Cytokines as therapeutic targets for cardio- and cerebrovascular diseases

Despite major advances in prevention and treatment, cardiac and cerebral atherothrombotic complications still account for substantial morbidity and mortality worldwide. In this context, inflammation is involved in the chronic process leading atherosclerotic plaque formation and its complications, as well as in the maladaptive response to acute ischemic events. For this reason, modulation of inflammation is nowadays seen as a promising therapeutic strategy to counteract the burden of cardio- and cerebrovascular disease. Being produced and recognized by both inflammatory and vascular cells, the complex network of cytokines holds key functions in the crosstalk of these two systems and orchestrates the progression of atherothrombosis. By binding to membrane receptors, these soluble mediators trigger specific intracellular signaling pathways eventually leading to the activation of transcription factors and a deep modulation of cell function. Both stimulatory and inhibitory cytokines have been described and progressively reported as markers of disease or interesting therapeutic targets in the cardiovascular field. Nevertheless, cytokine inhibition is burdened by harmful side effects that will most likely prevent its chronic use in favor of acute administrations in well-selected subjects at high risk. Here, we summarize the current state of knowledge regarding the modulatory role of cytokines on atherosclerosis, myocardial infarction, and stroke. Then, we discuss evidence from clinical trials specifically targeting cytokines and the potential implication of these advances into daily clinical practice

CD38 Exacerbates Focal Cytokine Production, Postischemic Inflammation and Brain Injury after Focal Cerebral Ischemia

BACKGROUND: Converging evidence suggests that inflammatory processes significantly influence brain injury and clinical impairment in ischemic stroke. Although early studies suggested a key role of lymphocytes, recent data has emphasized the orchestrating function of innate immunity, i.e., macrophages and microglia. The bifunctional receptor and ectoenzyme CD38 synthesizes calcium-mobilizing second messengers (e.g., cyclic ADP-ribose), which have been shown to be necessary for activation and migration of myeloid immune cells. Therefore, we investigated the dynamics of CD38 in stroke and the impact of CD38-deficiency on cytokine production, inflammation and cerebral damage in a mouse model of cerebral ischemia-reperfusion. METHODOLOGY/PRINCIPAL FINDINGS: We show that the local expression of the chemokine MCP-1 was attenuated in CD38-deficient mice compared with wildtype mice after focal cerebral ischemia and reperfusion. In contrast, no significant induction of MCP-1 expression was observed in peripheral blood after 6 hours. Flow cytometry analysis revealed less infiltrating macrophages and lymphocytes in the ischemic hemisphere of CD38-deficient mice, whereas the amount of resident microglia was unaltered. An up-regulation of CD38 expression was observed in macrophages and CD8(+) cells after focal cerebral ischemia in wildtype mice, whereas CD38 expression was unchanged in microglia. Finally, we demonstrate that CD38-deficiency decreases the cerebral ischemic injury and the persistent neurological deficit after three days of reperfusion in this murine temporary middle cerebral artery occlusion (tMCAO) model. CONCLUSION/SIGNIFICANCE: CD38 is differentially regulated following stroke and its deficiency attenuates the postischemic chemokine production, the immune cell infiltration and the cerebral injury after temporary ischemia and reperfusion. Therefore CD38 might prove a therapeutic target in ischemic stroke

Adult neural stem/progenitor cells in response to their microenvironment : proliferation, differentiation, and migration

The plasticity of adult neural stem/progenitor cells allows a differential response to a variety of environmental cues. Over the past decade, significant research efforts have been devoted into understanding the regulation of neural stem/progenitor cells due to their promising potential for cell replacement therapies in adult neurological diseases. It has been demonstrated that after brain injury both endogenous and grafted neural stem/progenitor cells have the ability to proliferate to expand their number, migrate long distances to the lesioned site and differentiate into new specific neurons to replace the ones that have been lost. All these procedure are regulated by extrinsic cue found in the microenvironment surrounding the neural stem/progenitor cells. Several chemokines and growth factors have been identified that stimulate the proliferation, differentiation, and migration of endogenous or exogenous neural stem/progenitor cells. The first part of this dissertation work (Chapter 5) identifies the role of several extrinsic factors expressed and secreted by hippocampal astrocytes that regulate the neuronal differentiation of adult neural stem/progenitor cells in the neurogenic region of the dentate gyrus. While in non-neurogenic regions, astrocytes secrete factors that inhibit the differentiation of adult neural stem/progenitor cells. Cell migration is an essential component of neurogenesis in both embryonic and adult brains. Many critical signaling factors and molecules are involved in governing the dynamic process of cell migration, which includes chemotaxis, cytoskeleton restructuring, nuclear translocation, and extracellular matrix remodeling. Extracellular molecules regulate the interaction and communication of the cell with its microenvironment. Investigators have shown that extracellular matrix and matrix remodeling factors play a critical role in directing stem cell migration during development and in the response to brain injury. Identification of the molecular pathways and mechanisms of these factors, involved in regulating stem cell fate choice and homing into the damaged areas, is vital for new treatments in brain injury. In the second part of this dissertation (Chapter 6), I focus on demonstrating that several matrix metalloproteinases are demonstrated to play a role in both the migration and differentiation of adult neural stem cells/progenitor in response to stroke-induced chemokines. The role of matrix metalloproteinase in differentiation may be the first evidence of extracellular molecules effecting the intrinsic regulation of adult neural stem/progenitor fate choice

Upregulation Of Microglial Zeb1 Ameliorates Brain Damage After Acute Ischemic Stroke

Microglia are a key immune-competent cell type that respond to environmental and physiological changes during ischemic stroke. However, the molecular mechanisms controlling post-ischemic microglia activity are unclear. Understanding these mechanisms may ultimately reduce disease burden and allow the manipulation of microglia responses to shape the outcomes of stroke. Here, we report that, after experimentally induced stroke, ZEB1 is highly expressed in ipsilateral cerebral hemisphere, where it is upregulated mainly in microglia. Using a conditional transgenic mouse, we found that ZEB1 upregulation in microglia regulates immune responses in the CNS and alleviates brain injury after ischemic stroke. Our data indicate that ZEB1 overexpression mediates microglia responses and, in turn, inhibits the production of astrocytic CXCL1 through the TGF-β1-dependent pathway. Reduced CXCL1 leads to a decline in neutrophil infiltration into the brain, thereby reducing CNS inflammation. Our results demonstrate the importance of ZEB1 in microglia-orchestrated neuroinflammation and suggest a potential means for reducing stroke-induced neurological injury. Li et al. show that ZEB1 overexpression mediates microglia responses and, in turn, inhibits production of astrocytic CXCL1 through the TGF-β1-dependent pathway. Reduced CXCL1 leads to the decline of neutrophil infiltration into the brain. This demonstrates the importance of ZEB1 in microglia-orchestrated neuroinflammation and suggests a potential means for reducing stroke-induced neurological injury