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Peripheral inflammation can trigger a number of neuroinflammatory events in the CNS, such as activation of microglia and increases of proinflammatory cytokines. We have previously identified an interesting phenomenon, termed "euflammation", which can be induced by repeated subthreshold infectious challenges. Euflammation causes innate immune alterations without overt neuroimmune activation. In the current study, we examined the protective effect of euflammation against peripheral inflammation-induced neuroinflammation and the underlying mechanisms. When Escherichia coli or lipopolysaccharide (LPS) was injected inside or outside the euflammation induction locus (EIL), sickness behavior, global microglial activation, proinflammatory cytokine production in the brain, expression of endothelial cyclooxygenase II and induction of c-fos expression in the paraventricular nucleus of the hypothalamus were all attenuated in the euflammatory mice compared with those in the control unprimed mice. Euflammation also modulated innate immunity outside the EIL by upregulating receptors for pathogen-associated molecular patterns in spleen cells. In addition, euflammation attenuated CNS activation in response to an intra-airpouch (outside the EIL) injection of LPS without suppressing the cytokine expression in the airpouch. Collectively, our study demonstrates that signaling of peripheral inflammation to the CNS is modulated dynamically by peripheral inflammatory kinetics. Specifically, euflammation can offer effective protection against both bacterial infection and endotoxin induced neuroinflammation.

IL-1R1 signaling is important for the pathogenesis for almost all CNS diseases. Here, we demonstrate the cell-type specific IL-1R1 expression patterns in the brain using a knockin reporter. The functions of IL-1R1 are then investigated by selective reciprocal deletion or expression of IL-1R1 on specific cell types. Endothelial IL-1R1 is found to mediate sickness behavior, leukocyte recruitment, and inflammatory microglial activation, whereas ventricular IL-1R1 is found critical for monocyte recruitment and non-inflammatory microglial activation. In contrast, the astrocytic IL-1R1 signaling dampens inflammatory cytokines. Chronic hippocampal expression of IL-1 suppresses neurogenesis, through endothelial IL-1R1, but induces microglial activation through neuronal IL-1R1. In addition, IL-1 stimulates its own production in microglia indirectly through eIL-1R1. Collectively, these findings describe the structural and functional cytoarchitecture of the brain IL-1R1 expressing system and lay a foundation for the dissection and identification of IL-1R1 signaling pathways in the pathogenesis of numerous CNS diseases.

Glucocorticoid (GC) resistance is a severe problem associated with various inflammatory diseases. Previous studies have shown that repeated social stress induces GC resistance in innate immune cells, but the underlying molecular mechanisms have not been fully elucidated. Therefore, the purpose of this study was to examine potential underlying molecular mechanism(s) of repeated social defeat (RSD) stress on GC resistance in splenic macrophages. It was hypothesized that mRNA expression of receptors for GC and nuclear translocating-associated regulators in splenic macrophages would be affected by RSD, and that these changes would be associated with epigenetic modification. The data showed that the mRNA expression of GC and mineralocorticoid receptors were significantly decreased in splenic macrophages by RSD. RSD also induced a significantly decreased mRNA expression in FK506-binding protein 52 (FKBP52), consequently resulting in a significantly increased ratio of FKBP51 to FKBP52. Moreover, DNA methyltransferases 3a and 3b showed a significant decrease in their mRNA expression in the RSD group as did mRNA expression of histone deacetyltransferase 2. The RSD group also showed a significantly reduced quantity of methylated DNA in splenic macrophages. Based on microRNA (miRNA) profiling data, it was determined that RSD induced significantly increased expression of 9 different miRNAs that were predicted to interact with mRNAs of the GC receptor (6 miRNAs), mineralocorticoid receptor (3 miRNAs) and FKBP52 (2 miRNAs). Spearman correlation analysis revealed significantly strong correlations between the expression of 2 miRNAs and their target mRNA expression for GC receptors. Among these miRNAs, we verified direct effects of miRNA-29b and -340 overexpression on mRNA expression of GC receptors in L929 cells. The overexpression of miRNA-29b or -340 in L929 cells significantly reduced LPS-induced overexpression of GC receptors. In conclusion, this study provides evidence that epigenetic regulation, such as DNA methylation and miRNA expression, may play a role in the RSD-induced GC resistance that we have observed in splenic macrophages.

We showed previously that COX-2 is induced in the brain by excitotoxin in two distinct cell populations, neurons and non-neuronal cells. When cox-2 gene is selectively deleted in non-neuronal cells in a conditional knockout mouse line (KO), brain injury volumes induced by excitotoxin were nearly twice as large as those in WT controls, suggesting that the COX-2 expression in non-neuronal cells plays a neuroprotective role. In this study, we investigated the cellular and molecular mechanisms underlying COX-2-dependent neuroprotection. Correlated with the smaller lesion in WT mice, PGI2-producing leukocytes were found to infiltrate into the brain parenchyma in and near the site of lesion in WT, but not the KO, mice. At the site of injury, the level of PGI2 increased significantly after excitotoxin injection in WT, but not the KO, mice. In addition, inhibition of the PGI2 synthesis in WT animals induced an increase in the lesion size, whereas injection of PGI2 agonist in the KO mice reduced the lesion size. Further, after receiving adoptive transfer of blood leukocytes from WT mice, PGI2-expressing cells were found at the site of excitotoxic lesion in the KO animals with a concomittant reduction of lesion volume. These data suggest that PGI2 produced by the infiltrating leukocytes mediates the neuroprotective effect of the non-neuronal expression of COX-2.