RESUMEN
The triggering receptor expressed on myeloid cells 1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of angiotensin II-induced (AngII-induced) AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalized with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide, limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2, and Mmp9 mRNA expression, and led to a decreased macrophage content due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L upregulation and promoted proinflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII receptor type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared with patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in humans.
Asunto(s)
Angiotensina II/efectos adversos , Aneurisma de la Aorta Abdominal/metabolismo , Movimiento Celular/efectos de los fármacos , Monocitos/metabolismo , Receptor Activador Expresado en Células Mieloides 1/metabolismo , Angiotensina II/farmacología , Animales , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/patología , Movimiento Celular/genética , Eliminación de Gen , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Noqueados para ApoE , Monocitos/patología , Receptor Activador Expresado en Células Mieloides 1/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: To determine the consequences of specific inhibition of EGFR (epidermal growth factor receptor) in myeloid cells in atherosclerosis development. APPROACH AND RESULTS: Atherosclerotic lesion size was significantly reduced in irradiated Ldlr-/- mice reconstituted with LysMCre+Egfrlox/lox bone marrow, compared with chimeric Ldlr-/- mice reconstituted with LysMCre-Egfrlox/lox bone marrow, after 4 (-43%; P<0.05), 7 (-34%; P<0.05), and 12 weeks (-54%; P<0.001) of high-fat diet. Reduction of lesion size was associated with marked reduction in macrophage accumulation and necrotic core size. Specific deletion of Egfr in myeloid cells reduced TNF-α (tumor necrosis factor-α) and IL (interleukin)-6 production by stimulated macrophages but had no effect on IL-10 and IL-12p70 secretion. Finally, we found that myeloid deletion of Egfr limited cytoskeletal rearrangements and also lipid uptake by macrophages through a downregulation of the scavenger receptor CD36 (cluster of differentiation 36). CONCLUSIONS: Gene deletion of Egfr in myeloid cells limits IL-6 and TNF-α production, lipid uptake, and consecutively reduces atherosclerosis development.
Asunto(s)
Aterosclerosis/prevención & control , Receptores ErbB/deficiencia , Eliminación de Gen , Macrófagos/metabolismo , Animales , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Trasplante de Médula Ósea , Antígenos CD36/metabolismo , Citoesqueleto/metabolismo , Citoesqueleto/patología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Receptores ErbB/genética , Interleucina-6/metabolismo , Macrófagos/patología , Macrófagos/trasplante , Masculino , Ratones Noqueados , Necrosis , Placa Aterosclerótica , Receptores de LDL/deficiencia , Receptores de LDL/genética , Factor de Necrosis Tumoral alfa/metabolismo , Irradiación Corporal TotalRESUMEN
Angiotensin II (AngII) promotes hypertension, atherogenesis, vascular aneurysm and impairs post-ischemic cardiac remodeling through concerted roles on vascular cells, monocytes and T lymphocytes. However, the role of AngII in B lymphocyte responses is largely unexplored. Here, we show that chronic B cell depletion (Baffr deficiency) significantly reduces atherosclerosis in Apoe -/- mice infused with AngII. While adoptive transfer of B cells in Apoe -/- /Baffr -/- mice reversed atheroprotection in the absence of AngII, infusion of AngII in B cell replenished Apoe -/- /Baffr -/- mice unexpectedly prevented the progression of atherosclerosis. Atheroprotection observed in these mice was associated with a significant increase in regulatory CD1dhiCD5+ B cells, which produced high levels of interleukin (IL)-10 (B10 cells). Replenishment of Apoe -/- /Baffr -/- mice with Il10 -/- B cells reversed AngII-induced B cell-dependent atheroprotection, thus highlighting a protective role of IL-10+ regulatory B cells in this setting. Transfer of AngII type 1A receptor deficient (Agtr1a -/-) B cells into Apoe -/- /Baffr -/- mice substantially reduced the production of IL-10 by B cells and prevented the AngII-dependent atheroprotective B cell phenotype. Consistent with the in vivo data, AngII synergized with BAFF to induce IL-10 production by B cells in vitro via AngII type 1A receptor. Our data demonstrate a previously unknown synergy between AngII and BAFF in inducing IL-10 production by B cells, resulting in atheroprotection.