Macrophage HM13/SPP Enhances Foamy Macrophage Formation and Atherogenesis.
Summary
Network analysis and mechanistic studies identify HM13/SPP as a macrophage driver of lipid loading and foamy cell formation by promoting ERAD-dependent degradation of HO-1. Myeloid HM13 overexpression accelerates atherosclerosis, whereas knockout is protective; AIP suppresses HM13 via AHR–p38–c-JUN signaling.
Key Findings
- AIP negatively correlates with HM13/SPP in human atherosclerosis (STAGE cohort), oxLDL-treated macrophages, and plaque foam cells.
- AIP via AHR chaperoning inhibits p38–c-JUN-mediated HM13 transactivation, reducing macrophage lipid accumulation.
- Myeloid HM13/SPP overexpression increases foam cell formation and atherogenesis in vivo; knockout has opposite, protective effects.
- HM13/SPP promotes ERAD-dependent proteasomal degradation of HO-1, linking ER proteostasis to foam cell biology.
Clinical Implications
Therapeutic modulation of HM13/SPP or reinforcement of HO-1 stability may reduce foam cell burden and atherosclerosis; AHR–AIP pathway tuning could offer anti-atherogenic strategies.
Why It Matters
Reveals a previously unrecognized ERAD–HO-1 axis in foamy macrophage biology and atherogenesis, nominating HM13/SPP as a targetable node downstream of AIP/AHR signaling.
Limitations
- Pharmacologic HM13/SPP inhibition was not tested; off-target or systemic effects remain to be characterized.
- Translational validation in human intervention studies is lacking.
Future Directions
Develop selective HM13/SPP inhibitors or HO-1 stabilizers; assess efficacy in preclinical atherosclerosis models and explore AHR–AIP pathway modulation in humans.
Study Information
- Study Type
- Basic/Mechanistic research
- Research Domain
- Pathophysiology
- Evidence Level
- III - Mechanistic multi-model experimental work integrating human data and mouse genetics.
- Study Design
- OTHER