Macrophage HM13/SPP Enhances Foamy Macrophage Formation and Atherogenesis

Abstract Aryl Hydrocarbon Receptor‐Interacting Protein (AIP) reduces macrophage cholesterol‐ester accumulation and may prevent atherogenic foamy macrophage formation. Analyzing AIP ‐associated regulatory gene networks can aid in identifying key regulatory mechanism(s) underlying foamy macrophage formation. A weighted gene co‐expression network analysis on the Stockholm Atherosclerosis Gene Expression (STAGE) patient cohort identifies AIP as a negative correlate of Histocompatibility Minor 13 ( HM13 ), which encodes the ER‐associated degradation (ERAD) protein Signal Peptide Peptidase (HM13/SPP). The negative correlation between AIP and HM13/SPP on mRNA and protein levels is validated in oxLDL‐stimulated macrophages and human plaque foamy macrophages. Mechanistically, AIP, via its chaperone interaction with Aryl Hydrocarbon Receptor (AHR), inhibits p38‐c‐JUN‐mediated HM13 transactivation, thereby suppressing macrophage lipid accumulation. Myeloid HM13/SPP overexpression enhances oxLDL‐induced foamy macrophage formation in vitro as well as atherogenesis and plaque foamy macrophage load in vivo, while myeloid HM13/SPP knockout produces the opposite effects. Mechanistically, myeloid HM13/SPP enhances oxLDL‐induced foamy macrophage formation in vitro as well as atherogenesis and plaque foamy macrophage load in vivo via promoting ERAD‐mediated proteasomal degradation of the metabolic regulator Heme Oxygenase‐1 (HO‐1). In conclusion, AIP downregulates macrophage HM13/SPP, a driver of oxLDL‐induced lipid loading, foamy macrophage generation, and atherogenesis.