Abstract
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, and 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 were done, 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 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.
Highlights
Angiostronglyiasis is a serious foodborne parasitic disease caused by infection of Angiostrongylus cantonensis (AC), which parasitizes in the brain of the nonpermissive host mouse and human and leads to serious eosinophilic meningitis; the underlying mechanism remains poorly understood
We observed a significant increase in the protein level of Chi3l3 in BMDMs treated with IL-13 and 10 AC L4
A striking increase of Chi3l3 level was observed when BMDMs were treated with 10 AC L4 in the presence of IL-13 (Figure 1B), suggesting that the ES products of AC L4 could significantly promote macrophage M2 polarization
Summary
Angiostronglyiasis is a serious foodborne parasitic disease caused by infection of AC, which parasitizes in the brain of the nonpermissive host mouse and human and leads to serious eosinophilic meningitis; the underlying mechanism remains poorly understood. It is widely assumed that helminth could modulate host immune responses through its ES products, including proteins, glycans [3, 4], and exosomes [5,6,7]. Acanthocheilonema viteae– derived AvCystatin was shown to induce IL-10 production of macrophages and inhibit T cell proliferation and restore allergic airway inflammation [9]. Numerous studies have highlighted the importance of glycans as their interactions with the host immune system, as they were found on the surfaces of helminths and within their ES products [15, 16], which might interact with host glycan-binding proteins, such as C-type lectin receptors and galectins, shaping innate and adaptive immune responses upon infection. Identification of the important compound or protein that has the function of modulating host immune responses is of great significance for understanding the interaction of parasite and host
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