Absence of trauma-induced leukocyte rolling in mice deficient in both P-selectin and intercellular adhesion molecule 1
Absence of trauma-induced leukocyte rolling in mice deficient in both P-selectin and intercellular adhesion molecule 1
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DOI：
10.1084/jem.183.1.57
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发表时间：
1996-01-01
影响因子：
15.3
通讯作者：
Ley, K
中科院分区：
文献类型：
--
作者：
Kunkel, EJ;Jung, U;Ley, K
炎症过程中白细胞的募集是通过多步骤模式实现的，包括边缘化、选择素介导的滚动、β 2整合素介导的牢固粘附、迁出和迁移到炎症部位。我们使用小鼠提睾肌作为创伤和肾上腺素诱导的炎症模型，研究细胞间粘附分子（ICAM）1在白细胞滚动中的可能作用，使用ICAM-1，P-选择素，以及P-选择素和ICAM-1的组合缺陷的基因靶向小鼠。滚动流量和平均白细胞滚动速度在ICAM-1缺陷型小鼠与野生型小鼠没有差异，但P-选择素/ICAM-1缺陷型小鼠手术创伤后至少2小时内完全没有滚动。创伤后60-120分钟，野生型和ICAM-1缺陷型小鼠的滚动均被P-选择素单克隆抗体（mAb）（RB40.34）显著抑制。相反，阻断ICAM-1与白细胞功能相关抗原1结合的mAb（KAT-1）并不能阻断P-选择素缺陷小鼠的残留滚动。TNF-α诱导P-选择素/ICAM-1缺陷小鼠的白细胞滚动，但滚动nux分数显著低于TNF-α治疗的ICAM-1缺陷小鼠。在用TNF-α处理3小时的P-选择素/ICAM-1缺陷小鼠中，白细胞滚动被E-选择素mAb（9A 9 E3）完全阻断，并且被L-选择素mAb（MEL-14）部分阻断。这清楚地证明了体内E-选择素依赖性滚动。TNF-α治疗后白细胞滚动速度显著降低，野生型和基因靶向菌株相似。我们的结论是，残留的创伤诱导的白细胞滚动P-选择素缺陷小鼠中看到的是完全废除伴随ICAM-1缺陷。这种白细胞滚动的严重缺陷可能解释了在早期时间点（小于或等于4 h）P-选择素/ICAM-1缺陷小鼠的炎症腹膜腔中没有白细胞募集。
Leukocyte recruitment during inflammation is achieved through a multistep paradigm that includes margination, selectin-mediated rolling, beta(2) integrin-mediated firm adhesion, emigration, and migration into the site of inflammation. We have used the mouse cremaster muscle as a model of trauma- and cytokine-induced inflammation to study the possible role of intercellular adhesion molecule (ICAM) 1 in leukocyte rolling using gene-targeted mice deficient in ICAM-1, P-selectin, and a combination of P-selectin and ICAM-1. Rolling flux and average leukocyte rolling velocity in ICAM-1-deficient mice was not different from wild-type mice, but P-selectin/ICAM-1-deficient mice showed a total absence of rolling for at least 2 h after surgical trauma. Rolling in both wild-type and ICAM-1-deficient mice 60-120 min after trauma was significantly inhibited by a P-selectin monoclonal antibody (mAb) (RB40.34). In contrast, an mAb (KAT-1) blocking ICAM-1 binding to leukocyte function-associated antigen 1 did not block residual rolling in P-selectin-deficient mice. TNF-alpha induced leukocyte rolling in P-selectin/ICAM-1-deficient mice, but the rolling nux fraction was significantly lower than in TNF-alpha-treated ICAM-1-deficient mice. Leukocyte rolling in P-selectin/ICAM-1-deficient mice treated with TNF-alpha for 3 h was completely blocked by an E-selectin mAb (9A9E3), and partially by an L-selectin mAb (MEL-14). This clearly demonstrates E-selectin-dependent rolling in vivo. Leukocyte rolling velocities were significantly reduced after TNF-alpha treatment and were similar in wild-type and gene-targeted strains. We conclude that the residual trauma-induced leukocyte rolling seen in P-selectin-deficient mice is completely abolished by concomitant ICAM-1 deficiency. This severe defect in leukocyte rolling may explain the absence of leukocyte recruitment into the inflamed peritoneal cavity of P-selectin/ICAM-1-deficient mice at early time points (less than or equal to 4 h).