Journal of Neuroimmune Pharmacology最新文献

Repetitive exposure of innate immune cells to a subthreshold dosage of endotoxin components may modulate inflammatory responses. However, the regulatory mechanisms in the interactions between the central nervous system (CNS) and the immune system remain unclear. This study aimed to investigate the effects of lipopolysaccharide (LPS) preconditioning in repeated social defeat stress (RSDS)-induced abnormal immune responses and behavioral impairments. This study aimed to elucidate the mechanisms that underlie the protective effects of repeated administration of a subthreshold dose LPS on behavioral impairments using the RSDS paradigm. LPS preconditioning improved abnormal behaviors in RSDS-defeated mice, accompanied by decreased monoamine oxidases and increased glucocorticoid receptor expression in the hippocampus. In addition, pre-treated with LPS significantly decreased the recruited peripheral myeloid cells (CD11b⁺CD45^hi), mainly circulating inflammatory monocytes (CD11b⁺CD45^hiLy6C^hiCCR2⁺) into the brain in response to RSDS challenge. Importantly, we found that LPS preconditioning exerts its protective properties by regulating lipocalin-2 (LCN2) expression in microglia, which subsequently induces expressions of chemokine CCL2 and pro-inflammatory cytokine. Subsequently, LPS-preconditioning lessened the resident microglia population (CD11b⁺CD45^intCCL2⁺) in the brains of the RSDS-defeated mice. Moreover, RSDS-associated expressions of leukocytes (CD11b⁺CD45⁺CCR2⁺) and neutrophils (CD11b⁺CD45⁺Ly6G⁺) in the bone marrow, spleen, and blood were also attenuated by LPS-preconditioning. In particular, LPS preconditioning also promoted the expression of endogenous antioxidants and anti-inflammatory proteins in the hippocampus. Our results demonstrate that LPS preconditioning ameliorates lipocalin 2-associated microglial activation and aberrant immune response and promotes the expression of endogenous antioxidants and anti-inflammatory protein, thereby maintaining the homeostasis of pro-inflammation/anti-inflammation in both the brain and immune system, ultimately protecting the mice from RSDS-induced aberrant immune response and behavioral changes.

Microglia, the resident immune cells of the brain, regulate neuroinflammation which can lead to secondary neuronal damage and cognitive impairment under pathological conditions. Two of the many molecules that can elicit an inflammatory response from microglia are lipopolysaccharide (LPS), a component of gram-negative bacteria, and interferon gamma (IFNγ), an endogenous pro-inflammatory cytokine. We thoroughly examined the concentration-dependent relationship between LPS from multiple bacterial species and IFNγ in cultured microglia and macrophages. We measured the effects that these immunostimulatory molecules have on pro-inflammatory activity of microglia and used a battery of signaling inhibitors to identify the pathways that contribute to the microglial response. We found that LPS and IFNγ interacted synergistically to induce a pro-inflammatory phenotype in microglia, and that inhibition of JAK1/2 completely blunted the response. We determined that this synergistic action of LPS and IFNγ was likely dependent on JNK and Akt signaling rather than typical pro-inflammatory mediators such as NF-κB. Finally, we demonstrated that LPS derived from Escherichia coli, Klebsiella pneumoniae, and Akkermansia muciniphila can elicit different inflammatory responses from microglia and macrophages, but these responses could be consistently prevented using ruxolitinib, a JAK1/2 inhibitor. Collectively, this work reveals a mechanism by which microglia may become hyperactivated in response to the combination of LPS and IFNγ. Given that elevations in circulating LPS and IFNγ occur in a wide variety of pathological conditions, it is critical to understand the pharmacological interactions between these molecules to develop safe and effective treatments to suppress this process.

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The occurrence of major asthma symptoms is largely attributed to airway vagal hypertonia, of which the central mechanisms remain unclear. This study tests the hypotheses that endothelin-1-mediated brainstem glial activation produces asthmatic airway vagal hypertonia via enhanced action of adenosine 5’-triphosphate on neuronal purinergic P2X4 receptors. A rat model of asthma was prepared using ovalbumin. Airway vagal tone was evaluated by the recurrent laryngeal discharge and plethysmographic measurement of pulmonary function. The changes in the brainstem were examined using ELISA, Western blot, luciferin-luciferase, quantitative reverse transcription-polymerase chain reaction, enzyme activity assay and immunofluorescent staining, respectively. The results showed that in the medulla of rats, endothelin receptor type B and P2X4 receptors were primarily expressed in astrocytes and neurons, respectively, and both of which, along with endothelin-1 content, were significantly increased after ovalbumin sensitization. Ovalbumin sensitization significantly increased recurrent laryngeal discharge, which was blocked by acute intracisternal injection of P2X4 receptor antagonist 5-BDBD, knockdown of brainstem P2X4 receptors, and chronic intraperitoneal injection of endothelin receptor type B antagonist BQ788, respectively. Ovalbumin sensitization activated microglia and astrocytes and significantly decreased ecto-5’-nucleotidase activity in the medulla, and all of which, together with the increase of medullary P2X4 receptor expression and decrease of pulmonary function, were reversed by chronic BQ788 treatment. These results demonstrated that in rats, allergic airway challenge activates both microglia and astrocytes in the medulla via enhanced endothelin-1/endothelin receptor type B signaling, which subsequently causes airway vagal hypertonia via augmented adenosine 5’-triphosphate/P2X4 receptor signaling in central neurons of airway vagal reflex.

