Interleukin 15 expression in the CNS: blockade of its activity prevents glial activation after an inflammatory injury.
ABSTRACT Although reactive glia formation after neuronal degeneration or traumatic damage is one of the hallmarks of central nervous system (CNS) injury, we have little information on the signals that direct activation of resting glia. IL-15, a pro-inflammatory cytokine involved in regulating the response of T and B cells, may be also key for the regulation of early inflammatory events in the nervous system. IL-15 was expressed in the CNS, most abundantly in cerebellum and hippocampus, mainly in astrocytes and in some projection neurons. Using a rodent model of acute inflammatory injury [lipopolysaccharide (LPS) injection], we found enhanced expression of IL-15 in both reactive astroglia and microglia, soon after CNS injury. Blockade of IL-15 activity with an antibody to the cytokine, reversed activation of both glial types, suggesting that IL-15 has a major role in the generation of gliotic tissue and in the regulation of neuroimmune responses. Because IL-15 appears to modulate the inflammatory environment acutely generated after CNS injury, regulating IL-15 expression seems a clear antiinflammatory therapy to improve the outcome of neurodegenerative diseases and CNS trauma.
SourceAvailable from: Donald Royall[Show abstract] [Hide abstract]
ABSTRACT: Interleukin (IL-15), a pro-inflammatory cytokine has been studied as a possible marker of Alzheimer's disease (AD); however its exact role in neuro-inflammation or the pathogenesis AD is not well understood yet. A Multiple Indicators Multiple Causes (MIMIC) approach was used to examine the relationship between serum IL-15 levels and AD in a well characterized AD cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). Instead of categorical diagnoses, we used two latent construct d (for dementia) and g' (for cognitive impairments not contributing to functional impairments) in our analysis. The results showed that the serum IL-15 level has significant effects on cognition, exclusively mediated by latent construct d and g'. Contrasting directions of association lead us to speculate that IL-15's effects in AD are mediated through functional networks as d scores have been previously found to be specifically related to default mode network (DMN). Our finding warrants the need for further research to determine the changes in structural and functional networks corresponding to serum based biomarkers levels.PLoS ONE 01/2015; 10(2):e0117282. DOI:10.1371/journal.pone.0117282 · 3.53 Impact Factor
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ABSTRACT: The expansion of the microglial population is one of the hallmarks of numerous brain disorders. The addition of circulating progenitors to the pool of brain macrophages can contribute to the progression of brain disease and needs to be precisely defined to better understand the evolution of the glial and inflammatory reactions in the brain. We have analyzed the degree of infiltration/recruitment of circulating monocytes to the microglial pool, in a prion disease model of chronic neurodegeneration. Our results indicate a minimal/absent level of CCR2-dependent recruitment of circulating monocytes, local proliferation of microglia is the main driving force maintaining the amplification of the population. A deficiency in CCR2, and thus the absence of recruitment of circulating monocytes, does not impact microglial dynamics, the inflammatory profile or the temporal behavioral course of prion disease. However, the lack of CCR2 has unexpected effects including the failure to recruit perivascular macrophages in diseased but not healthy CNS and a small reduction in microglia proliferation. These data define the composition of the CNS-resident macrophage populations in prion disease and will help to understand the dynamics of the CNS innate immune response during chronic neurodegeneration. GLIA 2014Glia 03/2014; DOI:10.1002/glia.22660 · 5.47 Impact Factor
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ABSTRACT: The study of neurogenesis during chronic neurodegeneration is crucial in order to understand the intrinsic repair mechanisms of the brain, and key to designing therapeutic strategies. In this study, using an experimental model of progressive chronic neurodegeneration, murine prion disease, we define the temporal dynamics of the generation, maturation and integration of new neurons in the hippocampal dentate gyrus, using dual pulse-chase, multicolour γ-retroviral tracing, transmission electron microscopy and patch-clamp. We found increased neurogenesis during the progression of prion disease, which partially counteracts the effects of chronic neurodegeneration, as evidenced by blocking neurogenesis with cytosine arabinoside, and helps to preserve the hippocampal function. Evidence obtained from human post-mortem samples, of both variant Creutzfeldt-Jakob disease and Alzheimer's disease patients, also suggests increased neurogenic activity. These results open a new avenue into the exploration of the effects and regulation of neurogenesis during chronic neurodegeneration, and offer a new model to reproduce the changes observed in human neurodegenerative diseases.Brain 06/2014; DOI:10.1093/brain/awu155 · 10.23 Impact Factor