RESUMEN
Chronic inflammation is a hallmark of atherosclerosis and results from an imbalance between proinflammatory and proresolving signaling. The human GPR32 receptor, together with the ALX/FPR2 receptor, transduces biological actions of several proresolving mediators that stimulate resolution of inflammation. However, since no murine homologs of the human GPR32 receptor exist, comprehensive in vivo studies are lacking. Using human atherosclerotic lesions from carotid endarterectomies and creating a transgenic mouse model expressing human GPR32 on a Fpr2×ApoE double-KO background (hGPR32myc×Fpr2-/-×Apoe-/-), we investigated the role of GPR32 in atherosclerosis and self-limiting acute inflammation. GPR32 mRNA was reduced in human atherosclerotic lesions and correlated with the immune cell markers ARG1, NOS2, and FOXP3. Atherosclerotic lesions, necrotic core, and aortic inflammation were reduced in hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice as compared with Fpr2-/-×Apoe-/- nontransgenic littermates. In a zymosan-induced peritonitis model, the hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice had reduced inflammation at 4 hours and enhanced proresolving macrophage responses at 24 hours compared with nontransgenic littermates. The GPR32 agonist aspirin-triggered resolvin D1 (AT-RvD1) regulated leukocyte responses, including enhancing macrophage phagocytosis and intracellular signaling in hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice, but not in Fpr2-/-×Apoe-/- nontransgenic littermates. Together, these results provide evidence that GPR32 regulates resolution of inflammation and is atheroprotective in vivo.
Asunto(s)
Aterosclerosis , Macrófagos/metabolismo , Transducción de Señal/genética , Animales , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/genética , Ácidos Docosahexaenoicos/metabolismo , Femenino , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/prevención & control , Masculino , Ratones , Ratones Noqueados para ApoE , Peritonitis/inducido químicamente , Peritonitis/genética , Peritonitis/metabolismo , Fagocitosis/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Dyslipidaemia and inflammation are closely interconnected in their contribution to atherosclerosis. In fact, low-density lipoprotein (LDL)-lowering drugs have anti-inflammatory effects. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) has shown that interleukin (IL)-1ß blockade reduces the incidence of cardiovascular events in patients with previous myocardial infarction and C-reactive protein levels >2 mg/L. These data confirm the connection between lipids and inflammation, as lipids activate the Nod-like receptor protein 3 inflammasome that leads to IL-1ß activation. LDL-lowering drugs are the foundation of cardiovascular prevention. Now, the CANTOS trial demonstrates that combining them with IL-1ß blockade further decreases the incidence of cardiovascular events. However, both therapies are not at the same level, given the large evidence showing that LDL-lowering drugs reduce cardiovascular risk as opposed to only one randomized trial of IL-1ß blockade. In addition, IL-1ß blockade has only been studied in patients with C-reactive protein >2 mg/L, while the benefit of LDL-lowering is not restricted to these patients. Also, lipid-lowering drugs are not harmful even at very low ranges of LDL, while anti-inflammatory therapies may confer a higher risk of developing fatal infections and sepsis. In the future, more clinical trials are needed to explore whether targeting other inflammatory molecules, both related and unrelated to the IL-1ß pathway, reduces the cardiovascular risk. In this regard, the ongoing trials with methotrexate and colchicine may clarify whether the cardiovascular benefit of IL-1ß blockade extends to other anti-inflammatory mechanisms. A positive result would represent a major change in the future treatment of atherosclerosis.
