formed using actin remodelling and acidification of the phagosome lumen kills unwanted intruders. During this event the maturing vacuole drastically changes its composition, keeping its size, via fusion and secession with endosomes of distinct developmental stages (early and late endosomes) and lysosomes containing acidic material (proteolytic enzymes and oxidants). The maturation process ends in the generation of a microbicidal phagolysosome capable of degrading ingested material. Processed antigens are mainly presented via major MHC-II to recruit T- and B-cells for activation of the primary immune response.

    Phagocytosis in inflammation and wound healing
    The microenvironment helps determine distinct populations of macrophages classified as M1 and M2. The M2 macrophages can further be subdivided into M2a, M2b and M2c depending on the cytokine milieu . In the presence of IFNg and/or LPS, classical activated macrophages (M1) evolve and promote host-defense via secretion of a pro-inflammatory effector molecule cocktail including IL-1, IL-6, IL-8, IL-12, IL-23, CXCL10, CCL5 and TNF-alpha (20,21). M1 control pathogen infiltration by producing reactive oxygen species (ROS), nitric oxide (NO), leukotrienes , platelet activating factor (PAF), prostaglandins , and plasminogen activator enzymes among others. Secretion of these cytokines and chemokines results in recruitment and activation of T-, B-, NK-cells, and inflammatory monocytes. The removal of apoptotic or necrotic cell debris is one of the "classical" tasks of M1.

    Clearance of cells (apoptotic or (secondary) necrotic) induces immunoregulatory pathways. The subsequent immune response, either pro- or antiflammatory, is dependent on many different factors such as the type of cell, the stage of the dying cell, the type of cell death, mechanism of uptake and the microenvironment. Phagocytosis of early apoptotic cells induces an anti-inflammatory response leading to inhibition of monocyte recruitment and tolerance, uptake of late apoptotic and necrotic cells typically induces inflammation promoting autoimmunity. Phagocytosis is influenced by cytokines, for exampleIFN-g and IL-4 inhibit phagocytosis, tumor necrosis factor-alpha (TNF-a ) expedites it. Interestingly, the intrinsic process of phagocytosis cannot affect apoptosis of Mphi , whereas the uptake of certain substances can induceor protect from cellular death . Considering anti-inflammatory issues, phagocytosis even encourages Mphi to induce apoptosis in neutrophils .
    Late Neutrophil Surrounded Platelets, Platelet attachment.php?s=46b857f3e9044a80fd0df98d081b6c02&attachmentid=1440&d=1439748222

    Monocyte/macrophage-depleted animals exhibit defective wound repair such as delays in angiogenesis and re-epithelialization, suggesting an important role for Mphi in these processes . Administration of Mphi into wounds resulted in considerably improved healing . It is of note, that the presence of Mphi not only creates an aseptic wound-milieu but initiates proliferation and synthesis of new matrix components, whereas the incidence of keloid decreases. These Mphi are characterized as low IL-12 producers and can be subdivided into three groups M2a, M2b and M2c. M2a macrophages known as alternatively activated macrophages, differentiate in the presence of IL-4, IL-13 or IL-21 and participate in tissue repair. In contrast to classical activated pro-inflammatory M1 macrophages, M2a phagocytes exhibit an anti-inflammatory cytokine profile enabeling them to limit and terminate inflammation. M2a's act via secretion of cytokines involved in wound healing, angiogenic and immune-regulatory cytokines and growth factors such as IL-10, TGF-beta and VGEF. Regulation also happens through upregulation of arginase-1 expression which causes a shift from NO synthases towards ornithine production and collagen synthesis and through limitation of pro-inflammatory activated granulocytes via induction of apoptosis through Fas-ligand and TNF-a production. Debris is eliminated, healing is initiated, and in cooperation with dendritic cells self- tolerance (T-cell tolerance) is induced. If termination of inflammation is not regulated, chronic inflammation and autoimmune diseases can arise Immune complexes and ligands of IL-1R and TLRs lead to the differentiation of M2b, while M2c macrophages are induced via IL-10, TGFbeta or glucocorticoids. These subsets have also regulatory functions.

    Phagocytosis in human disease
    Atherosclerosis has been classified as a chronic inflammatory disease due to the accumulation of white blood cells and formation of atheromatous plaques Hence, it is not surprising that findings to date elucidated a complex role of macrophage phagocytosis in atherogenesis Much of the previous investigations on atherogenesis focused on the mechanisms by which monocytes are attracted and tethered to the endothelial layer emphasising the role of different receptors and the functions of macrophages/foam cells in intravascular lipid metabolism. Nowadays, we learn more and more about enzymatic activities leading to angiogenesis, bleeding, coagulation, rupture, and the different actions and types of Mphi involved in this process.

