Kobayashi Y, Miyaji C, Watanabe H, Umezu H, Hasegawa G, Abo T, Arakawa M, Kamata N, Suzuki H, Kodama T, Naito M
Second Department of Pathology, Niigata University School of Medicine, Niigata 951-8510, Japan.
J Pathol. 2000 Oct;192(2):263-72. doi: 10.1002/1096-9896(2000)9999:9999<::AID-PATH692>3.0.CO;2-U.
Lipopolysaccharide (LPS) is known to bind to several receptors on macrophages, including CD14 and macrophage scavenger receptor class A types I and II (MSR-A), and stimulates macrophages to release various inflammatory mediators. MSR-A recognizes a broad range of polyanionic ligands such as chemically modified lipoproteins, LPS of Gram-negative bacteria, and lipoteichoic acid of Gram-positive bacteria, suggesting a role in host defence. In this study, mice lacking MSR-A were used to elucidate the role of MSR-A in endotoxin shock. Peritoneal macrophages from MSR-A-deficient (MSR-A(-/-)) mice bound less remarkably to LPS than those from wild-type (MSR-A(+/+)) mice and the binding activity of MSR-A(+/+) macrophages to LPS was reduced by the addition of an anti-MSR-A antibody. Clearance of LPS in serum was retarded in MSR-A(-/-) mice after intraperitoneal administration of LPS. LPS-induced expression of cytokines in the liver was similar in MSR-A(+/+) and MSR-A(-/-) mice, but levels of interleukin (IL)-1beta expression and serum IL-1beta were lower in MSR-A(-/-) mice. Administration of large doses of LPS resulted in a higher mortality of MSR-A(+/+) mice and pretreatment with an IL-1 receptor antagonist reduced the mortality. Thus, MSR-A-mediated macrophage activation plays a negative role in protecting mice from endotoxin shock by enhancing IL-1beta production by macrophages.
脂多糖（LPS）已知可与巨噬细胞上的多种受体结合，包括CD14以及巨噬细胞清道夫受体A类I型和II型（MSR-A），并刺激巨噬细胞释放各种炎症介质。MSR-A可识别多种多阴离子配体，如化学修饰的脂蛋白、革兰氏阴性菌的LPS以及革兰氏阳性菌的脂磷壁酸，提示其在宿主防御中发挥作用。在本研究中，利用缺乏MSR-A的小鼠来阐明MSR-A在内毒素休克中的作用。与野生型（MSR-A(+/+)）小鼠的腹膜巨噬细胞相比，MSR-A缺陷型（MSR-A(-/-)）小鼠的腹膜巨噬细胞与LPS的结合不那么明显，并且添加抗MSR-A抗体可降低MSR-A(+/+)巨噬细胞与LPS的结合活性。腹腔注射LPS后，MSR-A(-/-)小鼠血清中LPS的清除延迟。MSR-A(+/+)和MSR-A(-/-)小鼠肝脏中LPS诱导的细胞因子表达相似，但MSR-A(-/-)小鼠中白细胞介素（IL）-1β的表达水平和血清IL-1β水平较低。给予大剂量LPS导致MSR-A(+/+)小鼠的死亡率更高，而用IL-1受体拮抗剂预处理可降低死亡率。因此，MSR-A介导的巨噬细胞活化通过增强巨噬细胞产生IL-1β，在保护小鼠免受内毒素休克方面发挥负面作用。
