The pattern-recognition molecule mindin binds integrin Mac-1 to promote macrophage phagocytosis via Syk activation and NF-κB p65 translocation
The pattern-recognition molecule mindin binds integrin Mac-1 to promote macrophage phagocytosis via Syk activation and NF-κB p65 translocation
复制标题
模式识别分子 Mindin 结合整合素 Mac-1，通过 Syk 激活和 NF-κ B p65 易位促进巨噬细胞吞噬作用
DOI：
10.1111/jcmm.14236
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发表时间：
2019-05-01
影响因子：
5.3
通讯作者：
Guleng, Bayasi
中科院分区：
文献类型：
--
作者：
Liu, Yuan-sheng;Wan, Li-fen;Guleng, Bayasi
Mindin在先天免疫系统中具有广泛的作用，包括巨噬细胞迁移、抗原吞噬和细胞因子产生。Mindin作为微生物病原体的模式识别分子发挥作用。然而，mindin介导的吞噬作用及其确切的膜受体的潜在机制还没有很好地建立。在本文中，我们使用CRISPR-Cas9系统产生了mindin缺陷小鼠，并表明mindin缺陷小鼠的腹腔巨噬细胞在吞噬大肠杆菌的能力方面存在严重缺陷。当大肠杆菌或荧光颗粒与mindin预孵育时，吞噬作用增强，表明mindin直接与细菌或非病原体颗粒结合并促进吞噬作用。我们定义了（131）I标记的mindin与整合素Mac-1（CD 11b/CD 18）结合，mindin的F-脊椎蛋白（FS）片段与Mac-1的α（M）-I结构域结合，并且mindin作为Mac-1的新配体。使用中和抗体或si-Mac-1阻断Mac-1的α（M）-I结构域可有效阻断mindin诱导的吞噬作用。此外，mindin激活Syk和MAPK信号通路，促进NF-κ B B进入细胞核。我们的数据表明，mindin与整合素Mac-1结合，通过Syk激活和NF-κ B p65转位促进巨噬细胞吞噬，表明mindin/Mac-1轴在先天免疫应答中起着关键作用。
Mindin has a broad spectrum of roles in the innate immune system, including in macrophage migration, antigen phagocytosis and cytokine production. Mindin functions as a pattern-recognition molecule for microbial pathogens. However, the underlying mechanisms of mindin-mediated phagocytosis and its exact membrane receptors are not well established. Herein, we generated mindin-deficient mice using the CRISPR-Cas9 system and show that peritoneal macrophages from mindin-deficient mice were severely defective in their ability to phagocytize E coli. Phagocytosis was enhanced when E coli or fluorescent particles were pre-incubated with mindin, indicating that mindin binds directly to bacteria or non-pathogen particles and promotes phagocytosis. We defined that( 131)I-labelled mindin binds with integrin Mac-1 (CD11b/CD18), the F-spondin (FS)-fragment of mindin binds with the alpha(M) -I domain of Mac-1 and that mindin serves as a novel ligand of Mac-1. Blockade of the alpha(M) -I domain of Mac-1 using either a neutralizing antibody or si-Mac-1 efficiently blocked mindin-induced phagocytosis. Furthermore, mindin activated the Syk and MAPK signalling pathways and promoted NF-kappa B entry into the nucleus. Our data indicate that mindin binds with the integrin Mac-1 to promote macrophage phagocytosis through Syk activation and NF-kappa B p65 translocation, suggesting that the mindin/Mac-1 axis plays a critical role during innate immune responses.