Umbarkar Prachi, Tousif Sultan, Jaiswal Ashish, Bhati Arvind Singh, Toro Cora Angelica, Sethi Rohan, Zhang Qinkun, Lal Hind
Division of Cardiovascular Disease, The University of Alabama at Birmingham, AL, USA.
Division of Cardiovascular Disease, The University of Alabama at Birmingham, AL, USA.
Biochim Biophys Acta Mol Basis Dis. 2025 Mar;1871(3):167703. doi: 10.1016/j.bbadis.2025.167703. Epub 2025 Jan 31.
Excessive fibrosis and chronic inflammation are vital to adverse cardiac remodeling of the MI heart. The crosstalk of fibroblasts (FBs) (primary drivers of fibrosis) and immune cells (that govern inflammation) is critical for the repair and remodeling of the injured heart. However, the molecular mechanisms through which FBs communicate with immune cells are poorly understood. In the MI heart, substantial cardiac cell damage releases alarmins, which trigger an immune response through the TLR/MyD88 pathway. The role of MyD88-dependent signaling is well characterized in immune cell biology. However, the role of FB-derived MyD88 signaling in MI heart injury is unknown.
To define the role of FB-MyD88 in MI pathology.
MyD88 was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or Postn- promoter-driven Cre recombinase. Control and MyD88 KO mice were subjected to permanent LAD ligation (MI injury), and cardiac parameters were evaluated. Additionally, co-culture experiments and chemokine profiling were conducted to identify mechanisms facilitating FB-immune cell crosstalk. FB-specific MyD88 deletion restricted MI-induced adverse cardiac remodeling and cardiac dysfunction. Surprisingly, FB-specific MyD88 deletion reduced myeloid cell recruitment and molecular markers of chronic inflammation in the KO heart. The mechanistic studies confirmed that MyD88 is required for the activation of NF-κB in FBs. Additionally, co-culture experiments demonstrated that FB-MyD88 facilitates immune cell crosstalk through chemokines and promotes an inflammatory gene program.
These findings suggest that FB-MyD88 promotes MI-induced chronic inflammation and cardiac dysfunction. Therefore, targeting MyD88 could serve as a potential therapeutic strategy.
过度纤维化和慢性炎症对于心肌梗死（MI）心脏的不良心脏重塑至关重要。成纤维细胞（FBs，纤维化的主要驱动因素）与免疫细胞（控制炎症）之间的相互作用对于受损心脏的修复和重塑至关重要。然而，FBs与免疫细胞通讯的分子机制尚不清楚。在MI心脏中，大量心肌细胞损伤会释放警报素，通过Toll样受体（TLR）/髓样分化因子88（MyD88）途径触发免疫反应。MyD88依赖性信号传导在免疫细胞生物学中的作用已得到充分表征。然而，FB来源的MyD88信号传导在MI心脏损伤中的作用尚不清楚。
确定FB-MyD88在MI病理中的作用。
利用他莫昔芬诱导的Tcf21或Postn启动子驱动的Cre重组酶，从成纤维细胞或肌成纤维细胞中删除MyD88。对对照小鼠和MyD88基因敲除（KO）小鼠进行永久性左冠状动脉前降支结扎（MI损伤），并评估心脏参数。此外，进行了共培养实验和趋化因子分析，以确定促进FB-免疫细胞相互作用的机制。FB特异性MyD88缺失限制了MI诱导的不良心脏重塑和心脏功能障碍。令人惊讶的是，FB特异性MyD88缺失减少了KO心脏中髓样细胞的募集和慢性炎症的分子标志物。机制研究证实，MyD88是FBs中核因子κB（NF-κB）激活所必需的。此外，共培养实验表明，FB-MyD88通过趋化因子促进免疫细胞相互作用，并促进炎症基因程序。
这些发现表明，FB-MyD88促进MI诱导的慢性炎症和心脏功能障碍。因此，靶向MyD88可能是一种潜在的治疗策略。
