TOLL RECEPTORS IN MACROPHAGE & DENDRITIC CELL ACTIVATION

描述：(改编自申请人的摘要)巨噬细胞正常摄取 并以促炎的方式杀死病原体，从而导致 有效的免疫，但清除凋亡细胞而不刺激 对自身的炎症或免疫反应。相比之下，最近的数据表明 树突状细胞(DC)释放促炎细胞因子以应对 凋亡性细胞。对凋亡细胞的反应通常是非炎症性的。 非免疫原性表明，凋亡细胞的能力 抗炎反应可能在以下方面发挥关键和上位性作用 自我宽容。或许与这个概念一致的是，凋亡细胞 系统性红斑狼疮(SLE)巨噬细胞清除不良 患者，可以激活这些患者的巨噬细胞，并在他们的 使SLE抗体识别的核抗原起泡，这可能是 疾病发展中的因素。该应用程序的目标是解决 凋亡细胞调节巨噬细胞反应的机制 和DC向凋亡细胞和炎症激动剂转化。假设是这样的 Toll样受体(TLRs)在这些过程中起着关键作用。TLR是 最近发现的先天免疫受体可以传递信号以响应 以脂多糖(LPS)和其他微生物成分。TLR可能是 在巨噬细胞被凋亡细胞下调中很重要，因为：1) 凋亡细胞下调巨噬细胞对内毒素的反应，从而发出信号 2)凋亡细胞和TLRs共同调节巨噬细胞的细胞因子 3)CD14对吞噬凋亡细胞很重要，而且 增强TLR信号；4)TLR被募集到吞噬小体中。目标1是 小鼠TLR表达检测试剂的研究进展 功能。AIMS 2和3使用这些试剂评估TLR 2、4和5 吞噬细胞凋亡前后巨噬细胞和树突状细胞的表达 并确定凋亡细胞是通过TLRs发出信号还是通过 TLRs的表达和信号转导。

DESCRIPTION: (adapted from applicant's abstract) Macrophages normally ingest and kill pathogens in a pro-inflammatory manner that leads to the development of effective immunity, but clear apoptotic cells without stimulating an inflammatory or immune response to self. By contrast, recent data suggest that dendritic cells (DCs) release pro-inflammatory cytokines in response to apoptotic cells. The response to apoptotic cells is normally non-inflammatory and non-immunogenic indicating that the abilities of apoptotic cells to counter pro-inflammatory responses may play a critical and epistatic role in self-tolerance. Perhaps consistent with this notion, apoptotic cells are poorly cleared by macrophages from systemic lupus erythematosus (SLE) patients, can activate macrophages in these patients, and contain within their blebs the nuclear antigens that are recognized by SLE antibodies, which may be factors in disease development. The goals of the application are to address the mechanisms by which apoptotic cells modulate the response of macrophages and DCs to apoptotic cells and inflammatory agonists. The hypothesis is that Toll-like receptors (TLRs) play a critical role in these processes. TLRs are recently identified innate immune receptors that transduce signals in response to lipopolysaccharide (LPS) and other microbial components. TLRs may be important in macrophage down-regulation by apoptotic cells because: 1) apoptotic cells down-regulate macrophage responses to LPS, which signal through TLRs; 2) apoptotic cells and TLRs both regulate macrophage cytokine production; 3) CD14 is important for phagocytosis of apoptotic cells and also enhances TLR signaling; and 4) TLRs are recruited to phagosomes. Aim 1 is the development of reagents for the evaluation of murine TLR expression and function. Aims 2 and 3 uses these reagents to evaluate TLR 2, 4, and 5 expression in macrophages and DCs before and after phagocytosis of apoptotic cells and determines whether apoptotic cells signal through TLRs or modulate the expression and signaling by TLRs.