Wen Jiaxing, Guan Ya, Niu Hong, Dang Yu, Guan Jianjun
Institute of Materials Science and Engineering, Washington University in St. Louis. St. Louis, MO 63130, USA.
Department of Mechanical Engineering and Materials Science, Washington University in St. Louis. St. Louis, MO 63130, USA.
Acta Biomater. 2024 Aug 23. doi: 10.1016/j.actbio.2024.08.025.
After myocardial infarction (MI), cardiac resident CCR2+ macrophages release various cytokines and chemokines, notably monocyte chemoattractant protein-1 (MCP-1). MCP-1 is instrumental in recruiting CCR2+ monocytes to the damaged region. The excessive arrival of these monocytes, which then become macrophages, perpetuates inflammation at the site of injury. This continuous inflammation leads to adverse tissue remodeling and compromises cardiac function over time. We hypothesized that neutralizing the MCP-1 secreted by cardiac resident CCR2+ macrophages can mitigate post-MI inflammation by curtailing the recruitment of monocytes and their differentiation into macrophages. In this work, we developed nanoparticles that target the infarcted heart, specifically accumulating in the damaged area after intravenous (IV) administration, and docking onto CCR2+ macrophages. These nanoparticles were designed to slowly release an MCP-1 binding peptide, HSWRHFHTLGGG (HSW), which neutralizes the upregulated MCP-1. We showed that the HSW reduced monocyte migration, inhibited pro-inflammatory cytokine upregulation, and suppressed myofibroblast differentiation in vitro. After IV delivery, the released HSW significantly decreased monocyte recruitment and pro-inflammatory macrophage density, increased cardiac cell survival, attenuated cardiac fibrosis, and improved cardiac function. Taken together, our findings support the strategy of MCP-1 neutralization at the acute phase of MI as a promising way to alleviate post-MI inflammation. STATEMENT OF SIGNIFICANCE: After a myocardial infarction (MI), CCR2+ macrophages resident in the heart release various cytokines and chemokines, notably monocyte chemoattractant protein-1 (MCP-1). MCP-1 is instrumental in attracting CCR2+ monocytes to the damaged region. The excessive arrival of these monocytes, which then become macrophages, perpetuates inflammation at the site of injury. This continuous inflammation leads to adverse tissue remodeling and compromises cardiac function over time. In this work, we tested the hypothesis that neutralizing the MCP-1 secreted by cardiac CCR2+ macrophages can mitigate post-MI inflammation by curtailing the recruitment of monocytes.
心肌梗死（MI）后，心脏驻留的CCR2⁺巨噬细胞会释放多种细胞因子和趋化因子，尤其是单核细胞趋化蛋白-1（MCP-1）。MCP-1有助于将CCR2⁺单核细胞募集到受损区域。这些单核细胞过度聚集，随后转变为巨噬细胞，使损伤部位的炎症持续存在。这种持续的炎症会导致不良的组织重塑，并随着时间的推移损害心脏功能。我们推测，中和心脏驻留的CCR2⁺巨噬细胞分泌的MCP-1，可以通过减少单核细胞的募集及其向巨噬细胞的分化来减轻心肌梗死后的炎症。在这项研究中，我们开发了靶向梗死心脏的纳米颗粒，静脉注射（IV）后能特异性地在受损区域积聚，并与CCR2⁺巨噬细胞结合。这些纳米颗粒被设计用于缓慢释放一种MCP-1结合肽HSWRHFHTLGGG（HSW），以中和上调的MCP-1。我们发现，HSW在体外可减少单核细胞迁移、抑制促炎细胞因子上调并抑制成肌纤维细胞分化。静脉注射后，释放的HSW显著减少单核细胞募集和促炎巨噬细胞密度，增加心脏细胞存活率，减轻心脏纤维化，并改善心脏功能。综上所述，我们的研究结果支持在心肌梗死急性期中和MCP-1这一策略，认为这是减轻心肌梗死后炎症的一种有前景的方法。重要意义声明：心肌梗死（MI）后，心脏驻留的CCR2⁺巨噬细胞会释放多种细胞因子和趋化因子，尤其是单核细胞趋化蛋白-1（MCP-1）。MCP-1有助于将CCR2⁺单核细胞吸引到受损区域。这些单核细胞过度聚集，随后转变为巨噬细胞，使损伤部位的炎症持续存在。这种持续的炎症会导致不良的组织重塑，并随着时间的推移损害心脏功能。在这项研究中，我们验证了中和心脏CCR2⁺巨噬细胞分泌的MCP-1可以通过减少单核细胞募集来减轻心肌梗死后炎症的假设。
