scholarly journals Autophagy Inhibitors Treatment Alleviates Degree of Infection and Cerebral Inflammatory Responses in Mouse Model of Japanese Encephalitis

2021 ◽  
Author(s):  
Jinhua Zhang ◽  
Wei Han ◽  
changqing xie ◽  
mingxing Gao ◽  
Xugang Wang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Viral Infection ◽  
Japanese Encephalitis ◽  
Host Response ◽  
Inflammatory Responses ◽  
Heart Diseases ◽  
Brain Inflammation ◽  
Specific Mechanism ◽  
Epidemic Disease ◽  
The Brain

Abstract Background: Japanese Encephalitis (JE) is a zoonotic natural epidemic disease caused by Japanese Encephalitis Virus (JEV) infection. Currently, there is no specific medicine for Japanese encephalitis. At present, autophagy regulating drugs have played an important role in the treatment of tumors, heart diseases and other diseases. We hope that by studying the effects of autophagy-regulating drugs on JEV infection and host response in mice, will provide effective clinical trials for autophagy-regulating drugs in the treatment of Japanese encephalitis and other viral infectious diseases. Methods: After establishing appropriate animal model. We observed the neurological symptoms of the mice and counted their survival rate. We compared the degree of viral infection in the brain of mice infected with JE virus. We compared the extent of neuroinflammatory responses in the brain of mice and explored the signaling processes involved in neuroinflammation.Results: We found autophagy inhibitors wortmannin (Wort) and chloroquine (CQ) alleviate degree of viral infection in the brain of JEV-infected mice. Autophagy inhibitors reduced the neuroinflammation in Mouse Model of Japanese encephalitis. We speculated that autophagy inhibitors may attenuate the activation of the PI3K/AKT/NF-kB pathway, thereby reducing the brain inflammation in mice, thereby protecting mice from JEV-induced death. This result is not significant enough, the specific mechanism still needs further study.Conclusions: Our study suggests that autophagy inhibitors wortmannin and chloroquine could reduce the degree of viral infection and inflammatory response in the brain of JEV infected mice, providing a clinical basis for the treatment of Japanese encephalitis.

scholarly journals Autophagy Inhibitors Treatment Alleviates Degree of Infection and Cerebral Inflammatory Responses in Mouse Model of Japanese Encephalitis

2021 ◽  
Author(s):  
Jinhua Zhang ◽  
Wei Han ◽  
Changqing Xie ◽  
Mingxing Gao ◽  
Xugang Wang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Viral Infection ◽  
Japanese Encephalitis ◽  
Host Response ◽  
Inflammatory Responses ◽  
Heart Diseases ◽  
Brain Inflammation ◽  
Specific Mechanism ◽  
Epidemic Disease ◽  
The Brain

Abstract Background: Japanese Encephalitis (JE) is a zoonotic natural epidemic disease caused by Japanese Encephalitis Virus (JEV) infection. Currently, there is no specific medicine for Japanese encephalitis. At present, autophagy regulating drugs have played an important role in the treatment of tumors, heart diseases and other diseases. We hope that by studying the effects of autophagy-regulating drugs on JEV infection and host response in mice, will provide effective clinical trials for autophagy-regulating drugs in the treatment of Japanese encephalitis and other viral infectious diseases. Methods: After establishing appropriate animal model. We observed the neurological symptoms of the mice and counted their survival rate. We compared the degree of viral infection in the brain of mice infected with JE virus. We compared the extent of neuroinflammatory responses in the brain of mice and explored the signaling processes involved in neuroinflammation.Results: We found autophagy inhibitors wortmannin (Wort) and chloroquine (CQ) alleviate degree of viral infection in the brain of JEV-infected mice. Autophagy inhibitors reduced the neuroinflammation in Mouse Model of Japanese encephalitis. We speculated that autophagy inhibitors may attenuate the activation of the PI3K/AKT/NF-kB pathway, thereby reducing the brain inflammation in mice, thereby protecting mice from JEV-induced death. This result is not significant enough, the specific mechanism still needs further study.Conclusions: Our study suggests that autophagy inhibitors wortmannin and chloroquine could reduce the degree of viral infection and inflammatory response in the brain of JEV infected mice, providing a clinical basis for the treatment of Japanese encephalitis.

