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rFIP-nha activates macrophages towards a pro-inflammatory phenotype via AIM2 inflammasome modulation

文献类型： 外文期刊

作者： Yusi Liu;Zhen Li;Harry Wichers;Shanna Bastiaan-Net;Tamara Hoppenbrouwers

作者机构：

关键词： AIM2 inflammasome;glycosylation;IL-1β;immunomodulatory protein;macrophage;pro-inflammatory

期刊名称： Frontiers in Cell and Developmental Biology

ISSN： 2296-634X

年卷期： 2025 年 13 卷

页码：

收录情况： SCIE（2025版）

摘要： Fungal immunomodulatory proteins (FIPs) are small proteins from fungi with considerable immunomodulatory activity. FIP-nha (Nectria haematococca) contains two glycosylation sites at positions N5 and N39, and displays a high thermostability and notable anti-tumour activity. However, FIP-nha’s immunomodulatory activity on macrophages and the associated mechanism remain unclear. In this study, three rFIP-nha glycan mutants (N5A, N39A, N5+39A) were recombinantly expressed in Pichia pastoris. To test the impact on FIP-nha’s immunomodulatory activity, the phagocytotic activity, cytokine secretion, and gene expression of THP-1 macrophages were investigated. rFIP-nha and its mutants reduced macrophage phagocytosis, and induced IL-1β, IL-12 and IL-10 cytokine secretion significantly, indicating that the protein confers a pro-inflammatory behaviour on THP-1 macrophages. However, there were no obvious differences among the different glycan mutants, indicating that the observed activation mechanisms are likely glycosylation-independent. Furthermore, to study the immunomodulatory mechanism, four kinds of inflammasomes (NLRP1, NLRP3, NLRC4 and AIM2) were tested at transcriptional level. AIM2 was found to be 10-fold upregulated. Then, THP1-KO-ASC cells and AIM2 related inhibitors showed that IL-1β release induced by rFIP-nha is ASC signalling pathway dependent. Taken together, these findings suggest that rFIP-nha activates THP-1 macrophages in a pro-inflammatory way by activating the AIM2 inflammasome.

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