    The enrichment of modified lipids such as oxidized LDL on the arterial wall, but also a change in blood rheology or inflammation, results in the activation of endothelial cells . This stimulation leads to an increased expression of adhesion molecules for monocytes and T cells such as P- and E-selectin, VCAM and ICAM facilitating the recruitment of these cells. Mature macrophages phagocytose oxidized LDL mainly via the scavenger receptors A, lectin-like oxLDL receptor, and CD36 leading to accumulation of lipid droplets in the cytoplasm and causing the transformation into foam cells , and subsequently to the classical pro-inflammatory activation of these lipid-laden macrophages . However, despite the detrimental effects of foam cell formation on atherogenesis, pharmacological approaches to suppress foam cell generation through inhibition of acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) failed, and resulted paradoxically in increased atherosclerosis

    An alternative recruitment of monocytes into these lipid-rich plaques occurs via the vasa vasorum, a network of microvessels . Activated macrophages produce and secrete proangiogenic factors inducing neovascularization most likely under hypoxic and inflammatory conditions leading to vulnerable intraplaque (neo-)vessels. Microhemorrhage and subsequent cell leakage results in iron accumulation and phagocytosis of these cells by plaque macrophages turning into foam cells . Subsequent aggregation of these foam cells results in the onset of a necrotic core while concurrently deposition of extracellular matrix components and smooth muscle cell recruitment expedites the fibrous cap formation and the progression and vulnerability of the plaque.

    Advanced plaques contain many apoptotic cells (AC) derived from all types of cells involved in atherosclerosis, including macrophages, foam cells, T-cells, and smooth muscle cells . Within the lesion inductors of apoptosis, i.e. hypoxia, growth factor withdrawal, high concentrations of free cholesterol and oxidised LDL, production of pro-apoptotic cytokines such as TNF-a or the release of excessive amounts of ROS/RNS by macrophages in addition to direct cell to cell interactions (e.g., binding of Fas Ligand to Fas) are present in abundance. As mentioned before, phagocytosis of AC also known as efferocytosis creates an anti-inflammatory environment via IL-10 and TGF-b and PGE2 production inducing repair. AC that are not scavenged in plaques become secondarily necrotic after loss of membrane integrity, accumulate in the growing plaque and contribute to the development of inflammation and via activation of thrombin to thrombosis. This elucidates the importance and beneficial effects of efficient phagocytosis of AC inside atherosclerotic lesions.

    Tumors were originally thought to be effectively reduced by macrophage invasion. However, over the last few years, conflicting results have challenged this paradigm by showing that different macrophage subsets can be linked with either protective or pathogenic roles in tumor growth M1 macrophages are part of the anti-tumor response through inflammatory cytokine production and counteracting the immunosuppressive and protumoral activities of M2 and regulatory subsets. However, tumors are capable of inducing differentiation of tumor-associated macrophages (TAM) changing their immunologically active state into a M2-like immunosuppressive and tumor promoting phenotype. Nevertheless, it is generally accepted that macrophages play an important regulatory role in tumor progression, metastasis, invasion and angiogenesis

    Interestingly, monocyte chemoattractant protein-1 (MCP-1) also known as CCL2 is a chemokine involved in monocyte/macrophage recruitment and has been implied in angiogenesis. Although it has angiogenic and protumoral effects, MCP-1 application was successfully used to treat tumors by attraction and activation of monocytes This apparently contradictory statement could be explained by the different macrophage subsets involved. M2 macrophages could be responsible and/or maybe dysregulated . In fact, dysregulation of MCP-1/Mphi was shown to be critical in autoimmune myocarditis Otherwise alternative activation of monocytes through phagocytosis of apoptotic cells, meaning deactivation of antitumor activity, could be involved

    Dysregulation of phagocytosis promotes the development of many more different diseases such as atopic dermatitis, alzheimer�s disease and fungal infection. In gout the effects of uncoated monosodium urate crystals on articular inflammation are well described . Urate crystals are encountered by synovial Mphi, which induces CD14 mediated release of prostaglandins, proteases, and pro-inflammatory cytokines including TNF-alpha, IL-1β, IL-6, and IL-8 Phagocytosed crystals cause lysis of the phagolysosome, release of its toxic contents and evoke cellular necrosis. Additional effects may be caused by perforation of cell membranes.

    Phagocytosis plays obviously an important role in healing and disease but it is also an essential process targeted by viruses, bacteria, parasites and drugs. The Human immunodeficiency virus infects CD4+ Mphi via membrane fusion, while bacteria like Mycobacterium tuberculosis or protozoa such as Leishmania species even developed strategies using phagocytosis to invade Mphi. However, the mechanism of phagocytosis is also utilized by physicians for drug delivery when they apply e.g., AmBisome ®, which is Amphotericin B packed in liposomes and taken up by the infected macrophages, to treat leishmaniasis in patients.

    Taken together, receptor binding/activation of Mphi initiates various biological functions such as phagocytosis, subsequent intracellular dismantling of pathogens, production of ROS/RNS, production and release of inflammatory messengers (Table 1), cell mediated cytotoxicity, and enhancement of antigen presentation. Phagocytosis itself drives Mphi in dependency of the absorbed materials into certain modes of activation. Phagocytosis is pivotal for uptake and degradation of pathogenes, debris and senescent cells also taking part in tissue remodelling, development, and immune response.


    Last edited by Medical Photos; 08-16-2015 at 06:03 PM.

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