Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
J Immunol. 2014 Mar 15;192(6):2800-11. doi: 10.4049/jimmunol.1302556. Epub 2014 Feb 14.
S100A8 is considered proinflammatory by activating TLR4 and/or the receptor for advanced glycation end products. The aim was to investigate inflammatory effects of S100A8 in murine lung. S100A8 was administered to BALB/c mice by nasal inhalation and genes induced over a time-course assessed. LPS was introduced intranasally either alone or 2 h after pretreatment of mice with intranasal application of S100A8 or dexamethasone. A Cys(42)-Ala(42) mutant S100A8 mutant was used to assess whether S100A8's effects were via pathways that were dependent on reactive oxygen species. S100A8 induced IL-10 mRNA, and expression was apparent only in airway epithelial cells. Importantly, it suppressed acute lung injury provoked by LPS inhalation by suppressing mast-cell activation and induction of mediators orchestrating leukocyte recruitment, possibly by reducing NF-κB activation via an IκBα/Akt pathway and by downmodulating pathways generating oxidative stress. The Cys(42)-Ala(42) S100A8 mutant did not induce IL-10 and was less immunosuppressive, indicating modulation by scavenging oxidants. S100A8 inhibition of LPS-mediated injury was as potent, and outcomes were remarkably similar to immunosuppression by dexamethasone. We challenge the notion that S100A8 is an agonist for TLR4 or the receptor for advanced glycation end products. S100A8 induced IL-10 in vivo and initiates a feedback loop that attenuates acute lung injury.
S100A8 通过激活 TLR4 和/或晚期糖基化终产物受体被认为具有促炎作用。目的是研究 S100A8 在小鼠肺中的炎症作用。通过鼻腔吸入将 S100A8 给予 BALB/c 小鼠，并评估随时间推移诱导的基因。单独给予 LPS 或在鼻腔应用 S100A8 或地塞米松预处理 2 小时后给予 LPS。使用 Cys(42)-Ala(42)突变 S100A8 突变体来评估 S100A8 的作用是否通过依赖于活性氧的途径。S100A8 诱导 IL-10 mRNA 的表达，并且仅在气道上皮细胞中明显。重要的是，它通过抑制肥大细胞激活和诱导协调白细胞募集的介质来抑制 LPS 吸入引起的急性肺损伤，可能通过 IκBα/Akt 途径减少 NF-κB 激活，并通过下调产生氧化应激的途径来实现。Cys(42)-Ala(42) S100A8 突变体不诱导 IL-10，并且免疫抑制作用较弱，表明通过清除氧化剂进行调节。S100A8 抑制 LPS 介导的损伤与地塞米松的免疫抑制作用一样有效，结果非常相似。我们对 S100A8 是 TLR4 或晚期糖基化终产物受体的激动剂的观点提出质疑。S100A8 在体内诱导 IL-10，并引发一个反馈回路，从而减轻急性肺损伤。
