Toll样受体2依赖NF-κB/ AP-1活化通过吸附在聚合物表面的损伤相关分子模式,ACS Biomaterials Science & Engineering

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Toll样受体2依赖NF-κB/ AP-1活化通过吸附在聚合物表面的损伤相关分子模式
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2018-07-11 00:00:00 , DOI: 10.1021/acsbiomaterials.8b00613
Laura A. McKiel ₁ , Lindsay E. Fitzpatrick ₁

Affiliation

异物反应是对植入的生物材料的慢性炎症反应，最终导致植入物的纤维包封。广泛接受的是，宿主对植入生物材料的反应很大程度上取决于吸附在材料表面的蛋白质的种类和构型，这是由于被吸附物在介导细胞与植入材料相互作用中的作用。尽管细胞对吸附的血清来源的蛋白质的反应已得到广泛研究，但对吸附的蛋白质层中炎症的内源性，基质和细胞来源的介体的存在及其对细胞与物质相互作用的影响尚不清楚。损伤相关分子模式（DAMP）是受压或受损组织释放的内源性配体，可通过Toll样受体（TLR）和其他模式识别受体刺激无菌炎症反应。本研究使用细胞裂解物作为细胞衍生的DAMPs的复杂来源，并以聚甲基丙烯酸甲酯（PMMA）和聚二甲基硅氧烷（PDMS）膜为模型，研究了组织衍生的促炎刺激物在巨噬细胞对生物材料反应中的潜在作用。生物材料。我们显示，与血清吸附的表面相比，裂解物吸附的PMMA和PDMS表面强烈诱导RAW-Blue巨噬细胞细胞系中的NF-κB/ AP-1转录因子活性和促炎性细胞因子分泌。TLR2中和抗体会大大削弱裂解液依赖性NF-κB/ AP-1的激活和细胞因子的表达，而TLR4的抑制则导致适度的降低。这些数据表明，DAMP以其在材料表面的吸附构型，可能在通过TLR信号传导的巨噬细胞活化中起重要作用，并且TLR途径，特别是TLR2，值得进一步研究，作为调节宿主对植入生物材料反应的潜在治疗靶标。

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Toll-like Receptor 2-Dependent NF-κB/AP-1 Activation by Damage-Associated Molecular Patterns Adsorbed on Polymeric Surfaces

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.

更新日期：2018-07-11

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