Laboratory of Inflammation, Biophysics Institute Carlos Chagas Filho, Rio de Janeiro, RJ, Brazil.
Department of Immunology, Institute of Microbiology Professor Paulo de Góes, Rio de Janeiro, RJ, Brazil.
Mediators Inflamm. 2017;2017:2086840. doi: 10.1155/2017/2086840. Epub 2017 Aug 15.
TLRs recognize a broad spectrum of microorganism molecules, triggering a variety of cellular responses. Among them, phagocytosis is a critical process for host defense. Leukotrienes (LTs), lipid mediators produced from 5-lipoxygenase (5-LO) enzyme, increase FcR-mediated phagocytosis. Here, we evaluated the participation of TLR2, TLR3, TLR4, and TLR9 in FcR-mediated phagocytosis and whether this process is modulated by LTs. Rat alveolar macrophages (AMs), murine bone marrow-derived macrophages (BMDMs), and peritoneal macrophages (PMs) treated with TLR2, TLR3, and TLR4 agonists, but not TLR9, enhanced IgG-opsonized sheep red blood cell (IgG-sRBC) phagocytosis. Pretreatment of AMs or BMDMs with drugs that block LT synthesis impaired the phagocytosis promoted by TLR ligands, and TLR potentiation was also abrogated in PMs and BMDMs from 5-LO mice. LTB production induced by IgG engagement was amplified by TLR ligands, while cys-LTs were amplified by activation of TLR2 and TLR4, but not by TLR3. We also noted higher ERK1/2 phosphorylation in IgG-RBC-challenged cells when preincubated with TLR agonists. Furthermore, ERK1/2 inhibition by PD98059 reduced the phagocytic activity evoked by TLR agonists. Together, these data indicate that TLR2, TLR3, and TLR4 ligands, but not TLR9, amplify IgG-mediated phagocytosis by a mechanism which requires LT production and ERK-1/2 pathway activation.
TLRs 识别广泛的微生物分子，引发多种细胞反应。其中，吞噬作用是宿主防御的关键过程。白三烯（LTs）是由 5-脂氧合酶（5-LO）酶产生的脂质介质，可增加 FcR 介导的吞噬作用。在这里，我们评估了 TLR2、TLR3、TLR4 和 TLR9 在 FcR 介导的吞噬作用中的参与程度，以及该过程是否受到 LTs 的调节。用 TLR2、TLR3 和 TLR4 激动剂处理大鼠肺泡巨噬细胞（AMs）、鼠骨髓来源巨噬细胞（BMDMs）和腹腔巨噬细胞（PMs），但不是 TLR9，增强 IgG 调理的绵羊红细胞（IgG-sRBC）吞噬作用。用抑制 LT 合成的药物预处理 AMs 或 BMDMs 会损害 TLR 配体促进的吞噬作用，并且来自 5-LO 小鼠的 PMs 和 BMDMs 中的 TLR 增强作用也被消除。IgG 结合诱导的 LTB 产生被 TLR 配体放大，而 cys-LTs 被 TLR2 和 TLR4 的激活放大，但不被 TLR3 放大。我们还注意到在用 TLR 激动剂预孵育时，在 IgG-RBC 挑战的细胞中 ERK1/2 磷酸化增加。此外，用 PD98059 抑制 ERK1/2 减少了 TLR 激动剂引起的吞噬活性。总之，这些数据表明 TLR2、TLR3 和 TLR4 配体，但不是 TLR9，通过需要 LT 产生和 ERK-1/2 途径激活的机制放大 IgG 介导的吞噬作用。
