TOLL RECEPTORS IN MACROPHAGE & DENDRITIC CELL ACTIVATION

描述：（改编自申请人摘要）巨噬细胞通常摄取 并以促炎的方式杀死病原体， 有效的免疫力，但清除凋亡细胞，而不刺激 炎症或自身免疫反应。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， 凋亡细胞对凋亡细胞的反应通常是非炎症性的 和非免疫原性，表明凋亡细胞的能力， 对抗促炎反应可能在 自我宽容也许与这一观点一致，凋亡细胞是 系统性红斑狼疮（SLE）的巨噬细胞清除不良 患者，可以激活这些患者中的巨噬细胞，并在其体内含有 水泡的核抗原被SLE抗体识别，这可能是 疾病发展的因素。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 以及DC对凋亡细胞和炎性激动剂的作用。前提是 Toll样受体（TLR）在这些过程中起关键作用。tlr是 最近发现的先天性免疫受体， 脂多糖（LPS）和其他微生物成分。TLR可以是 在凋亡细胞下调巨噬细胞中很重要，因为：1） 凋亡细胞下调巨噬细胞对LPS的反应， 2）凋亡细胞和TLRs共同调节巨噬细胞因子 3）CD 14对于凋亡细胞的吞噬作用是重要的， 增强TLR信号传导;和4）TLR被募集到吞噬体。 目标1是 开发用于评价鼠TLR表达的试剂， 功能目的2和3使用这些试剂评价TLR 2、4和5 巨噬细胞和树突状细胞吞噬凋亡细胞前后的表达 细胞，并确定凋亡细胞是否通过TLR信号或调节 TLRs的表达和信号传导。

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.