scholarly journals Innate immune stimulation by monophosphoryl lipid A prevents chronic social defeat stress-induced anxiety-like behaviors in mice

2022 ◽  
Vol 19 (1) ◽  
Author(s):  
Fu Li ◽  
Haitao Xiang ◽  
Yue Gu ◽  
Ting Ye ◽  
Xu Lu ◽  
...  
Keyword(s):  
Lipid A ◽  
Social Defeat ◽  
Innate Immune ◽  
Stress Exposure ◽  
Preventive Effect ◽  
Social Defeat Stress ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Chronic Social Defeat Stress ◽  
The Brain

Abstract Background Innate immune pre-stimulation can prevent the development of depression-like behaviors in chronically stressed mice; however, whether the same stimulation prevents the development of anxiety-like behaviors in animals remains unclear. We addressed this issue using monophosphoryl lipid A (MPL), a derivative of lipopolysaccharide (LPS) that lacks undesirable properties of LPS but still keeps immune-enhancing activities. Methods The experimental mice were pre-injected intraperitoneally with MPL before stress exposure. Depression was induced through chronic social defeat stress (CSDS). Behavioral tests were conducted to identify anxiety-like behaviors. Real-time polymerase chain reaction (PCR) and biochemical assays were employed to examine the gene and protein expression levels of pro-inflammatory markers. Results A single MPL injection at the dose of 400 and 800 μg/kg 1 day before stress exposure prevented CSDS-induced anxiety-like behaviors, and a single MPL injection (400 μg/kg) five but not 10 days before stress exposure produced similar effect. The preventive effect of MPL on anxiety-like behaviors was also observed in CSDS mice who received a second MPL injection 10 days after the first MPL injection or a 4 × MPL injection 10 days before stress exposure. MPL pre-injection also prevented the production of pro-inflammatory cytokines in the hippocampus and medial prefrontal cortex in CSDS mice, and inhibiting the central immune response by minocycline pretreatment abrogated the preventive effect of MPL on CSDS-induced anxiety-like behaviors and pro-inflammatory cytokine productions in the brain. Conclusions Pre-stimulation of the innate immune system by MPL can prevent chronic stress-induced anxiety-like behaviors and neuroinflammatory responses in the brain in mice.

scholarly journals Cannabinoid receptor 1 signalling modulates stress susceptibility and microglial responses to chronic social defeat stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eva C. Beins ◽  
Thomas Beiert ◽  
Imke Jenniches ◽  
Jan N. Hansen ◽  
Este Leidmaa ◽  
...  
Keyword(s):  
Stress Responses ◽  
Cannabinoid Receptor ◽  
Inflammatory Responses ◽  
Myeloid Cells ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Cannabinoid Receptor 1 ◽  
Behavioural Phenotype ◽  
Chronic Social Defeat Stress ◽  
The Brain

AbstractPsychosocial stress is one of the main environmental factors contributing to the development of psychiatric disorders. In humans and rodents, chronic stress is associated with elevated inflammatory responses, indicated by increased numbers of circulating myeloid cells and activation of microglia, the brain-resident immune cells. The endocannabinoid system (ECS) regulates neuronal and endocrine stress responses via the cannabinoid receptor 1 (CB1). CB1-deficient mice (Cnr1−/−) are highly sensitive to stress, but if this involves altered inflammatory responses is not known. To test this, we exposed Cnr1+/+ and Cnr1−/− mice to chronic social defeat stress (CSDS). Cnr1−/− mice were extremely sensitive to a standard protocol of CSDS, indicated by an increased mortality rate. Therefore, a mild CSDS protocol was established, which still induced a behavioural phenotype in susceptible Cnr1−/− mice. These mice also showed altered glucocorticoid levels after mild CSDS, suggesting dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. Mild CSDS induced weak myelopoiesis in the periphery, but no recruitment of myeloid cells to the brain. In contrast, mild CSDS altered microglial activation marker expression and morphology in Cnr1−/− mice. These microglial changes correlated with the severity of the behavioural phenotype. Furthermore, microglia of Cnr1−/− mice showed increased expression of Fkbp5, an important regulator of glucocorticoid signalling. Overall, the results confirm that CB1 signalling protects the organism from the physical and emotional harm of social stress and implicate endocannabinoid-mediated modulation of microglia in the development of stress-related pathologies.

Effect on cellular recruitment and the innate immune response by combining saponin, monophosphoryl lipid-A and Incomplete Freund’s Adjuvant with Leishmania (Viannia) braziliensis antigens for a vaccine formulation

Vaccine ◽  
2019 ◽  
Vol 37 (49) ◽  
pp. 7269-7279 ◽  
Author(s):  
Juliana Vitoriano-Souza ◽  
Fernando Augusto Siqueira Mathias ◽  
Nádia das Dores Moreira ◽  
Rodrigo Dian de Oliveira Aguiar-Soares ◽  
Paula Melo de Abreu Vieira ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Lipid A ◽  
Innate Immune ◽  
Vaccine Formulation ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Cellular Recruitment ◽  
Incomplete Freund’S Adjuvant ◽  
Freund's Adjuvant

scholarly journals Chronic Social Defeat Stress Shifts Peripheral Circadian Clocks in Male Mice in a Tissue-Specific and Time-of-Day Dependent Fashion

2022 ◽  
pp. 074873042110653
Author(s):  
Xiangpan Kong ◽  
Simone M. Ota ◽  
Deborah Suchecki ◽  
Andy Lan ◽  
Anouk I. Peereboom ◽  
...  
Keyword(s):  
Acute Stress ◽  
Social Defeat ◽  
Time Of Day ◽  
Dark Phase ◽  
Stress Exposure ◽  
Social Defeat Stress ◽  
Peripheral Tissues ◽  
Tissue Specific ◽  
Chronic Social Defeat Stress ◽  
Peripheral Clocks

