SR-A ligand and M-CSF dynamically regulate SR-A expression and function in primary macrophages via p38 MAPK activation

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.SR-A is a multifunctional macrophage receptor that is upregulated during monocyte differentiation into macrophages, and is further increased in pathological conditions such as diabetes [1-3]. SR-A is also highly expressed by macrophages in atherosclerotic lesions and Alzheimer's plaques [4-6]. In contrast, decreased SR-A expression is associated with increased susceptibility to bacterial infection, progression of prostate cancer, and enhanced cytokine production [7-9]. Such results suggest important and complex roles for SR-A in modulating immune function and inflammation.Macrophage differentiation and recruitment during inflammation is mediated by changes in the local environment and the secretion of cytokines/chemokines such as M-CSF. M-CSF, which is pro