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Author Spotlight: Advancing Reproductive Immunology with a Protocol for the Quantitative Evaluation of Endometrial Immune Cells
Published on: October 13, 2023
Grim-19 deficiency promotes decidual macrophage autophagy in recurrent spontaneous abortion
Yang Yang1,2, Haoran Liu2, Yue Zhao2
1Key Laboratory for Experimental Teratology of Ministry of Education, Department of Anatomy and Histoembryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Abstract:
Dysregulation of decidual macrophages leads to the occurrence of recurrent spontaneous abortion (RSA). However, the role of macrophages in RSA occurrence remains unclear. In this study, we found that the expression of Grim-19 was decreased, and the expression of autophagy related proteins Beclin1, LC3B II/I and BNIP3 was markedly upregulated in decidual macrophages of RSA patients compared with the normal pregnancy group. Furthermore, we demonstrated that downregulation of GRIM-19 increased the expression of autophagy related proteins Beclin1, LC3B II/I, BNIP3 and the proinflammatory cytokines IL1B, IL6 and TNFa in uterine mononuclear cells of GRIM-19 mice. The proportion of CD45+CD11b+F4/80+LC3B+ cells in GRIM-19 mouse uteri was significantly higher than that in WT mouse uteri. In addition, we confirmed that inhibition of Grim-19 by siRNA enhanced the expression of autophagy related proteins in RAW264.7 cells and THP-1 cells. More importantly, downregulation of Grim-19 in RAW264.7 cells promoted the release of proinflammatory cytokines and promoted phagocytic activity, which could be reversed by autophagy blockade. For THP-1-derived macrophages, the results of RNA-seq suggested that Grim-19 mainly modulates immune and inflammatory-related pathways, leading to cytokine production, and thus contributing to inflammation. Therefore, our data reveal that Grim-19 deficiency influences macrophage function, characterized by enhanced proinflammatory cytokines and phagocytic activity, and this might be regulated by autophagy. This may represent a novel mechanism for the occurrence of RSA.
Insights
Grim-19 deficiency in decidual macrophages enhances autophagy and inflammation, potentially causing recurrent spontaneous abortion (RSA). This study reveals Grim-19
Area of Science:
- Immunology and Reproductive Biology
- Cellular and Molecular Mechanisms of Inflammation
Background:
- Decidual macrophage dysregulation is linked to recurrent spontaneous abortion (RSA).
- The specific role of macrophages in RSA pathogenesis remains largely undefined.
Purpose of the Study:
- To investigate the role of Grim-19 in decidual macrophage function.
- To elucidate the molecular mechanisms linking Grim-19 deficiency to RSA.
- To explore the involvement of autophagy in Grim-19-mediated macrophage responses.
Main Methods:
- Comparative analysis of decidual macrophages from RSA patients and normal pregnancy groups.
- In vivo studies using GRIM-19 knockout mice and in vitro experiments with RAW264.7 and THP-1 cells.
- siRNA-mediated inhibition of Grim-19, autophagy blockade, and RNA sequencing (RNA-seq).
Main Results:
- Reduced Grim-19 expression and increased autophagy markers (Beclin1, LC3B II/I, BNIP3) in decidual macrophages of RSA patients.
- Downregulation of Grim-19 in mice and cell lines elevated autophagy, proinflammatory cytokines (IL1B, IL6, TNFa), and phagocytic activity.
- Autophagy blockade reversed the pro-inflammatory and phagocytic effects of Grim-19 deficiency in macrophages.
Conclusions:
- Grim-19 deficiency impairs decidual macrophage function, promoting inflammation and phagocytosis, potentially via autophagy.
- This mechanism represents a novel pathway contributing to the development of recurrent spontaneous abortion.
- Targeting Grim-19 or autophagy pathways may offer therapeutic strategies for RSA.