Uncontrollable stress is linked to the development of many diseases, some of which are associated with disrupted daily rhythms in physiology and behavior. While available data indicate that the master circadian pacemaker in the suprachiasmatic nucleus (SCN) is unaffected by stress, accumulating evidence suggest that circadian oscillators in peripheral tissues and organs can be shifted by a variety of stressors and stress hormones. In the present study, we examined effects of acute and chronic social defeat stress in mice and addressed the question of whether effects of uncontrollable stress on peripheral clocks are tissue specific and depend on time of day of stress exposure. We used mice that carry a luciferase reporter gene fused to the circadian clock gene Period2 (PER2::LUC) to examine daily rhythms of PER2 expression in various peripheral tissues. Mice were exposed to social defeat stress in the early (ZT13-14) or late (ZT21-22) dark phase, either once (acute stress) or repeatedly on 10 consecutive days (chronic stress). One hour after the last stressor, tissue samples from liver, lung, kidney, and white adipose tissue (WAT) were collected. Social defeat stress caused a phase delay of several hours in the rhythm of PER2 expression in lung and kidney, but this delay was stronger after chronic than after acute stress. Moreover, shifts only occurred after stress in the late dark phase, not in the early dark phase. PER2 rhythms in liver and WAT were not significantly shifted by social defeat, suggesting a different response of various peripheral clocks to stress. This study indicates that uncontrollable social defeat stress is capable of shifting peripheral clocks in a time of day dependent and tissue specific manner. These shifts in peripheral clocks were smaller or absent after a single stress exposure and may therefore be the consequence of a cumulative chronic stress effect.

scholarly journals Transcriptome-Wide Identification of G-to-A RNA Editing in Chronic Social Defeat Stress Mouse Models

2021 ◽  
Vol 12 ◽  
Author(s):  
Ji Tao ◽  
Chun-Yan Ren ◽  
Zhi-Yuan Wei ◽  
Fuquan Zhang ◽  
Jinyu Xu ◽  
...  
Keyword(s):  
Rna Editing ◽  
Mouse Models ◽  
Physiological Stress ◽  
Neurological Diseases ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Chronic Social Defeat Stress ◽  
Solute Carrier ◽  
The Brain

Emerging evidence suggests that RNA editing is associated with stress, neurological diseases, and psychiatric disorders. However, the role of G-to-A RNA editing in chronic social defeat stress (CSDS) remains unclear. We herein identified G-to-A RNA editing and its changes in the ventral tegmental area (VTA), a key region of the brain reward system, in CSDS mouse models under emotional stress (ES) and physiological stress (PS) conditions. Our results revealed 3812 high-confidence G-to-A editing events. Among them, 56 events were significantly downregulated while 23 significantly upregulated in CSDS compared to controls. Moreover, divergent editing patterns were observed between CSDS mice under ES and PS conditions, with 42 and 21 events significantly upregulated in PS and ES, respectively. Interestingly, differential RNA editing was enriched in genes with multiple editing events. Genes differentially edited in CSDS included those genetically associated with mental or neurodevelopmental disorders, especially mood disorders, such as FAT atypical cadherin 1 and solute carrier family 6 member 1. Notably, changes of G-to-A RNA editing were also implicated in ionotropic glutamate receptors, a group of well-known targets of adenosine-to-inosine RNA editing. Such results demonstrate dynamic G-to-A RNA editing changes in the brain of CSDS mouse models, underlining its role as a potential molecular mechanism of CSDS and stress-related diseases.

scholarly journals The Toll-Like Receptor 4 Agonist Monophosphoryl Lipid A Augments Innate Host Resistance to Systemic Bacterial Infection

2011 ◽  
Vol 79 (9) ◽  
pp. 3576-3587 ◽  
Author(s):  
Christopher D. Romero ◽  
Tushar K. Varma ◽  
Jason B. Hobbs ◽  
Aimee Reyes ◽  
Brandon Driver ◽  
...  
Keyword(s):  
Lipid A ◽  
Cytokine Production ◽  
Myeloid Cells ◽  
Innate Immune ◽  
Bacterial Clearance ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid ◽  
Systemic Dissemination

ABSTRACTMonophosphoryl lipid A (MPLA) is a Toll-like receptor 4 (TLR4) agonist that is currently used as a vaccine adjuvant in humans. In this study, we evaluated the effect of MPLA treatment on the innate immune response to systemic bacterial infections in mice. Mice treated with MPLA after burn injury showed improved survival and less local and systemic dissemination of bacteria in a model ofPseudomonas aeruginosaburn wound infection. Prophylactic treatment with MPLA significantly enhanced bacterial clearance at the site of infection and reduced systemic dissemination of bacteria despite causing attenuation of proinflammatory cytokine production during acute intra-abdominal infection caused by cecal ligation and puncture. Administration of MPLA at 1 h after CLP also improved bacterial clearance but did not alter cytokine production. MPLA treatment increased the numbers of granulocytes, double-positive myeloid cells, and macrophages at sites of infection and increased the percentage and total numbers of myeloid cells mediating phagocytosis of bacteria. Depletion of Ly6G+neutrophils, but not macrophages, eliminated the ability of MPLA treatment to improve bacterial clearance. The immunomodulatory effects of MPLA were absent in TLR4-deficient mice. In conclusion, these studies show that MPLA treatment significantly augments the innate immune response to bacterial infection by enhancing bacterial clearance despite the attenuation of proinflammatory cytokine production. The enhanced bacterial clearance is mediated, in part, by increased numbers of myeloid cells with effective phagocytic functions at sites of infection and is TLR4 dependent.

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