Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
BMC Immunol. 2011 Jul 7;12:37. doi: 10.1186/1471-2172-12-37.
Inflammation is characterized by dynamic changes in the expression of cytokines, such as M-CSF, and modifications of lipids and proteins that result in the formation of ligands for Class A Scavenger Receptors (SR-A). These changes are associated with altered SR-A expression in macrophages; however, the intracellular signal pathways involved and the extent to which SR-A ligands regulate SR-A expression are not well defined. To address these questions, SR-A expression and function were examined in resident mouse peritoneal macrophages incubated with M-CSF or the selective SR-A ligand acetylated-LDL (AcLDL).
M-CSF increased SR-A expression and function, and required the specific activation of p38 MAPK, but not ERK1/2 or JNK. Increased SR-A expression and function returned to basal levels 72 hours after removing M-CSF. We next determined whether prolonged incubation of macrophages with SR-A ligand alters SR-A expression. In contrast to most receptors, which are down-regulated by chronic exposure to ligand, SR-A expression was reversibly increased by incubating macrophages with AcLDL. AcLDL activated p38 in wild-type macrophages but not in SR-A-/- macrophages, and p38 activation was specifically required for AcLDL-induced SR-A expression.
These results demonstrate that in resident macrophages SR-A expression and function can be dynamically regulated by changes in the macrophage microenvironment that are typical of inflammatory processes. In particular, our results indicate a previously unrecognized role for ligand binding to SR-A in up-regulating SR-A expression and activating p38 MAPK. In this way, SR-A may modulate inflammatory responses by enhancing macrophage uptake of modified protein/lipid, bacteria, and cell debris; and by regulating the production of inflammatory cytokines, growth factors, and proteolytic enzymes.
炎症的特征是细胞因子（如 M-CSF）的表达发生动态变化，脂质和蛋白质发生修饰，从而形成 A 类清道夫受体（SR-A）的配体。这些变化与巨噬细胞中 SR-A 表达的改变有关；然而，涉及的细胞内信号通路以及 SR-A 配体调节 SR-A 表达的程度尚不清楚。为了解决这些问题，在孵育 M-CSF 或选择性 SR-A 配体乙酰化 LDL（AcLDL）的常驻小鼠腹腔巨噬细胞中检查了 SR-A 的表达和功能。
M-CSF 增加了 SR-A 的表达和功能，并且需要 p38 MAPK 的特异性激活，而不依赖于 ERK1/2 或 JNK。去除 M-CSF 72 小时后，SR-A 的表达和功能恢复到基础水平。我们接下来确定巨噬细胞与 SR-A 配体的长期孵育是否改变了 SR-A 的表达。与大多数受体不同，这些受体在慢性暴露于配体时被下调，而 SR-A 的表达在巨噬细胞用 AcLDL 孵育时被可逆地增加。AcLDL 在野生型巨噬细胞中激活了 p38，但在 SR-A-/-巨噬细胞中没有，并且 p38 的激活是 AcLDL 诱导的 SR-A 表达所必需的。
这些结果表明，在常驻巨噬细胞中，巨噬细胞微环境的变化可以动态调节 SR-A 的表达和功能，这种变化是炎症过程的典型特征。特别是，我们的结果表明，配体与 SR-A 的结合在上调 SR-A 表达和激活 p38 MAPK 方面具有以前未被认识到的作用。通过这种方式，SR-A 可以通过增强巨噬细胞对修饰蛋白/脂质、细菌和细胞碎片的摄取，以及通过调节炎症细胞因子、生长因子和蛋白水解酶的产生，来调节炎症反应。