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Past studies have observed that brain atrophy may accelerate after surgical procedures. Furthermore, an association of systemic inflammation with neurodegeneration has been described. We hypothesize that postoperative interleukin (IL) levels in circulation as well as the perioperative change in interleukin levels are associated with increased postoperative atrophy in the Nucleus basalis magnocellularis (of Meynert, NBM) which is the major source of cortical acetylcholine. We analyzed data from the BioCog cohort which included patients ≥ 65 years presenting for elective major surgery (≥ 60min). Blood samples were taken before surgery and on the first postoperative day. Magnetic resonance imaging of the brain and neuropsychological assessments were conducted before surgery and after three months follow-up. We used linear regression analysis to determine the association of three interleukins (IL6, IL8 and IL18) with NBM atrophy (in % volume change from baseline before surgery to follow-up), as well as to examine the associations of NBM atrophy and volume with postoperative cognitive ability and perioperative cognitive change. Receiver-operating curves were used to determine the prognostic value of preoperative interleukin levels. For IL8 (N = 97) and IL18 (N = 217), but not IL6 (N = 240), we observed significant associations of higher postoperative IL levels at the first postoperative day with higher NBM atrophy at three months after surgery. Subsequent analyses suggested that in both IL8 and IL18, this association was driven by a more general association of chronically elevated IL levels and NBM atrophy, reflected by preoperative IL concentrations, rather than IL response to surgery, measured as the difference between pre- and postoperative IL concentrations. At follow-up, NBM volume was positively associated with the level of cognitive performance, but NBM atrophy was not significantly related to perioperative cognitive change. Prognostic value of preoperative IL concentrations for NBM atrophy was low. Our results suggest that an association of postoperative interleukin levels with NBM atrophy is driven by preoperatively elevated interleukins due to pre-existing inflammation, rather than perioperative change in interleukin levels in response to surgery and anesthesia. The BioCog study has been registered at clinicaltrials.gov on Oct 15, 2014 (NCT02265263).

Inflammation plays an important role in the pathogenesis of depression; however, the underlying mechanisms remain unclear. Apart from the disordered circadian rhythm in animal models and patients with depression, dysfunction of clock genes has been reported to be involved with the progress of inflammation. This study aimed to investigate the role of circadian clock genes, especially brain and muscle ARNT-like 1 (Bmal1), in the linkage between inflammation and depression. Lipopolysaccharide (LPS)-challenged rats and BV2 cells were used in the present study. Four intraperitoneal LPS injections of 0.5 mg/kg were administered once every other day to the rats, and BV2 cells were challenged with LPS for 24 h at the working concentration of 1 mg/L, with or without the suppression of Bmal1 via small interfering RNA. The results showed that LPS could successfully induce depression-like behaviors and an “inflammatory storm” in rats, as indicated by the increased immobility time in the forced swimming test and the decreased saccharin preference index in the saccharin preference test, together with hyperactivity of the hypothalamic–pituitary–adrenal axis, hyperactivation of astrocyte and microglia, and increased peripheral and central abundance of tumor necrosis factor-α, interleukin 6, and C-reactive protein. Moreover, the protein expression levels of brain-derived neurotrophic factor, triggering receptor expressed on myeloid cells 1, Copine6, and Synaptotagmin1 (Syt-1) decreased in the hippocampus and hypothalamus, whereas the expression of triggering receptor expressed on myeloid cells 2 increased. Interestingly, the fluctuation of temperature and serum concentration of melatonin and corticosterone was significantly different between the groups. Furthermore, protein expression levels of the circadian locomotor output cycles kaput, cryptochrome 2, and period 2 was significantly reduced in the hippocampus of LPS-challenged rats, whereas Bmal1 expression was significantly increased in the hippocampus but decreased in the hypothalamus, where it was co-located with neurons, microglia, and astrocytes. Consistently, apart from the reduced cell viability and increased phagocytic ability, LPS-challenged BV2 cells presented a similar trend with the changed protein expression in the hippocampus of the LPS model rats. However, the pathological changes in BV2 cells induced by LPS were reversed after the suppression of Bmal1. These results indicated that LPS could induce depression-like pathological changes, and the underlying mechanism might be partly associated with the imbalanced expression of Bmal1 and its regulated dysfunction of the circadian rhythm.

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Conclusions In conclusion, our results indicated that LPS could induce depression-like behaviors and an “inflammatory storm” in vivo, activate microglia in vitro, together with a disruption of synaptic plasticity and circadian rhythm. This m

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With the advent of immunomodulatory therapies and the HIV epidemic, the impact of JC Virus (JCV) on the public health system has grown significantly due to the increased incidence of Progressive Multifocal Leukoencephalopathy (PML). Currently, there are no pharmaceutical agents targeting JCV infection for the treatment and the prevention of viral reactivation leading to the development of PML. As JCV primarily reactivates in immunocompromised patients, it is proposed that the immune system (mainly the cellular-immunity component) plays a key role in the regulation of JCV to prevent productive infection and PML development. However, the exact mechanism of JCV immune regulation and reactivation is not well understood. Likewise, the impact of host factors on JCV regulation and reactivation is another understudied area. Here we discuss the current literature on host factor-mediated and immune factor-mediated regulation of JCV gene expression with the purpose of developing a model of the factors that are bypassed during JCV reactivation, and thus are potential targets for the development of therapeutic interventions to suppress PML initiation. Graphical Abstract.