Mesenchymal stromal cells (MSCs) have become a promising treatment for inflammation-related diseases, and their therapeutic efficacy mainly depends on crosstalk between MSCs and inflammation. However, methods to improve the immunosuppressive efficiency of MSCs in different diseases still need to be developed. In this study, we investigated whether preconditioning MSCs with a disease-related inflammatory cytokine could increase their immunosuppressive properties and improve therapeutic efficacy. In a contact hypersensitivity (CHS) mouse model, inflammatory profile screening revealed that among all tested cytokines, monocyte chemotactic protein-1 (MCP-1) exhibited the most significantly increased level in the local microenvironment. As expected, MSCs preconditioned with MCP-1 (P-MSCs) exhibited an enhanced ability to downregulate proinflammatory cytokine secretion, induce regulatory T cells, inhibit T cell proliferation, and polarize M2-type macrophages. In vivo experiments showed that P-MSCs alleviated ear swelling and local proinflammatory cytokine production more effectively than control MSCs. Mechanistically, MCP-1 could significantly activate the signal transducer and activator of transcription 3 (STAT3) signaling pathway and induce the expression of cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) in MSCs. STAT3 inhibitor reversed the MCP-1-mediated enhancing of their immunosuppressive ability. Collectively, our findings demonstrate that CHS-related MCP-1 preconditioning enhanced the immunomodulatory effects of MSCs and improved their therapeutic efficacy in CHS. Enhancing the immunosuppressive efficacy of MSCs by preconditioning with certain disease-related inflammatory cytokines may provide a new strategy for MSC-based therapies for inflammatory diseases.

中文翻译：

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MCP-1 启动通过激活 COX2-PGE2/STAT3 通路增强了人类间充质基质细胞对接触性过敏小鼠的治疗效果。

间充质基质细胞 (MSCs) 已成为治疗炎症相关疾病的一种很有前景的方法，其治疗效果主要取决于 MSCs 与炎症之间的串扰。然而，仍需要开发提高MSCs在不同疾病中的免疫抑制效率的方法。在这项研究中，我们研究了用疾病相关的炎性细胞因子预处理 MSC 是否可以增加其免疫抑制特性并提高治疗效果。在接触性超敏反应 (CHS) 小鼠模型中，炎症特征筛选显示，在所有测试的细胞因子中，单核细胞趋化蛋白 1 (MCP-1) 在局部微环境中的水平升高最为显着。正如预期的那样，用 MCP-1 (P-MSCs) 预处理的 MSCs 表现出增强的下调促炎细胞因子分泌、诱导调节性 T 细胞、抑制 T 细胞增殖和极化 M2 型巨噬细胞的能力。体内实验表明，P-MSCs 比对照 MSCs 更有效地减轻耳肿胀和局部促炎细胞因子的产生。从机制上讲，MCP-1 可以显着激活信号转导和转录激活因子 3 (STAT3) 信号通路，并诱导 MSCs 中环氧合酶-2 (COX2) 和前列腺素 E2 (PGE2) 的表达。STAT3 抑制剂逆转了 MCP-1 介导的免疫抑制能力增强。总的来说，我们的研究结果表明 CHS 相关的 MCP-1 预处理增强了 MSCs 的免疫调节作用并提高了它们在 CHS 中的治疗效果。