scholarly journals Hypoxia Augments Cerebral Inflammation in a Dextran Sulfate Sodium-Induced Colitis Mouse Model

2020 ◽  
Vol 14 ◽  
Author(s):  
Ying Han ◽  
Liping Ding ◽  
Xiang Cheng ◽  
Ming Zhao ◽  
Tong Zhao ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Responses ◽  
Brain Dysfunction ◽  
Brain Inflammation ◽  
Control Group ◽  
Hypoxia Exposure ◽  
Hypoxic Conditions ◽  
Hypoxia Group ◽  
Cerebral Inflammation ◽  
The Brain

The importance of hypoxia in the pathophysiology of inflammatory bowel disease (IBD) is increasingly being realized; also, hypoxia seems to be an important accelerator of brain inflammation, as has been reported by our group and others. IBD is a chronic intestinal disorder that leads to the development of inflammation, which is related to brain dysfunction. However, no studies have reported whether hypoxia is associated with IBD-induced neuroinflammation. Therefore, the objective of the present study was to determine whether hypoxia augments cerebral inflammation in a DSS-induced colitis mouse model. The mouse model was developed using 3% DSS for five days combined with exposure to hypoxic conditions (6,000 m) for two days. Mice were randomly divided into four groups: control group, DSS group, hypoxia group, and DSS plus hypoxia group. The results demonstrated that DSS combined with hypoxia resulted in up-regulation of colonic and plasmatic proinflammatory cytokines. Meanwhile, DSS plus hypoxia increased expression of Iba1, which is a marker of activated microglia, accompanied by increased expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the brain. Moreover, the expression of tight junction proteins, such as zonula occludens-1 (ZO-1), occludin, and claudin-5, was markedly downregulated. The current study provides new insight into how hypoxia exposure induces excessive inflammatory responses andpathophysiological consequences in the brain in a DSS-induced colitis model.

scholarly journals Autophagy inhibitor treatment alleviates cerebral inflammatory responses in a mouse model of Japanese encephalitis

2020 ◽  
Author(s):  
Jinhua Zhang ◽  
Wei Han ◽  
Changqing Xie ◽  
Mingxing Gao ◽  
Xugang Wang ◽  
...  
Keyword(s):  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Inflammatory Responses ◽  
Degradation Process ◽  
Encephalitis Virus ◽  
Neurological Symptoms ◽  
Epidemic Disease ◽  
Autophagy Pathway ◽  
The Brain

Abstract Background Japanese Encephalitis (JE) is a zoonotic natural epidemic disease caused by Japanese Encephalitis Virus (JEV) infection. Currently, there is no specific medicine for Japanese encephalitis. Autophagy is a lysosomal degradation process that plays an important role in viral infection and cellular immunity. In vitro studies have shown that the Japanese encephalitis virus replication mechanism is related to the autophagy pathway. We hope that by studying the effects of autophagy-regulating drugs on JEV infection and host response in mice, will provide effective clinical trials for autophagy-regulating drugs in the treatment of Japanese encephalitis and other viral infectious diseases. Methods After establishing appropriate animal model. We observed the neurological symptoms of the mice and counted their survival rate. We observed histopathological changes in brain tissues of mice. We compared the extent of neuroinflammatory responses in the brain of mice and explored the signaling processes involved in neuroinflammation. Results We found autophagy inhibitors wortmannin (Wort) and chloroquine (CQ) slow down the occurrence of neurological symptoms and reduce the prevalence of JEV-infected mice. As expected, autophagy inhibitors can inhibit the activation of the PI3K/AKT/NF-kB pathway to alleviate cerebral inflammatory responses in mice, thereby protecting the mice from JEV-induced death. Conclusions Our study suggests that autophagy inhibitors wortmannin and chloroquine could attenuate the inflammatory response in the brain of JEV infected mice, providing a clinical basis for the treatment of Japanese encephalitis

scholarly journals Development and characterization of an animal model of Japanese encephalitis virus infection in adolescent C57BL/6 mice

