信号调节蛋白α在加重肺纤维化并发细菌感染中的关键作用

R. Yamaguchi, A. Sakamoto, M. Haraguchi, S. Narahara, H. Sugiuchi, Y. Yamaguchi
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引用次数: 0

摘要

肺纤维化的发病机制尚不清楚。然而,特发性肺纤维化患者的细菌感染是加重疾病的严重并发症。已知肺纤维化患者血清表面活性蛋白D (SPD)水平升高,但SPD在肺纤维化合并细菌感染中的作用尚不清楚。脂多糖上调白细胞介素(IL)-12p40的表达,IL-12p40促进干扰素γ (IFNγ)的产生,通过信号转导和转录激活因子4 (STAT4)信号传导诱导T辅助细胞1 (Th1)免疫应答。缺乏IFNγ会将免疫反应从Th1转移到Th2。IL-4是一种促纤维化Th2细胞因子,可激活成纤维细胞。IL-1和tnf - α诱导的粒细胞-巨噬细胞集落刺激因子在Th1免疫应答过程中上调信号调节蛋白α (SIRPα)的表达。干扰素调节因子1 (IRF1)在LPS刺激后作为IL-12p40的启动子激活因子发挥作用。SPD是SIRPα的配体,SPD/SIRPα连接激活丝裂原活化蛋白激酶(MAPK)/细胞外信号相关激酶(ERK)信号级联;ERK下调干扰素调节因子1 (IRF1)的表达。因此,SPD/SIRPα信号通路在暴露于LPS后减少人巨噬细胞IL-12p40的产生。IL-12p40是细菌感染中促进T淋巴细胞产生IFNγ的关键免疫调节因子。肺成纤维细胞被IL-4/IL-4R连接激活。IFNγ通过STAT1信号诱导IRF1, IRF1作为IL-4的启动子抑制因子来减弱其产生。IFNγ也抑制IL-4R的表达。通过SPD/SIRPα信号通路,IL-12p40缺失导致IFNγ减少,从而增强IL-4和IL-4R的表达,从而增强成纤维细胞的活性。这一发现表明,在细菌感染期间,SPD/SIRPα信号通路加重了肺纤维化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The Pivotal Role of Signal Regulatory Protein α in Exacerbating Pulmonary Fibrosis Complicated with Bacterial Infection
The pathogenesis of pulmonary fibrosis remains unknown. However, bacterial infections in patients with idiopathic pulmonary fibrosis are a serious complication that exacerbate the disease. Serum levels of Surfactant Protein D (SPD) are known to be elevated in patients with pulmonary fibrosis, but the role of SPD in pulmonary fibrosis complicated with bacterial infection is unknown. Lipopolysaccharide upregulates Interleukin (IL)-12p40 expression and IL-12p40 promotes Interferon Gamma (IFNγ) production to induce the T helper cell 1 (Th1) immune response via Signal Transducers and Activators of Transcription 4 (STAT4) signaling. A lack of IFNγ shifts the immune response from Th1 to Th2. IL-4 is a profibrotic Th2 cytokine that activates fibroblasts. Granulocyte-macrophage colony-stimulating factor induced by IL-1 and TNFα during the Th1 immune response upregulates Signal Regulatory Protein α (SIRPα) expression. Interferon Regulatory Factor 1 (IRF1) functions as the promoter activator of IL-12p40 after stimulation with LPS. SPD is a ligand for SIRPα, and SPD/SIRPα ligation activates the Mitogen-Activated Protein Kinase (MAPK)/Extracellular Signal-Related Kinase (ERK) signal cascade; ERK downregulates Interferon Regulatory Factor 1 (IRF1) expression. Consequently, the SPD/SIRPα signaling pathway decreases IL-12p40 production in human macrophages after exposure to LPS. IL-12p40 is a key immunoregulatory factor in bacterial infection that promotes production of IFNγ by T lymphocytes. Pulmonary fibroblasts are activated by IL-4/IL-4R ligation. IFNγ induces IRF1 via STAT1 signaling, and IRF1 acts as the promoter repressor of IL-4 to attenuate its production. IFNγ also inhibits IL-4R expression. A reduction in IFNγ induced by IL-12p40 deficiency via the SPD/SIRPα signaling pathway enhances IL-4 and IL-4R expression to augment the activity of fibroblasts. This finding indicates that pulmonary fibrosis is exacerbated by SPD/SIRPα signaling during bacterial infection.
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