Extracellular ATP (eATP), the most abundant among nucleotides, can act as a mediator during inflammatory responses by binding to plasmamembrane P2 purinergic receptors, which are widely expressed on cells of the immune system. eATP is generally considered as a classical danger signal, which stimulates immune responses in the presence of tissue damage. Converging evidence from several studies using murine models of chronic inflammation have supported this hypothesis; however, the role of eATP in the regulation of human immune function appears to be more complex. Chronic stimulation with micromolar eATP concentrations inhibits the proliferation of T and NK lymphocytes and enhances the capacity of dendritic cells to promote tolerance. The effect of eATP depends on multiple factors, such as the extent of stimulation, eATP concentration, presence/absence of other mediators in the microenvironment, and pattern of P2 receptor engagement.Small but significant differences in the pattern of P2 receptor expression in mice and humans confer the diverse capacities of ATP in regulating the immune response. Such diversity, which is often overlooked, should therefore be carefully considered when evaluating the role of eATP in human inflammatory and autoimmune diseases. (Blood. 2012;120(3): 511-518) Sources of eATPNucleotides are the constituents of nucleic acids, represent the energy store of the cell, and are involved in intracellular signaling as well as in cell-to-cell communication. 1 During the past 2 decades, increasing evidence has shown that extracellular ATP (eATP) is an important immune modulator. 2 ATP is present at relatively high levels in the cytoplasm of cells, where its concentration ranges from 1 to 10mM. In the extracellular space, its physiologic concentration is considerably lower, ranging between 1 and 10nM. Because of the steep concentration gradient as well as its small size and high mobility, ATP can be rapidly released together with other cellular components after mechanical stress, cell damage, or death. Increased ATP concentration in the extracellular milieu is therefore closely associated with tissue stress or damage. [3][4][5][6] However, nonlytic nucleotide release may occur in many cell types under a variety of conditions. Living cells in the steady-state release ATP through passive leakage. 7,8 Activated platelets represent a relevant source of ATP and release the nucleotide concomitantly with several inflammatory mediators during clot formation. 9 T lymphocytes release ATP during the early stages of activation through pannexin 1 (panx1) channels. 10 In addition, ATP is released during exercise from skeletal muscle as well as from vascular endothelial cells during conditions of increased blood flow or on mechanical stimulus. 11-13 Moreover, nonlytic ATP secretion from endothelial cells and leukocytes may be induced by pathogen-associated molecules, such as lipopolysaccharide. 14-17 ATP is also increased in draining lymph nodes during a contact hypersensitivity reaction. 18 ATP is released during ...

Manipulating the metabolism to redirect macrophage polarization might be useful in various pathologies, including an efficient skeletal muscle regeneration. Unraveling the complexity pertaining to metabolic signatures that are specific for the different macrophage subsets is crucial for identifying new compounds that are able to trigger macrophage polarization and that might be used for therapeutical purposes.

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Vascular smooth muscle cell (VSMC) proliferation contributes to vascular remodeling in atherosclerosis and hypertension. Calcium-dependent signaling through calcium/calmodulin-dependent kinase II (CaMKII) and ERK1/2 activation plays an important role in the regulation of VSMC proliferation by agents such as alpha-adrenergic receptor agonists. Nevertheless, how the CaMKII and ERK pathways interact in VSMCs has yet to be characterized. The aim of the present study was to clarify this interaction in response to alpha(1)-adrenergic receptor-mediated VSMC proliferation. We discovered that phenylephrine stimulation resulted in complex formation between CaMKII and ERK in a manner that facilitated phosphorylation of both protein kinases. To assess the effects of CaMKII/ERK association on VSMC proliferation, we inhibited endogenous CaMKII either pharmacologically or by adenoviral-mediated gene transfer of a kinase-inactive CaMKII mutant. Inhibition of CaMKII activation but not CaMKII autonomous activity significantly decreased formation of the CaMKII/ERK complex. On the contrary, the expression of constitutively active CaMKII enhanced VSMC growth and CaMKII/ERK association. In addressing the mechanism of this effect, we found that CaMKII could not directly phosphorylate ERK but instead enhanced Raf1 activation. By contrast, ERK interaction with CaMKII facilitated CaMKII phosphorylation and promoted its nuclear localization. Our results reveal a critical role for CaMKII in VSMC proliferation and imply that CaMKII facilitates assembly of the Raf/MEK/ERK complex and that ERK enhances CaMKII activation and influences its subcellular localization.

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