2021 ◽  
Author(s):  
Aarti Tripathi ◽  
Arup Banerjee ◽  
Sudhanshu Vrati
Keyword(s):  
Mouse Model ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Encephalitis Virus ◽  
Brain Inflammation ◽  
Japanese Encephalitis Virus Infection ◽  
Molecular Events ◽  
Tnf Α ◽  
The Brain

A mouse-adapted isolate of Japanese encephalitis virus (JEV), designated as JEV-S3, was generated by serially passaging the P20778 strain of the virus in 3-4 weeks old C57BL/6 mice. The blood-brain barrier leakage was evident in JEV-S3 infected mice, where viral antigens and RNA were consistently demonstrated in the brain and infiltration of activated immune cells as evidenced by an increased level of CD45+CD11b+ cell population. Histopathology studies showed the presence of perivascular cuffing, haemorrhage and necrotic foci in the virus-infected brain conforming to the pathological changes seen in the brain of JEV-infected patients. Mass spectrometry studies characterized the molecular events leading to brain inflammation in the infected mice. Notably, a significant induction of inflammatory cytokines such as IFN-γ, Il-6, TNF-α, and TGF-β was observed. Further, genome sequencing of the JEV-S3 isolate identified the mutations selected during the mouse passage of the virus. Overall, we present an in-depth characterization of a robust and reproducible mouse model of JEV infection. The JEV-S3 isolate will be a useful tool to screen antivirals and study the virus pathogenesis in the adolescent mouse model.

scholarly journals Differential Virological and Immunological Outcome of Severe Acute Respiratory Syndrome Coronavirus Infection in Susceptible and Resistant Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2

2009 ◽  
Vol 83 (11) ◽  
pp. 5451-5465 ◽  
Author(s):  
Naoko Yoshikawa ◽  
Tomoki Yoshikawa ◽  
Terence Hill ◽  
Cheng Huang ◽  
Douglas M. Watts ◽  
...  
Keyword(s):  
T Cells ◽  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Viral Infection ◽  
Inflammatory Responses ◽  
Fatal Outcome ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Inflammatory Infiltrates ◽  
The Brain

ABSTRACT We previously reported that transgenic (Tg) mice expressing human angiotensin-converting enzyme 2 (hACE2), the receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), were highly susceptible to SARS-CoV infection, which resulted in the development of disease of various severity and even death in some lineages. In this study, we further characterized and compared the pathogeneses of SARS-CoV infection in two of the most stable Tg lineages, AC70 and AC22, representing those susceptible and resistant to the lethal SARS-CoV infection, respectively. The kinetics of virus replication and the inflammatory responses within the lungs and brains, as well as the clinical and pathological outcomes, were assessed in each lineage. In addition, we generated information on lymphocyte subsets and mitogen-mediated proliferation of splenocytes. We found that while both lineages were permissive to SARS-CoV infection, causing elevated secretion of many inflammatory mediators within the lungs and brains, viral infection appeared to be more intense in AC70 than in AC22 mice, especially in the brain. Moreover, such infection was accompanied by a more profound immune suppression in the former, as evidenced by the extensive loss of T cells, compromised responses to concanavalin A stimulation, and absence of inflammatory infiltrates within the brain. We also found that CD8+ T cells were partially effective in attenuating the pathogenesis of SARS-CoV infection in lethality-resistant AC22 mice. Collectively, our data revealed a more intense viral infection and immunosuppression in AC70 mice than in AC22 mice, thereby providing us with an immunopathogenic basis for the fatal outcome of SARS-CoV infection in the AC70 mice.

scholarly journals Sustained TREM2 stabilization accelerates microglia heterogeneity and Abeta pathology in a mouse model of Alzheimer s disease

2021 ◽  
Author(s):  
Rahul Dhandapani ◽  
Marilisa Neri ◽  
Mario Bernhard ◽  
Irena Brzak ◽  
Tatjana Schweizer ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Responses ◽  
Transmembrane Protein ◽  
Proteolytic Cleavage ◽  
Cell Surface Receptor ◽  
Pathological Conditions ◽  
Mouse Cortex ◽  
Surface Receptor ◽  
And Function ◽  
The Brain

