Axon loss in the CNS is characteristic of many neurodegenerative diseases but the mechanisms of axon degeneration are poorly understood. In particular, we know little of the inflammatory response triggered by CNS axon degeneration with comparison to that provoked by death of the neuronal cell body. We show that Wallerian degeneration of the mouse optic nerve induces transcription of TGF-beta1 and TNF-alpha, but not pro-inflammatory cytokines IL-1beta and IL-6 and microglial activation. This atypical inflammatory response resembles macrophages that have phagocytosed apoptotic cells and prion-infected CNS. Significantly, peripheral endotoxin challenge after injury switched this profile by inducing IL-1beta, IL-6 transcripts, other inflammation-associated products and reducing neurofilament immunoreactivity. We propose that microglia are activated by Wallerian degeneration and persist in an atypical but "primed" state and can be switched by systemic inflammation to provoke a classical pro-inflammatory profile with potentially deleterious consequences.
"TGFb, particularly, is associated with a non-inflammatory microglial response to chronic and acute CNS injury that presumably reflects a phagocytic phenotype, similar to an M2 macrophage, rather than a classic M1-like inflammatory macrophage. Both of these studies have shown that peripheral challenge, usually with bacterial endotoxin lipopolysaccharide (LPS), can switch the phenotype of macrophages and microglia to pro-inflammatory, with a considerable increase in IL-1b and IL-6 output and a consequent increase in neuronal damage (Murray et al., 2011; Palin et al., 2008). These data indicate that even in chronic CNS disease, the nature of the disease is variable and dependant on perturbation of the peripheral immune system. "
"For AVP, apelin, IL-1β, TNF-α and Trpv2, total RNA was extracted on Qiagen RNeasy microcolumns, and contaminating DNA was degraded with Qiagen RNase-free DNase1, according to the manufacturer's instructions (Qiagen, Crawley, UK). The methods for RT-PCR and mRNA quantification have been described elsewhere . Briefly, PCR primers were designed with Primer Express 1.0 software, using published sequences for rat (Sigma-Genosys Ltd, Poole, UK). "
[Show abstract][Hide abstract] ABSTRACT: Normal aging is associated with vasopressin neuron adaptation, but little is known about its effects on the release of apelin, an aquaretic peptide colocalized with vasopressin. We found that plasma vasopressin concentrations were higher and plasma apelin concentrations lower in aged rats than in younger adults. The response of AVP/apelin neurons to osmotic challenge was impaired in aged rats. The overactivity of vasopressin neurons was sustained partly by the increased expression of Transient receptor potential vanilloid2 (Trpv2), because central Trpv blocker injection reversed the age-induced increase in plasma vasopressin concentration without modifying plasma apelin concentration. The morphofunctional plasticity of the supraoptic nucleus neuron-astrocyte network normally observed during chronic dehydration in adults appeared to be impaired in aged rats as well. IL-6 overproduction by astrocytes and low-grade microglial neuroinflammation may contribute to the modification of neuronal functioning during aging. Indeed, central treatment with antibodies against IL-6 decreased plasma vasopressin levels and increased plasma apelin concentration toward the values observed in younger adults. Conversely, minocycline treatment (inhibiting microglial metabolism) did not affect plasma vasopressin concentration, but increased plasma apelin concentration toward control values for younger adults. This study is the first to demonstrate dual vasopressin/apelin adaptation mediated by inflammatory molecules and neuronal Trpv2, during aging.
PLoS ONE 02/2014; 9(2):e87421. DOI:10.1371/journal.pone.0087421 · 3.23 Impact Factor
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