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Nematode ascarosides attenuate mammalian type 2 inflammatory responses

ABSTRACT: Mounting evidence suggests that helminthic infection can protect against disorders of immune dysregulation. Administration of live parasites or their excretory/secretory products (ES) has shown therapeutic effects across a wide range of animal models for immune disorders including asthma. Human clinical trials of live parasite ingestion for the treatment of immune disorders have produced promising results, yet concerns persist regarding ingestion of pathogenic organisms and unpredictable immune responses towards their protein components. Despite extensive efforts toward defining active components of ES, no small molecules with immune regulatory activity have been identified from nematodes. OBJECTIVE: Here we have aimed to identify the effect of evolutionarily conserved family of nematode pheromones called ascaroside, which is a small molecule produced by several animal parasitic nematode species, on pulmonary immune response and asthma severity in mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE196470 | GEO | 2022/02/13

REPOSITORIES: GEO

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Trichuris secretome - proteome data analysis

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Project description:In this study, Angiostrongylus cantonensis (AC), which parasitizes in the brain of the non-permissive host, such as mouse and human, is an etiologic agent of eosinophilic meningitis. Excretory-secretory (ES) products play an important role in the interaction between parasites and hosts’ immune responses. Inflammatory macrophages are responsible for eosinophilic meningitis induced by AC, and the soluble antigens of Angiostrongylus cantonensis fourth stage larva (AC L4), a mimic of dead AC L4, aggravate eosinophilic meningitis in AC-infected mice model via promoting alternative activation of macrophages. While whether AC L4 ES products, as well as its exosome-depleted excretory-secretory products (exofree) component play a role on macrophage activation remains unknown. In order to identify the AC L4 exofree signature regulating genes, BMDMs were treated with PBS (ctr), free (AC L4 exofree), IL-4, com (IL-4+AC L4 exofree) for 6h, 12h, and 24 h respectively and RNA-seq analysis was performed.

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Project description:Angiostrongylus cantonensis (AC), which parasitizes in the brain of the non-permissive host, such as mouse and human, is an etiologic agent of eosinophilic meningitis. Excretory-secretory (ES) products play an important role in the interaction between parasites and hosts’ immune responses. Inflammatory macrophages are responsible for eosinophilic meningitis induced by AC, and the soluble antigens of Angiostrongylus cantonensis fourth stage larva (AC L4), a mimic of dead AC L4, aggravate eosinophilic meningitis in AC-infected mice model via promoting alternative activation of macrophages. In this study, we investigated the key molecules in the ES products of AC L4 on macrophages and observed the relationship between metabolic reprogramming and the PI3K-Akt pathway. First, a co-culture system of macrophage and AC L4 was established to define the role of AC L4 ES products on macrophage polarization. Then, AC L4 exosome and exosome-depleted excretory-secretory products (exofree) were separated from AC L4 ES products using differential centrifugation, their distinct roles on macrophage polarization were confirmed using qPCR and ELISA experiments. Moreover, AC L4 exofree induced alternative activation of macrophages, which is partially associated with metabolic reprogramming by the PI3K-Akt pathway. Next, lectin blot and deglycosylation assay suggesting the key role of N-linked glycoproteins in exofree. Then, glycoproteomic analysis of exofree and RNA-seq analysis of exofree-treated macrophage were performed. Bi-layer PPI network analysis based on these results identified that macrophage-related protein Hexa as a key molecule in inducing alternative activation of macrophages. Our results indicate a great value for research of helminth-derived immunoregulatory molecules, which might contribute to drug development for immune-related diseases.

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