Loss of macrophage fibroblast growth factor 12 attenuates cardiac fibrosis in pressure-overloaded myocardium

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-04-05 DOI:10.1016/j.intimp.2025.114614

Santie Li , Mei Xue , Junjie Lu , Lingli Chen , Sihang Li , Leyi Shen , Junbo Ye , Qiaoyan Shi , Meifan Jiang , Kunxuan Zhu , Junfu Fan , Gaozan Tong , Xiaojing Yi , Xu Wang , Weitao Cong , Xueqiang Guan

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引用次数: 0

Abstract

Background

Cardiac fibrosis, a leading cause of death worldwide, plays a functional role in the development of heart failure. Unfortunately, there are currently no therapeutic strategies in clinical practice that can specifically attenuate the activation of cardiac fibroblasts, the effector cells of fibrosis in the heart. In this study, we aimed to identify a novel approach to target myocardial fibrosis through the crosstalk between macrophages and fibroblasts.

Methods

We investigated the expression of fibroblast growth factor 12 (FGF12), a novel regulator of macrophage activation, in both human subjects and mouse models. We also generated myeloid cell-specific FGF12 knockout mice to determine the role of FGF12 in cardiac fibrosis. For in vitro studies, we isolated mouse primary bone marrow-derived macrophages (BMDMs) and cardiac fibroblasts to explore the mechanism by which FGF12 controls macrophage polarization and fibroblast activation.

Results

We found that FGF12 expression was significantly upregulated in both human failing hearts and mouse pressure-overloaded myocardium. RNA sequencing revealed that FGF12 upregulation was associated with fibrosis progression, oxidative stress response, and macrophage activation in mouse heart tissues. Myeloid-specific knockout of FGF12 markedly attenuated pressure overload-induced myocardial fibrosis in our mouse models. We observed that FGF12 significantly affects interleukin-4-stimulated M2 polarization in BMDMs. Conditioned medium from FGF12 knockdown or overexpressed BMDMs also influenced cardiac fibroblast activation, primarily by affecting reactive oxygen species (ROS) accumulation in cardiac fibroblasts. Furthermore, we demonstrated that FGF12 controls BMDM M2 polarization through the SOCS/STAT pathway.

Conclusions

FGF12 is a novel regulator of myocardial fibrosis, acting through the modulation of crosstalk between macrophages and fibroblasts. Therapeutic approaches targeting FGF12 may represent a potential strategy to ameliorate cardiac fibrosis or other fibrosis-related diseases in the future.

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巨噬细胞成纤维细胞生长因子12的丧失可减轻压力过载心肌的心脏纤维化

背景：心脏纤维化是世界范围内死亡的主要原因，在心力衰竭的发展中起着功能性作用。不幸的是，目前在临床实践中没有治疗策略可以特异性地减弱心脏成纤维细胞（心脏纤维化的效应细胞）的激活。在这项研究中，我们旨在通过巨噬细胞和成纤维细胞之间的串扰来确定一种靶向心肌纤维化的新方法。方法研究了成纤维细胞生长因子12 （FGF12）在人和小鼠模型中的表达，FGF12是一种新的巨噬细胞活化调节因子。我们还生成了骨髓细胞特异性FGF12敲除小鼠，以确定FGF12在心脏纤维化中的作用。在体外研究中，我们分离小鼠原代骨髓源性巨噬细胞（bmdm）和心脏成纤维细胞，以探索FGF12控制巨噬细胞极化和成纤维细胞活化的机制。结果FGF12在人类衰竭心脏和小鼠压力过载心肌中的表达均显著上调。RNA测序显示，FGF12上调与小鼠心脏组织纤维化进展、氧化应激反应和巨噬细胞活化有关。在我们的小鼠模型中，骨髓特异性敲除FGF12可显著减轻压力过载引起的心肌纤维化。我们观察到FGF12显著影响白介素-4刺激的bmdm中M2极化。FGF12敲低或BMDMs过表达的条件培养基也会影响心脏成纤维细胞的激活，主要是通过影响心脏成纤维细胞中的活性氧（ROS）积累。此外，我们证明FGF12通过SOCS/STAT通路控制BMDM M2极化。结论sfgf12是一种新的心肌纤维化调节剂，通过调节巨噬细胞和成纤维细胞之间的串扰起作用。靶向FGF12的治疗方法可能代表未来改善心脏纤维化或其他纤维化相关疾病的潜在策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.