Antibody neutralization experiments demonstrated that the key MSCderived soluble factor responsible for neutrophil protection from apoptosis was IL-6, which signaled by activating STAT-3 transcription factor. Furthermore, IL-6 expression was detected in MSC by real-time reverse transcriptionpolymerase chain reaction and enzyme-linked immunosorbent assay. Finally, recombinant IL-6 was found to protect neutrophils from apoptosis in a dose-dependent manner. MSC had no effect on neutrophil phagocytosis, expression of adhesion molecules, and chemotaxis in response to IL-8, f-MLP, or C5a. These results support the following conclusions: (a) in the bone marrow niche, MSC likely protect neutrophils of the storage pool from apoptosis, preserving their effector functions and preventing the excessive or inappropriate activation of the oxidative metabolism, and (b) a novel mechanism whereby the inflammatory potential of activated neutrophils is harnessed by inhibition of apoptosis and reactive oxygen species production without impairing phagocytosis and chemotaxis has been identified. STEM CELLS 2008;26:151-162 Disclosure of potential conflicts of interest is found at the end of this article.

The exudation of neutrophils is the hallmark of a form of inflammatory response occurring after tissue colonization by invading bacteria or as an expression of various non-infectious diseases. All these diseases are characterized by a high risk of developing irreversible tissue injury. Neutrophil-endothelium interactions, activation-induced functional and structural changes of responding neutrophils, regulatory systems of neutrophil function, and oxidative-proteolytic pathways responsible for histotoxicity are reviewed here. Finally, perspectives for rational approaches to handle the development of tissue injury during neutrophilic inflammation are considered.

Background and Purpose-The concept of "vulnerable plaque" has been extended to the more recent definition of the "cardiovascular vulnerable patient," in which "intraplaque" and "systemic" factors contribute to the cumulative risk of acute cardiovascular events. Thus, we investigated the possible role of systemic and intraplaque inflammation in patients asymptomatic versus symptomatic for ischemic stroke. Methods-Regions upstream and downstream the blood flow were isolated from internal carotid plaques of patients asymptomatic (nϭ63) or symptomatic (nϭ18) for ischemic stroke. Specimens were analyzed for lipid, collagen, macrophage, lymphocyte, neutrophil, mast cell and smooth muscle cell content, and chemokine and cytokine mRNA expression. Chemokine receptors and adhesion molecules were assessed on circulating leukocytes by flow cytometry. Systemic inflammatory markers and biochemical parameters were measured on total blood, plasma, and serum. Results-Tumor necrosis factor-␣ and CCL5 serum levels as well as intercellular adhesion molecule-1 expression on circulating neutrophils were increased in symptomatic as compared with asymptomatic patients. Collagen content and smooth muscle cell infiltration were decreased in symptomatic plaques. In upstream regions of symptomatic plaques, lipid content and lymphocyte infiltration were increased. In downstream regions of symptomatic plaques, macrophage, neutrophil, and mast cell infiltration were increased. Intraplaque collagen content was positively correlated with smooth muscle cell infiltration and inversely correlated with macrophages, neutrophils, or serum tumor necrosis factor-␣. Collagen reduction in downstream regions and serum tumor necrosis factor-␣ were independently associated with the likelihood of being symptomatic. Conclusions-Inflammatory mediators are increased in ischemic stroke. Despite statistically significant, the correlation between tumor necrosis factor-␣ serum level and intraplaque vulnerability was weak and probably of limited biological importance. (Stroke. 2010;41:1394-1404.)Key Words: carotid artery Ⅲ carotid endarterectomy Ⅲ inflammation Ⅲ leukocytes V ariations in plaque composition, size, and severity of lumen stenosis have been identified as crucial aspects of plaque vulnerability. 1,2 Inflammation, thin or fissured cap with large lipid core, and severe stenosis increase plaque vulnerability. In addition, superficial calcified nodules, hemorrhages, endothelial dysfunction, and expansive (positive) remodeling could also contribute to atherosclerotic plaque destabilization. More recently, clinical studies suggested that acute ischemic events could be also influenced by systemic factors and peripheral tissue resistance to hypoxia. 3 Nonspecific serum markers of altered lipid profile, inflammation, and hypercoagulability have been identified. 4 Thus, the concept of "vulnerable plaque" has been extended to the more recent definition of the "cardiovascular vulnerable patient," in which "intraplaque" and systemic factors contribute to the cumulati...

ARG1, expressed by human PMNs, inhibits T cell proliferation by depleting extracellular L-arginine. Here, we report that ARG1, released from gelatinase granules by PMNs, is inactive at physiological pH unless activated by factor(s) stored in azurophil granules. Whereas ARG1 exocytosis was induced by TNF-α or ionomycin, only the latter mediated the release of both granules, resulting in extracellular ARG enzyme activity at physiological pH. Furthermore, after fractionation of the different classes of granules, only the mixture of gelatinase and azurophil granules resulted in ARG1 activity at physiological pH. The use of protease inhibitors indicated the involvement of a PMSF- and leupeptin-susceptible serine protease in ARG1 processing and activation. Finally, the supernatant of viable PMNs undergoing frustrated phagocytosis, which mediates gelatinase and azurophil granule release, inhibited T cell proliferation through ARG-dependent mechanisms. In vivo, high ARG1 concentrations and increased ARG enzyme activity, sufficient to inhibit T cell proliferation, were observed in synovial fluids from RA. These findings suggest that PMNs, recruited at sites of immune complex deposition, induce ARG1-dependent immune suppression through concomitant exocytosis of gelatinase and azurophil granules.

The microenvironment of rheumatoid SF is a proinflammatory milieu responsible for the in loco persistence of activated and long-surviving neutrophils. Adenosine plays a crucial role in this phenomenon, which is related to anti-apoptotic activity.