McKiel Laura A, Fitzpatrick Lindsay E
Department of Chemical Engineering, Queen's University, 19 Division Street, Kingston, Ontario K7L 3N6, Canada.
ACS Biomater Sci Eng. 2018 Nov 12;4(11):3792-3801. doi: 10.1021/acsbiomaterials.8b00613. Epub 2018 Aug 3.
The foreign body reaction is a chronic inflammatory response to an implanted biomaterial that ultimately leads to fibrous encapsulation of the implant. It is widely accepted that the host response to implanted biomaterials is largely dependent on the species and conformations of proteins adsorbed onto the material surface due to the adsorbate's role in mediating cellular interactions with the implanted material. While the cellular response to adsorbed serum-derived proteins has been studied extensively, the presence of endogenous, matrix- and cell-derived mediators of inflammation within the adsorbed protein layer and their impact on cell-material interactions is not well-understood. Damage associated molecular patterns (DAMPs) are endogenous ligands released by stressed or damaged tissues to stimulate sterile inflammatory responses via Toll-like receptors (TLRs) and other pattern recognition receptors. The present study investigated the potential role of tissue-derived, pro-inflammatory stimuli in macrophage responses to biomaterials using cell lysate as a complex source of cell-derived DAMPs and poly(methyl methacrylate) (PMMA) and polydimethylsiloxane (PDMS) films as model biomaterials. We show that lysate-adsorbed PMMA and PDMS surfaces strongly induced NF-κB/AP-1 transcription factor activity and pro-inflammatory cytokine secretion in the RAW-Blue macrophage cell line compared to serum-adsorbed surfaces. Lysate-dependent NF-κB/AP-1 activation and cytokine expression were strongly attenuated by TLR2 neutralizing antibodies, while TLR4 inhibition resulted in a modest reduction. These data suggest that DAMPs, in their adsorbed conformations on material surfaces, may play a significant role in macrophage activation through TLR signaling, and that TLR pathways, particularly TLR2, merit further investigation as potential therapeutic targets to modulate host responses to implanted biomaterials.
异物反应是对植入生物材料的慢性炎症反应，最终导致植入物被纤维包裹。人们普遍认为，宿主对植入生物材料的反应在很大程度上取决于吸附在材料表面的蛋白质的种类和构象，因为被吸附物在介导细胞与植入材料的相互作用中发挥着作用。虽然对吸附的血清衍生蛋白的细胞反应已进行了广泛研究，但吸附蛋白层中内源性、基质和细胞衍生的炎症介质的存在及其对细胞-材料相互作用的影响尚未得到充分理解。损伤相关分子模式（DAMPs）是应激或受损组织释放的内源性配体，通过 Toll 样受体（TLRs）和其他模式识别受体刺激无菌性炎症反应。本研究使用细胞裂解物作为细胞衍生 DAMPs 的复杂来源，以聚甲基丙烯酸甲酯（PMMA）和聚二甲基硅氧烷（PDMS）薄膜作为模型生物材料，研究了组织衍生的促炎刺激在巨噬细胞对生物材料反应中的潜在作用。我们发现，与血清吸附表面相比，吸附裂解物的 PMMA 和 PDMS 表面在 RAW-Blue 巨噬细胞系中强烈诱导 NF-κB/AP-1 转录因子活性和促炎细胞因子分泌。TLR2 中和抗体强烈减弱了裂解物依赖性 NF-κB/AP-1 激活和细胞因子表达，而 TLR4 抑制导致适度降低。这些数据表明，DAMPs 以其在材料表面的吸附构象，可能通过 TLR 信号在巨噬细胞激活中发挥重要作用，并且 TLR 途径，特别是 TLR2，作为调节宿主对植入生物材料反应的潜在治疗靶点值得进一步研究。
