SR‐A LIGAND AND M‐CSF DYNAMICALLY REGULATE SR‐A EXPRESSION AND FUNCTION IN PRIMARY MACROPHAGES VIA p38 MAPK ACTIVATION

Inflammation is characterized by dynamic changes in the expression of cytokines such as M‐CSF, and modifications of lipids and proteins that result in 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 affects 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. Together, these results suggest that SR‐A expression and function are dynamically regulated in resident macrophages by cytokine and SR‐A ligand. Supported by R01 HL089588