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Neuropeptide Y (NPY), a major autonomic nervous system and stress mediator, is emerging as an important regulator of inflammation, implicated in autoimmunity, asthma, atherosclerosis, and cancer. Yet the role of NPY in regulating phenotype and functions of dendritic cells (DCs), the professional antigen-presenting cells, remains undefined. Here we investigated whether NPY could induce DCs to migrate, mature, and polarize naive T lymphocytes. We found that NPY induced a dose-dependent migration of human monocyte-derived immature DCs through the engagement of NPY Y1 receptor and the activation of ERK and p38 mitogen-activated protein kinases. NPY promoted DC adhesion to endothelial cells and transendothelial migration. It failed to induce phenotypic DC maturation, whereas it conferred a T helper 2 (Th2) polarizing profile to DCs through the up-regulation of interleukin (IL)-6 and IL-10 production. Thus, during an immune/inflammatory response NPY may exert proinflammatory effects through the recruitment of immature DCs, but it may exert antiinflammatory effects by promoting a Th2 polarization. Locally, at inflammatory sites, cell recruitment could be amplified in conditions of intense acute, chronic, or cold stress. Thus, altered or amplified signaling through the NPY-NPY-Y1 receptor-DC axis may have implications for the development of inflammatory conditions.-Buttari, B., Profumo, E., Domenici, G., Tagliani, A., Ippoliti, F., Bonini, S., Businaro, R., Elenkov, I., Riganò, R. Neuropeptide Y induces potent migration of human immature dendritic cells and promotes a Th2 polarization.

Atherosclerosis initiation and progression is controlled by inflammatory molecular and cellular mediators. Cells of innate immunity, stimulated by various endogenous molecules that have undergone a transformation following an oxidative stress or nonenzymatic glycation processes, activate cells of the adaptive immunity, found at the borders of atheromas. In this way, an immune response against endogenous modified antigens takes place and gives rise to chronic low-level inflammation leading to the slow development of complex atherosclerotic plaques. These lesions will occasionally ulcerate, thus ending with fatal clinical events. Plaque macrophages represent the majority of leukocytes in the atherosclerotic lesions, and their secretory activity, including proinflammatory cytokines and matrix-degrading proteases, may be related to the fragilization of the fibrous cap and then to the rupture of the plaque. A considerable amount of work is currently focused on the identification of locally released proinflammatory factors that influence the evolution of the plaque to an unstable phenotype. A better understanding of these molecular processes may contribute to new treatment strategies. Mediators released by the immune system and associated with the development of carotid atherosclerosis are discussed.

Studies aimed at elucidating the pathogenetic mechanisms underlying the initiation and progression of human atherosclerosis have emphasized the central role of inflammatory and immune cells. Atherosclerotic plaques are infiltrated by activated macrophages, T and B lymphocytes, plasma cells, and mast cells, releasing inflammatory molecules, which amplify the severity of the disease. Endothelial cells subjected to various stress conditions express increased amounts of heat shock proteins (HSPs), some of the most successfully conserved proteins throughout evolution. Many experimental observations reviewed in this article draw attention to several HSPs targeted by a specific cellular and humoral immune response in patients with atherosclerotic disease. The review also reports preliminary data obtained by our group on the possible role of HSP90 as a candidate autoantigen in carotid atherosclerosis. Our study deals with the presence of specific antibodies and T cells directed against HSP90 in patients with carotid atherosclerotic plaques. In 60% of these subjects' sera but in none of the sera from healthy controls immunoblotting (IB) detected the presence of specific antibodies. Moreover, 20% of peripheral blood mononuclear cells (PBMC) samples from patients but none from healthy subjects proliferated in response to human purified HSP90. In vitro experiments showed an upregulation of HSP90 expression in endothelial cells exposed to oxidative stress by treatment with H(2)O(2) and greater release of soluble HSP90 in culture supernatants from H(2)O(2)-treated cells than from untreated cells.

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