Molecular bases of TLR4 induced gene expression in human neutrophils

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Neutrophils play an essential role in infection and innate immunity, providing early defense against invading microorganisms. They comprise approximately two-thirds of peripheral blood leukocytes and transit rapidly to sites of infection, where they limit infection and allow recruitment and activation of other immune cells through the release of inflammatory mediators and antimicrobial products, resulting in pathogen clearance and ultimately, in the initiation of an adaptive immune response (1). Excessive or inappropriate neutrophil activation can result in dysregulated inflammation and severe tissue damage and thus contributes to the pathology of a variety of noninfectious diseases, such as rheumatoid arthritis, inflammatory bowel disease, asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome (2, 3). Mature granulocytes originate (at a rate of 80 millions per minute) from pluripotential stem cells located in the bone marrow, under the influence of several growth factors named colony-stimulating factors (CSFs), which include multi-CSF (also known as Interleukin-3), Granulocyte and Macrophage CSF (GM-CSF), Granulocyte CSF (G-CSF), and Macrophage CSF (M-CSF) (4) (5). Neutrophils are members of the granulocyte family of leukocytes, which also comprises eosinophils (< 1.5 %) and basophils (<0.5 %). A1l three cell types contain distinct cytoplasmic granules, which are storage pools for intracellular enzymes, cationic proteins, receptors and other proteins. Within the circulation, neutrophils exist in two pools which are in a dynamic equilibrium: a circulating pool, and a ''marginated'' pool; the latter is believed to be 4 sequestered within the microvasculature of many organs. Under pathological conditions, such as bacterial infections, the number of circulating neutrophils may increase dramatically (even up to ten-fold), as a result of an accelerated release of neutrophils from the bone marrow, combined with a stimulated maturation of immature neutrophils by CSFs and demargination from the lungs or the spleen. Cell-labeling experiments have shown that the lifespan of neutrophils in the circulation, compared to the ones of other cell types such as monocytes/macrophages which may live for months or even years, is short, with a half-life of approximately 7 hours. Senescent neutrophils are thought to undergo apoptosis prior to removal by macrophages (6). This process may also play a role in terminating inflammatory responses, and its importance can be illustrated by the fact that PMN disintegration in vivo would cause the release of their cytotoxic content into the extracellular milieu and thus inflammation...