Description:
<jats:p> Toll-like Receptor 4 on Nonhematopoietic Cells Sustains CNS Inflammation during Endotoxemia, Independent of Systemic Cytokines </jats:p><jats:p> Chakravarty S, Herkenham M </jats:p><jats:p> J Neurosci 2005;25(7):1788–1796 </jats:p><jats:p> Inflammatory agonists such as lipopolysaccharide (LPS) induce robust systemic as well as CNS responses after peripheral administration. Responses in the innate immune system require triggering of toll-like receptor 4 (TLR4), but the origin of CNS sequelae has been controversial. We demonstrate expression of TLR4 transcripts in mouse brain in the meninges, ventricular ependyma, circumventricular organs, along the vasculature, and in parenchymal microglia. The contribution of TLR4 expressed in CNS resident versus hematopoietic cells to the development of CNS inflammation was examined using chimeric mice. Reciprocal bone marrow chimeras between wild-type and TLR4 mutant mice show that TLR4 on CNS resident cells is critically required for sustained inflammation in the brain after systemic LPS administration. Hematopoietic TLR4 alone supported the systemic release of acute phase cytokines, but transcription of proinflammatory genes in the CNS was reduced in duration. In contrast, TLR4 function in radiation-resistant cells was sufficient for inflammatory progression in the brains of chimeric mice, despite the striking absence of cytokine elevations in serum. Surprisingly, a temporal rise in serum corticosterone was also dependent on TLR4 signaling in nonhematopoietic cells. Our findings demonstrate a requirement for TLR4 function in CNS-resident cells, independent of systemic cytokine effects, for sustained CNS-specific inflammation and corticosterone rise during endotoxemia. </jats:p><jats:p> Innate Immune Reaction in Response to Seizures: Implications for the Neuropathology Associated with Epilepsy </jats:p><jats:p> Turrin NP, Rivest S </jats:p><jats:p> Neurobiol Dis 2004;16(2):321–334 </jats:p><jats:p> In the present study, the expression of proinflammatory transcripts was assessed across the brain of mice having undertaken pilocarpine-induced seizures. Pilocarpine-induced marked neurodegeneration and demyelination in multiple regions of the forebrain. The pattern of genes encoding toll-like receptor type 2 (TLR2) and I κB α (index of NF- κB activation) was associated with the neurodegenerating areas, but this was not the case for the mRNA encoding other inflammatory proteins. Scattered tumor necrosis factor-alpha (TNF- α)-expressing cells were found across brain, whereas the signals for monocytechemoattractant protein-1 and microsomal prostaglandin mPGES E synthase were robust in thalamus and cerebral cortex and weak in the hippocampus and amygdala. TLR2 and TNF- α transcripts were expressed mainly in microglia/macrophages. Cyclooxygenase-2 was induced specifically in the hippocampus and piriform cortex. A low increase in interleukin-12 mRNA was detected in the brain, but the signal for interferon-gamma (IFN- γ) remained undetectable. Although proinflammatory markers were induced in a different manner across the CNS, their patterns were not characteristic of those caused by other inflammatory challenges, such as endotoxin. These data suggest a different mechanism involved in regulating the innate immune reaction in response to seizures and could have direct implications for the neuropathology associated with epilepsy. </jats:p>