David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, USA.
Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
Nat Mater. 2017 Jun;16(6):671-680. doi: 10.1038/nmat4866. Epub 2017 Mar 20.
Host recognition and immune-mediated foreign body response to biomaterials can compromise the performance of implanted medical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate and adaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophages are indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13, lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knockout and CXCL13 neutralization. Interestingly, colony stimulating factor-1 receptor (CSF1R) is significantly increased following implantation of multiple biomaterial classes: ceramic, polymer and hydrogel. Its inhibition, like macrophage depletion, leads to complete loss of fibrosis, but spares other macrophage functions such as wound healing, reactive oxygen species production and phagocytosis. Our results indicate that targeting CSF1R may allow for a more selective method of fibrosis inhibition, and improve biomaterial biocompatibility without the need for broad immunosuppression.
宿主识别和免疫介导的异物反应会影响植入医疗器械的性能。为了确定关键的细胞和细胞因子靶点，我们在这里对啮齿动物和非人灵长类动物植入生物材料的固有和适应性免疫系统反应进行了深入的系统分析。虽然巨噬细胞对纤维增生级联反应是不可或缺的，但令人惊讶的是，中性粒细胞和补体并非如此。巨噬细胞通过 CXCL13 导致下游 B 细胞募集，进一步增强纤维化，这一点通过 B 细胞敲除和 CXCL13 中和得到证实。有趣的是，在植入多种生物材料（陶瓷、聚合物和水凝胶）后，集落刺激因子-1 受体（CSF1R）显著增加。其抑制作用，如巨噬细胞耗竭，会导致纤维化完全丧失，但不会影响其他巨噬细胞功能，如伤口愈合、活性氧物质产生和吞噬作用。我们的研究结果表明，靶向 CSF1R 可能为纤维化抑制提供一种更具选择性的方法，并改善生物材料的生物相容性，而无需广泛的免疫抑制。