TREM2 is a transmembrane protein expressed exclusively in microglia in the brain that regulates inflammatory responses to pathological conditions. Proteolytic cleavage of membrane TREM2 affects microglial function and is associated with Alzheimer s disease, but the consequence of reduced TREM2 proteolytic cleavage has not been determined. We generated a transgenic mouse model of reduced TREM2 shedding (Trem2-IPD) through amino acid substitution of ADAM-protease recognition site. We found that Trem2-IPD mice displayed increased TREM2 cell surface receptor load, survival and function in myeloid cells. Using single cell transcriptomic profiling of mouse cortex we show that sustained TREM2 stabilization induces a shift of fate in microglial maturation and accelerates microglial responses to Abeta pathology in a mouse model of Alzheimer s disease. Our data indicate that reduction of TREM2 proteolytic cleavage aggravates neuroinflammation during the course of AD pathology suggesting that TREM2 shedding is a critical regulator of microglial activity in pathological states.

scholarly journals Behavioural Fever Promotes an Inflammatory Reflex Circuit in Ectotherms

2021 ◽  
Vol 22 (16) ◽  
pp. 8860
Author(s):  
Nataly Sanhueza ◽  
Ricardo Fuentes ◽  
Andrea Aguilar ◽  
Beatriz Carnicero ◽  
Karina Vega ◽  
...  
Keyword(s):  
Viral Infection ◽  
Inflammatory Responses ◽  
Expression Patterns ◽  
Inflammatory Factors ◽  
Peripheral Tissues ◽  
Network Activation ◽  
Entry Points ◽  
Anti Inflammatory ◽  
The Brain

Background: The communication between the brain and the immune system is a cornerstone in animal physiology. This interaction is mediated by immune factors acting in both health and pathogenesis, but it is unclear how these systems molecularly and mechanistically communicate under changing environmental conditions. Behavioural fever is a well-conserved immune response that promotes dramatic changes in gene expression patterns during ectotherms’ thermoregulatory adaptation, including those orchestrating inflammation. However, the molecular regulators activating the inflammatory reflex in ectotherms remain unidentified. Methods: We revisited behavioural fever by providing groups of fish a thermal gradient environment during infection. Our novel experimental setup created temperature ranges in which fish freely moved between different thermal gradients: (1) wide thermoregulatory range; T° = 6.4 °C; and (2) restricted thermoregulatory range; T° = 1.4 °C. The fish behaviour was investigated during 5-days post-viral infection. Blood, spleen, and brain samples were collected to determine plasmatic pro- and anti-inflammatory cytokine levels. To characterize genes’ functioning during behavioural fever, we performed a transcriptomic profiling of the fish spleen. We also measured the activity of neurotransmitters such as norepinephrine and acetylcholine in brain and peripheral tissues. Results: We describe the first set of the neural components that control inflammatory modulation during behavioural fever. We identified a neuro-immune crosstalk as a potential mechanism promoting the fine regulation of inflammation. The development of behavioural fever upon viral infection triggers a robust inflammatory response in vivo, establishing an activation threshold after infection in several organs, including the brain. Thus, temperature shifts strongly impact on neural tissue, specifically on the inflammatory reflex network activation. At the molecular level, behavioural fever causes a significant increase in cholinergic neurotransmitters and their receptors’ activity and key anti-inflammatory factors such as cytokine Il10 and Tgfβ in target tissues. Conclusion: These results reveal a cholinergic neuronal-based mechanism underlying anti-inflammatory responses under induced fever. We performed the first molecular characterization of the behavioural fever response and inflammatory reflex activation in mobile ectotherms, identifying the role of key regulators of these processes. These findings provide genetic entry points for functional studies of the neural–immune adaptation to infection and its protective relevance in ectotherm organisms.

scholarly journals The Roles of IL-22 and Its Receptor in the Regulation of Inflammatory Responses in the Brain

