Unveiling the interplay between hepatocyte SATB1 and innate immunity in autoimmune hepatitis

IF 4.7 2区医学 Q2 IMMUNOLOGY International immunopharmacology Pub Date : 2025-01-10 DOI:10.1016/j.intimp.2024.113712

Shuhui Wang , Zheng Huang , Shangshu Nie , Yu Chen , Yu Lei , Wei Tu , Min Luo , Zhen-gang Zhang , De-an Tian , Jin Gong , Mei Liu

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Abstract

Background

Investigating the function of SATB1 in hepatocytes is essential for developing therapeutic strategies for autoimmune hepatitis (AIH). Although SATB1 has been extensively studied in immune cells, its specific activity in hepatocytes within the context of AIH remains unclear.

Methods

SATB1 expression in AIH hepatocytes was assessed by qRT-PCR, Western blotting, flow cytometry, and immunohistochemistry. In vivo modulation used RNA interference viruses and overexpression plasmids. SATB1′s proinflammatory effects were analyzed with protein microarray, immunohistochemistry, and flow cytometry. Chemotactic effects on RAW264.7 macrophages were tested in vitro, with mechanisms explored by dual-luciferase assays and CUT&RUN qPCR. Liver injury was evaluated by histopathology and serum biochemistry.

Results

SATB1 was significantly upregulated in hepatocytes of AIH patients and models, showing a stronger increase in hepatocytes than in CD45⁺ cells, and positively correlated with liver injury severity. In vivo RNAi-mediated SATB1 inhibition reduced liver inflammation, while SATB1 overexpression aggravated AIH progression. Both interference and overexpression experiments confirmed that SATB1 promotes liver injury by facilitating the infiltration of proinflammatory (Ly6C^high) macrophage. In vitro, supernatant from SATB1-overexpressing hepatocytes enriched chemokine signaling pathways, leading to increased CCL2 expression and release, which attracted macrophages and drove their proinflammatory polarization. Mechanistically, SATB1 promoted CCL2 transcription by binding to its DNA and recruiting p300/CBP.

Conclusions

This study reveals that SATB1 is upregulated in hepatocytes in AIH. Elevated SATB1 levels in liver cells contribute to autoimmune hepatitis by increasing CCL2 expression, promoting the recruitment of inflammatory monocyte-derived macrophage, and reshaping the composition of the liver immune microenvironment.

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揭示自身免疫性肝炎中肝细胞SATB1与先天免疫的相互作用。

背景：研究肝细胞中SATB1的功能对于制定自身免疫性肝炎（AIH）的治疗策略至关重要。尽管SATB1在免疫细胞中已被广泛研究，但其在AIH背景下在肝细胞中的特异性活性尚不清楚。方法：采用qRT-PCR、Western blotting、流式细胞术和免疫组织化学检测AIH肝细胞中SATB1的表达。体内调节使用RNA干扰病毒和过表达质粒。采用蛋白芯片、免疫组织化学和流式细胞术分析SATB1的促炎作用。体外检测对RAW264.7巨噬细胞的趋化作用，并通过双荧光素酶测定和CUT&RUN qPCR探讨其作用机制。采用组织病理学和血清生化评价肝损伤。结果：SATB1在AIH患者及模型肝细胞中显著上调，且在肝细胞中的表达强于CD45+细胞，且与肝损伤严重程度呈正相关。在体内，rnai介导的SATB1抑制减轻了肝脏炎症，而SATB1过表达加重了AIH的进展。干扰和过表达实验均证实SATB1通过促进促炎（Ly6Chigh）巨噬细胞的浸润而促进肝损伤。体外，satb1过表达肝细胞的上清液富集趋化因子信号通路，导致CCL2表达和释放增加，吸引巨噬细胞并驱动其促炎极化。从机制上讲，SATB1通过结合CCL2的DNA并招募p300/CBP来促进CCL2的转录。结论：本研究显示AIH患者肝细胞中SATB1表达上调。肝细胞中SATB1水平升高通过增加CCL2表达、促进炎性单核细胞源性巨噬细胞的募集和重塑肝脏免疫微环境的组成来促进自身免疫性肝炎。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.