CD147 Sparks Atherosclerosis by Driving M1 Phenotype and Impairing Efferocytosis

Abstract

BACKGROUND: Atherosclerosis is a globally prevalent chronic inflammatory disease with high morbidity and mortality. The development of atherosclerotic lesions is determined by macrophages. This study aimed to investigate the specific role of myeloid-derived CD147 in atherosclerosis and its translational significance. METHODS AND RESULTS: We generated mice with a myeloid-specific knockout of CD147 and mice with restricted CD147 overexpression, both in an apoE-deficient (ApoE –/– ) background. Here, the myeloid-specific deletion of CD147 ameliorated atherosclerosis and inflammation. Consistent with our in vivo data, macrophages isolated from myeloid-specific CD147 knockout mice exhibited a phenotype shift from proinflammatory to anti-inflammatory macrophage polarization in response to lipopolysaccharide/IFN (interferon)-γ. These macrophages demonstrated a weakened proinflammatory macrophage phenotype, characterized by reduced production of NO and reactive nitrogen species derived from iNOS (inducible NO synthase). Mechanistically, the TRAF6 (tumor necrosis factor receptor–associated factor 6)-IKK (inhibitor of κB kinase)-IRF5 (IFN regulatory factor 5) signaling pathway was essential for the effect of CD147 on proinflammatory responses. Consistent with the reduced size of the necrotic core, myeloid-specific CD147 deficiency diminished the susceptibility of iNOS-mediated late apoptosis, accompanied by enhanced efferocytotic capacity mediated by increased secretion of GAS6 (growth arrest–specific 6) in proinflammatory macrophages. These findings were consistent in a mouse model with myeloid-restricted overexpression of CD147. Furthermore, we developed a new atherosclerosis model in ApoE –/– mice with humanized CD147 transgenic expression and demonstrated that the administration of an anti-human CD147 antibody effectively suppressed atherosclerosis by targeting inflammation and efferocytosis. CONCLUSIONS: Myeloid CD147 plays a crucial role in the growth of plaques by promoting inflammation in a TRAF6-IKK-IRF5–dependent manner and inhibiting efferocytosis by suppressing GAS6 during proinflammatory conditions. Consequently, the use of anti-human CD147 antibodies presents a complementary therapeutic approach to the existing lipid-lowering strategies for treating atherosclerotic diseases.

The Role of Macrophage Efferocytosis in the Pathogenesis of Apical Periodontitis

“…In view of the crucial role of Mφ efferocytosis on apoptotic cells' clearance and Mφ polarization, it may not be surprising that Mφ efferocytosis is involved in the etiology and pathogenesis of multiple inflammatory diseases such as atherosclerosis (AS), osteoarthritis (OA) and periodontitis [13][14][15][16]. Lv et al demonstrated that increasing the Mφ efferocytosis ability in an AS model in ApoE −/− mice could effectively suppress AS progression, even leading to the resolution of AS [17]. Moreover, Sordo et al found that there was a marked reduction in the fraction of synovial tissue Mφs engaging in efferocytosis in patients with late-stage knee OA, resulting in the accumulation of apoptotic synovial cells and then exacerbating the disease activity in OA patients [18].…”