2022 ◽  
Vol 23 (2) ◽  
pp. 757
Author(s):  
Dahae Lee ◽  
Hyejung Jo ◽  
Cheolhyeon Go ◽  
Yoojin Jang ◽  
Naghyung Chu ◽  
...  
Keyword(s):  
Cell Line ◽  
Mouse Brain ◽  
Inflammatory Responses ◽  
Neuronal Cell ◽  
Brain Inflammation ◽  
Ht22 Cells ◽  
Stat3 Signaling ◽  
Microglial Cell Line ◽  
Microarray Analyses ◽  
The Brain

Interleukin (IL)-22 is a potent mediator of inflammatory responses. The IL-22 receptor consists of the IL-22Rα and IL-10Rβ subunits. Previous studies have shown that IL-22Rα expression is restricted to non-hematopoietic cells in the skin, pancreas, intestine, liver, lung, and kidney. Although IL-22 is involved in the development of inflammatory responses, there have been no reports of its role in brain inflammation. Here, we used RT-PCR, Western blotting, flow cytometry, immunohistochemical, and microarray analyses to examine the role of IL-22 and expression of IL-22Rα in the brain, using the microglial cell line, hippocampal neuronal cell line, and inflamed mouse brain tissue. Treatment of BV2 and HT22 cells with recombinant IL-22 increased the expression levels of the pro-inflammatory cytokines IL-6 and TNF-α, as well as cyclooxygenase (COX)-2 and prostaglandin E2. We also found that the JNK and STAT3 signaling pathways play an important role in IL-22-mediated increases in inflammatory mediators. Microarray analyses revealed upregulated expression of inflammation-related genes in IL-22-treated HT22 cells. Finally, we found that IL-22Rα is spontaneously expressed in the brain and is upregulated in inflamed mouse brain. Overall, our results demonstrate that interaction of IL-22 with IL-22Rα plays a role in the development of inflammatory responses in the brain.

scholarly journals Recent advances in understanding Japanese encephalitis

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1915 ◽  
Author(s):  
Arup Banerjee ◽  
Aarti Tripathi
Keyword(s):  
Japanese Encephalitis ◽  
Microglial Activation ◽  
Brain Inflammation ◽  
Neurological Damage ◽  
Virus Structure ◽  
Recent Advances ◽  
Inflammatory Processes ◽  
Heavy Burden ◽  
Neuro Inflammation ◽  
The Brain

Japanese encephalitis (JE) is a clinical manifestation of the brain inflammation caused by JE virus (JEV). This virus imparts permanent neurological damage, thus imposing a heavy burden on public health and society. Neuro-inflammation is the hallmark of JEV infection. The prolonged pro-inflammatory response is due primarily to microglial activation, which eventually leads to severe encephalitis. A continual effort is going on in the scientific community toward an understanding of cellular and molecular factors that are involved in JEV neuro-invasion and inflammatory processes. This review not only gives a comprehensive update on the recent advances on understanding virus structure and mechanisms of pathogenesis but also briefly discusses crucial unresolved issues. We also highlight challenging areas of research that might open new avenues for controlling virus-induced neuro-inflammation.

Ocular nerve growth factor administration (oNGF) affects disease severity and inflammatory response in the brain of rats with experimental allergic encephalitis (EAE)

2016 ◽  
Vol 94 (2) ◽  
pp. 177-184 ◽  
Author(s):  
Valentina Carito ◽  
Sara De Nicolò ◽  
Marco Fiore ◽  
Mattia Maccarone ◽  
Paola Tirassa
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Inflammatory Responses ◽  
Brain Inflammation ◽  
Autoimmune Encephalomyelitis ◽  
Nerve Growth ◽  
Cytokines And Chemokines ◽  
Experimental Allergic Encephalitis ◽  
The Brain ◽  
Experimental Allergic

The rat acute experimental autoimmune encephalomyelitis (EAE) model was used to investigate the effects of ocularly administered nerve growth factor (oNGF) on disease development and brain inflammation. It was found that oNGF affects clinical scores. However, EAE rats receiving oNGF treatment showed reduced expression of pro-inflammatory cytokines and chemokines in the cerebellum and the hippocampus, but not in the frontal cortex. These data confirm the ability of oNGF to counteract the effects of EAE in the brain and suggest a role for oNGF in the regulation of local inflammatory responses observed in the acute phase of EAE.

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