Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, 530021 Nanning, Guangxi, China.
Guangxi Key Laboratory of Precision Medicine in Cardio-cerebrovascular Diseases Control and Prevention, 530021 Nanning, Guangxi, China.
Front Biosci (Landmark Ed). 2024 Aug 22;29(8):303. doi: 10.31083/j.fbl2908303.
Rheumatic heart disease (RHD) is an autoimmune disease caused by recurrent infections of Group A streptococcus (GAS), ultimately leading to inflammation and the fibrosis of heart valves. Recent studies have highlighted the crucial role of C-C chemokine receptor type 2-positive (CCR2) macrophages in autoimmune diseases and tissue fibrosis. However, the specific involvement of CCR2 macrophages in RHD remains unclear.
This study established an RHD rat model using inactivated GAS and complete Freund's adjuvant, demonstrating a correlation between CCR2 macrophages and fibrosis in the mitral valves of these rats.
Intraperitoneal injection of the CCR2 antagonist Rs-504393 significantly reduced macrophage infiltration, inflammation, and fibrosis in valve tissues of RHD rats compared to the solvent-treated group . Existing evidence suggests that C-C motif chemokine ligand 2 (CCL2) acts as the primary recruiting factor for CCR2 cells. To validate this, human monocytic leukemia cells (THP-1) were cultured to assess the impact of recombinant CCL2 protein on macrophages. CCL2 exhibited pro-inflammatory effects similar to lipopolysaccharide (LPS), promoting M1 polarization in macrophages. Moreover, the combined effect of LPS and CCL2 was more potent than either alone. Knocking down expression in THP-1 cells using small interfering RNA suppressed the pro-inflammatory response and M1 polarization induced by CCL2.
The findings from this study indicate that CCR2 macrophages are pivotal in the valvular remodeling process of RHD. Targeting the CCL2/CCR2 signaling pathway may therefore represent a promising therapeutic strategy to alleviate valve fibrosis in RHD.
风湿性心脏病（Rheumatic heart disease，RHD）是由 A 组链球菌（Group A streptococcus，GAS）反复感染引起的自身免疫性疾病，最终导致心脏瓣膜炎症和纤维化。最近的研究强调了 C-C 趋化因子受体 2 阳性（C-C chemokine receptor type 2-positive，CCR2）巨噬细胞在自身免疫性疾病和组织纤维化中的关键作用。然而，CCR2 巨噬细胞在 RHD 中的具体作用尚不清楚。
本研究使用灭活的 GAS 和完全弗氏佐剂建立了 RHD 大鼠模型，证明了 CCR2 巨噬细胞与这些大鼠二尖瓣纤维化之间存在相关性。
与溶剂处理组相比，腹腔注射 CCR2 拮抗剂 Rs-504393 可显著减少 RHD 大鼠瓣膜组织中的巨噬细胞浸润、炎症和纤维化。现有的证据表明，C-C 基序趋化因子配体 2（C-C motif chemokine ligand 2，CCL2）是 CCR2 细胞的主要募集因子。为了验证这一点，培养人单核白血病细胞（THP-1）以评估重组 CCL2 蛋白对巨噬细胞的影响。CCL2 表现出类似于脂多糖（lipopolysaccharide，LPS）的促炎作用，促进巨噬细胞 M1 极化。此外，LPS 和 CCL2 的联合作用比单独作用更有效。用小干扰 RNA 敲低 THP-1 细胞中的表达，可抑制 CCL2 诱导的促炎反应和 M1 极化。
本研究结果表明，CCR2 巨噬细胞在 RHD 的瓣膜重塑过程中起着关键作用。因此，靶向 CCL2/CCR2 信号通路可能是缓解 RHD 瓣膜纤维化的一种有前途的治疗策略。
