Adipocytes promote interleukin-18 binding to its receptors during abdominal aortic aneurysm formation in mice
Adipocytes promote interleukin-18 binding to its receptors during abdominal aortic aneurysm formation in mice
复制标题
小鼠腹主动脉瘤形成过程中脂肪细胞促进白细胞介素 18 与其受体结合
DOI：
10.1093/eurheartj/ehz856
复制
发表时间：
2020-07-07
影响因子：
39.3
通讯作者：
Shi, Guo-Ping
中科院分区：
文献类型：
--
作者：
Liu, Cong-Lin;Ren, Jingyuan;Shi, Guo-Ping
旨在
肥胖是腹主动脉瘤（AAA）的危险因素。炎性细胞因子白细胞介素18（IL 18）有两种受体：IL 18受体（IL 18 r）和钠-氯协同转运蛋白（NCC）。在人类和小鼠AAA病变中，IL 18共定位于富含脂肪细胞的区域的受体，表明脂肪细胞在促进IL 18在AAA发展中的作用。
方法和结果
我们在人和小鼠AAA病变中定位了IL 18 r和NCC。小鼠AAA的发展需要两种受体。在小鼠AAA病变中，IL 18与这些受体的结合在富含脂肪细胞或邻近血管周围脂肪组织的区域增加。3 T3-L1脂肪细胞通过诱导巨噬细胞、主动脉平滑肌细胞（SMC）和内皮细胞上两种IL 18受体的表达来增强IL 18与这些细胞的结合。脂肪细胞还增强了T细胞和巨噬细胞的IL 18 r和IL 18表达，巨噬细胞的AAA相关蛋白酶表达，以及SMC凋亡。无论是饮食诱导的肥胖小鼠或瘦小鼠，但不是瘦素缺乏的ob/ob小鼠的脂肪组织血管周围植入加剧AAA的发展受体小鼠。进一步的实验确定了脂肪细胞瘦素和脂肪酸结合蛋白4（FABP 4）在通过诱导IL 18、IL 18 r和NCC的表达来促进IL 18与巨噬细胞和可能的其他炎症和血管细胞结合中的重要作用。
结论
白细胞介素-18使用IL 18 r和NCC两者来促进AAA形成。病变脂肪细胞和血管周围脂肪组织通过释放瘦素和FABP 4诱导IL 18、IL 18 r和NCC表达并促进IL 18作用而促成AAA发病。
AIMS
Obesity is a risk factor of abdominal aortic aneurysm (AAA). Inflammatory cytokine interleukin-18 (IL18) has two receptors: IL18 receptor (IL18r) and Na-Cl co-transporter (NCC). In human and mouse AAA lesions, IL18 colocalizes to its receptors at regions rich in adipocytes, suggesting a role of adipocytes in promoting IL18 actions in AAA development.
METHODS AND RESULTS
We localized both IL18r and NCC in human and mouse AAA lesions. Murine AAA development required both receptors. In mouse AAA lesions, IL18 binding to these receptors increased at regions enriched in adipocytes or adjacent to perivascular adipose tissue. 3T3-L1 adipocytes enhanced IL18 binding to macrophages, aortic smooth muscle cells (SMCs), and endothelial cells by inducing the expression of both IL18 receptors on these cells. Adipocytes also enhanced IL18r and IL18 expression from T cells and macrophages, AAA-pertinent protease expression from macrophages, and SMC apoptosis. Perivascular implantation of adipose tissue from either diet-induced obese mice or lean mice but not that from leptin-deficient ob/ob mice exacerbated AAA development in recipient mice. Further experiments established an essential role of adipocyte leptin and fatty acid-binding protein 4 (FABP4) in promoting IL18 binding to macrophages and possibly other inflammatory and vascular cells by inducing their expression of IL18, IL18r, and NCC.
CONCLUSION
Interleukin-18 uses both IL18r and NCC to promote AAA formation. Lesion adipocyte and perivascular adipose tissue contribute to AAA pathogenesis by releasing leptin and FABP4 that induce IL18, IL18r, and NCC expression and promote IL18 actions.