Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging, 180 Fenglin Road, Shanghai, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, China.
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, China.
Cytokine. 2024 Jul;179:156620. doi: 10.1016/j.cyto.2024.156620. Epub 2024 May 2.
The emergence of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, but these drugs can also cause severe immune-related adverse effects (irAEs), including myocarditis. Researchers have become interested in exploring ways to mitigate this side effect, and one promising avenue is the use of baricitinib, a Janus kinase inhibitor known to have anti-inflammatory properties. This study aimed to examine the potential mechanism by which baricitinib in ICIs-related myocarditis.
To establish an ICIs-related myocarditis model, BALB/c mice were administered murine cardiac troponin I (cTnI) peptide and anti-mouse programmed death 1 (PD-1) antibodies. Subsequently, baricitinib was administered to the mice via intragastric administration. Echocardiography, HE staining, and Masson staining were performed to evaluate myocardial functions, inflammation, and fibrosis. Immunofluorescence was used to detect macrophages in the cardiac tissue of the mice.In vitro experiments utilized raw264.7 cells to induce macrophage polarization using anti-PD-1 antibodies. Different concentrations of baricitinib were applied to assess cell viability, and the release of pro-inflammatory cytokines was measured. The activation of the JAK1/STAT3 signaling pathway was evaluated through western blot analysis.
Baricitinib demonstrated its ability to improve cardiac function and reduce cardiac inflammation, as well as fibrosis induced by ICIs. Mechanistically, baricitinib treatment promoted the polarization of macrophages towards the M2 phenotype. In vitro and in vivo experiments showed that anti-PD-1 promoted the release of inflammatory factors. However, treatment with baricitinib significantly inhibited the phosphorylation of JAK1 and STAT3. Additionally, the use of RO8191 reversed the effects of baricitinib, further confirming our findings.
Baricitinib demonstrated its potential as a protective agent against ICIs-related myocarditis by modulating macrophage polarization. These findings provide a solid theoretical foundation for the development of future treatments for ICIs-related myocarditis.
免疫检查点抑制剂（ICIs）的出现彻底改变了癌症治疗，但这些药物也会引起严重的免疫相关不良反应（irAEs），包括心肌炎。研究人员开始探索减轻这种副作用的方法，其中一种有前途的方法是使用巴利昔替尼，一种具有抗炎特性的 Janus 激酶抑制剂。本研究旨在探讨巴利昔替尼治疗 ICI 相关心肌炎的潜在机制。
为了建立 ICI 相关心肌炎模型，给 BALB/c 小鼠注射鼠心肌肌钙蛋白 I（cTnI）肽和抗鼠程序性死亡 1（PD-1）抗体。随后，通过灌胃给予巴利昔替尼。通过超声心动图、HE 染色和 Masson 染色评估心肌功能、炎症和纤维化。使用免疫荧光检测小鼠心脏组织中的巨噬细胞。体外实验中，使用抗 PD-1 抗体诱导 raw264.7 细胞发生巨噬细胞极化。应用不同浓度的巴利昔替尼评估细胞活力和促炎细胞因子的释放。通过 Western blot 分析评估 JAK1/STAT3 信号通路的激活情况。
巴利昔替尼可改善 ICI 引起的心脏功能障碍，减轻心脏炎症和纤维化。机制上，巴利昔替尼治疗促进了巨噬细胞向 M2 表型极化。体内外实验均表明抗 PD-1 促进了炎症因子的释放。然而，巴利昔替尼治疗可显著抑制 JAK1 和 STAT3 的磷酸化。此外，使用 RO8191 逆转了巴利昔替尼的作用，进一步证实了我们的发现。
巴利昔替尼通过调节巨噬细胞极化，显示出对 ICI 相关心肌炎的保护作用。这些发现为开发治疗 ICI 相关心肌炎的新方法提供了坚实的理论基础。
