To study the effect of viral inflammation induced by Polyinosinic:polycytidylic acid (PIC) on the cerebellum during a critical period of development in rats.
Neonatal rat pups were treated with PIC on postnatal days (PN) 8 and 10 after which we quantified RNA using Nanostring, qRT-PCR and RNAscope and analyzed immune cells through flow cytometry and immunohistochemistry on PN11. Using the same paradigm, we also analyzed play juvenile behavior, anxiety-like behavior, motor balance using the balance beam and the rotarod assays as well as fine motor behavior using the sunflower seed opening test.
We determined that male and female pups treated with PIC reacted with a significant increase in CCL5, a chemotactic cytokine that attracts T-cells, eosinophils and basophils to the site of inflammation, at PN11. PIC treatment also increased the expression of two receptors for CCL5, CCR1 and CCR5 in the cerebellar vermis in both males and females at PN11. In-situ hybridization (RNAscope®) for specific transcripts revealed that microglia express both CCL5 receptors under inflammatory and non-inflammatory conditions in both males and females. PIC treatment also increased the total number of CCL5+ cells in the developing cerebellum which were determined to be both natural killer cells and T-cells. There were modest but significant impacts of PIC treatment on large and fine motor skills and juvenile play behavior.
Our findings suggest an important role for CCL5 and other immune cells in mediating inflammation in the developing cerebellum that potentially impact the maturation of cerebellar neurons during a critical period of development.
© 2024 the author(s), published by De Gruyter, Berlin/Boston.

Passive immunotherapy is one of the most promising interventions for Alzheimer's disease (AD). However, almost all immune-modulating strategies fail in clinical trials with unclear causes although they attenuate neuropathology and cognitive deficits in AD animal models. Here, we showed that Aβ-targeting antibodies including their lgG1 and lgG4 subtypes induced microglial engulfment of neuronal synapses by activating CR3 or FcγRIIb via the complex of Aβ, antibody, and complement. Notably, anti-Aβ antibodies without Fc fragment, or with blockage of CR3 or FcγRIIb, did not exert these adverse effects. Consistently, Aβ-targeting antibodies, but not their Fab fragments, significantly induced acute microglial synapse removal and rapidly exacerbated cognitive deficits and neuroinflammation in APP/PS1 mice post-treatment, whereas the memory impairments in mice were gradually rescued thereafter. Since the recovery rate of synapses in humans is much lower than that in mice, our findings may clarify the variances in the preclinical and clinical studies assessing AD immunotherapies. Therefore, Aβ-targeting antibodies lack of Fc fragment, or with reduced Fc effector function, may not induce microglial synaptic pruning, providing a safer and more efficient therapeutic alternative for passive immunotherapy for AD.
© 2022. The Author(s).

The use of antibiotics as well as changes in the gut microbiota have been linked to development of food allergy in childhood. It remains unknown whether administration of a single clinically relevant antibiotic directly promotes food allergy development when administrated during the sensitisation phase in an experimental animal model. We investigated whether the antibiotic amoxicillin affected gut microbiota composition, development of cow's milk allergy (CMA) and frequencies of allergic effector cells and regulatory T cells in the intestine. Brown Norway rats were given daily oral gavages of amoxicillin for six weeks and whey protein concentrate (WPC) with or without cholera toxin three times per week for the last five weeks. Microbiota composition in faeces and small intestine was analysed by 16S rRNA sequencing. The development of CMA was assessed by WPC-specific IgE in serum, ear swelling response to WPC and body hypothermia following oral gavage of WPC. Allergic effector cells were analysed by histology, and frequencies of regulatory and activated T cells were analysed by flow cytometry. Amoxicillin administration reduced faecal microbiota diversity, reduced the relative abundance of Firmicutes and increased the abundance of Bacteroidetes and Proteobacteria. Despite these effects, amoxicillin did not affect the development of CMA, nor the frequencies of allergic effector cells or regulatory T cells. Thus, amoxicillin does not carry a direct risk for food allergy development when administrated in an experimental model of allergic sensitisation to WPC via the gut. This finding suggests that confounding factors may better explain the epidemiological link between antibiotic use and food allergy.
© 2022 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.

Right heart failure is the terminal stage of PAH. When PAH patients suffer from pulmonary infection or puerperal infection heart failure often rapidly develops. Low dose of lipopolysaccharide induces rapid right ventricular failure in rats with pulmonary arterial hypertension.
The objective of this study was to investigate whether the NLRP3 inflammasome mediates disturbance of the ventricular immune microenvironment of PAH rats and promotes right ventricular failure.
Intraperitoneal injection of monocrotaline was used to induce PAH in rats. Right ventricular function was measured via echocardiography before and after the rats were treated with lipopolysaccharide and MCC950. The degree of immune microenvironment disturbance in right ventricular tissue was measured with a rat chemokine and cytokine antibody array, Western blot, flow cytometry and quantitative real-time PCR analysis.
After the rats were injected with LPS, they exhibited right ventricular dysfunction and a significant increase in right ventricular tissue inflammation with elevated M1 macrophage proportion. Administration of MCC950 suppressed inflammation and improved right ventricular function. The number of M1 macrophages was decreased after MCC950 treatment. NLRP3 inflammasome inhibition ameliorated LPS-induced changes in the immune microenvironment in the right heart and right ventricular dysfunction in rats with PAH.
Selective inhibition of NLRP3 pathway interfered the interaction between hypertrophic cardiomyocytes and macrophages in the initial stage of inflammation and maintained the immune microenvironment balance, eventually contributing to attenuation of LPS-induced acute heart failure in PAH rats.
© 2021 Guo et al.

Inflammasomes are intracellular multiprotein complexes that help trigger and maintain the inflammatory response as part of the innate immune system. Recently, it has been increasingly recognized that aberrant inflammasome activation is critically involved in endothelial dysfunction in a variety of human diseases, such as atherosclerosis, acute lung injury (ALI), and type 2 diabetes. The molecular mechanisms underlying endothelial inflammasome activation, however, have not been completely elucidated. In the present study, we identified orphan nuclear receptor Nur77 as a novel regulator in controlling inflammasome activation in vascular endothelial cells (ECs). We demonstrated that LPS-induced inflammasome activation was significantly inhibited by ectopic overexpression of Nur77, predominantly through transcriptional suppression of caspase-1 expression in vascular ECs. Consistent with this observation, we found that LPS-induced inflammasome activation was significantly augmented in lung ECs isolated from Nur77-knockout mice. Mechanistically, we showed that Nur77-induced inhibition of caspase-1 expression was due to an inhibition of IRF1 (IFN regulatory factor 1) expression and its subsequent binding to the caspase-1 promoter. Importantly, in a mouse model of LPS-induced ALI, Nur77 knockout led to a marked activation of caspase-1 in the lung, increased alveolar and circulating IL-1β levels, and exacerbated ALI, all of which were substantially inhibited by administration of caspase-1 inhibitor. Together, our results support the presence of an important role for Nur77 in controlling inflammasome activation in vascular ECs and suggest that Nur77 could be a novel therapeutic target for the treatment of human diseases associated with aberrant inflammasome activation, such as ALI and atherosclerosis.