Vijayakumar Gayathri, Latha Anisha, Anil Aiswaria P, Surve Yogini, R Aiswarya, Nair Bipin G, Pillai Indulekha Cl
Stem Cells and Regenerative Biology Lab, Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, Kerala, India.
Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, Kerala, India.
Heliyon. 2025 Feb 6;11(4):e42452. doi: 10.1016/j.heliyon.2025.e42452. eCollection 2025 Feb 28.
Fibrosis is one of the major outcomes following injury in the heart. Immune response in the injury niche modulates fibrosis, yet little is known about how cell-autonomous immune signaling in adult cardiac fibroblasts regulates fibrosis. Using FACS, single-cell sequencing of cardiac fibroblasts from Collagen1-α1GFP mice and human heart failure patients, we demonstrate that TLR4 is the major immune sensor expressed in cardiac fibroblasts. Inhibition of TLR4 signaling reduces TGF-β induced fibrotic changes such as contractibility and migration of adult human cardiac fibroblasts in TGF-β treated fibrotic conditions. TGF-β treated cardiac fibroblastss show enhanced cytokine expression, and inhibition of TLR4 signaling reduces the expression of cytokines, thereby reducing TGF-β targets such as extracellular matrix genes. Thus, our data demonstrate that TLR4 and other signaling molecules downstream of TLR4 are expressed in cardiac fibroblast, and inhibition of TLR4 modulates fibrotic changes in vitro.
纤维化是心脏损伤后的主要后果之一。损伤微环境中的免疫反应调节纤维化，但关于成年心脏成纤维细胞中的细胞自主免疫信号如何调节纤维化，人们知之甚少。通过流式细胞术、对来自胶原蛋白1-α1绿色荧光蛋白小鼠和人类心力衰竭患者的心脏成纤维细胞进行单细胞测序，我们证明Toll样受体4（TLR4）是心脏成纤维细胞中表达的主要免疫传感器。抑制TLR4信号可减少转化生长因子-β（TGF-β）诱导的纤维化变化，如在TGF-β处理的纤维化条件下成年人类心脏成纤维细胞的收缩性和迁移。TGF-β处理的心脏成纤维细胞显示细胞因子表达增强，抑制TLR4信号可降低细胞因子的表达，从而减少TGF-β的靶标，如细胞外基质基因。因此，我们的数据表明TLR4及TLR4下游的其他信号分子在心脏成纤维细胞中表达，并且抑制TLR4可在体外调节纤维化变化。
