Loss of myeloid cell-specific SIRPα, but not CD47, attenuates inflammation and suppresses atherosclerosis

Bhupesh Singla, Hui Ping Lin, Won Mo Ahn, Jiean Xu, Qian Ma, Moses Sghayyer, Kunzhe Dong, Mary Cherian-Shaw, Jiliang Zhou, Yuqing Huo, Joseph White, Gábor Csányi

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

AIM: Inhibitors of the anti-phagocytic CD47-SIRPα immune checkpoint are currently in clinical development for a variety of hematological and solid tumors. Application of immune checkpoint inhibitors to the cardiovascular field is limited by the lack of preclinical studies using genetic models of CD47 and SIRPα inhibition. In this study, we comprehensively analyzed the effects of global and cell-specific SIRPα and CD47 deletion on atherosclerosis development.

METHODS AND RESULTS: Here we show that both SIRPα and CD47 expression are increased in human atherosclerotic arteries and primarily co-localize to CD68+ areas in the plaque region. Hypercholesterolemic mice homozygous for a Sirpa mutant lacking the signaling cytoplasmic region (Sirpamut/mut) and myeloid cell-specific Sirpa knockout mice are protected from atherosclerosis. Further, global Cd47-/- mice are protected from atherosclerosis but myeloid cell-specific deletion of Cd47 increased atherosclerosis development. Using a combination of techniques, we show that loss of SIRPα signaling in macrophages stimulates efferocytosis, reduces cholesterol accumulation, promotes lipid efflux, and attenuates oxidized LDL-induced inflammation in vitro and induces M2 macrophage phenotype and inhibits necrotic core formation in the arterial wall in vivo. Conversely, loss of myeloid cell CD47 inhibited efferocytosis, impaired cholesterol efflux, augmented cellular inflammation, stimulated M1 polarization and failed to decrease necrotic core area in atherosclerotic vessels. Finally, comprehensive blood cell analysis demonstrated lower hemoglobin and erythrocyte levels in Cd47-/-mice compared with wild-type and Sirpamut/mutmice.

CONCLUSION: Taken together, these findings identify SIRPα as a potential target in atherosclerosis and suggest the importance of cell-specific CD47 inhibition as a future therapeutic strategy.

TRANSLATIONAL PERSPECTIVE: Despite the extensive use of lipid-lowering and anti-hypertensive drugs, atherosclerotic plaque rupture responsible for myocardial infarction and stroke remains the leading cause of death worldwide. Although stimulation of phagocytic removal of apoptotic cells in atherosclerotic arteries to preserve lesion stability seems an attractive therapeutic strategy, comprehensive genetic studies using preclinical models are still lacking. Using human atherosclerotic arteries, global and myeloid cell-specific CD47 and SIRPα knockout mice and in vitro techniques, we identify SIRPα as a potential therapeutic target in atherosclerosis. Further, our results suggest that cell-specific inhibition of CD47 could also be considered as a future therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)3097-3111
Number of pages15
JournalCardiovascular Research
Volume118
Issue number15
Early online dateDec 23 2021
DOIs
StatePublished - Dec 9 2022

Keywords

  • Atherosclerosis
  • CD47
  • Efferocytosis
  • Inflammation
  • SIRPα

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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