ROCK1 via LIM kinase regulates growth, maturation and actin based functions in mast cells.
ROCK1 via LIM kinase regulates growth, maturation and actin based functions in mast cells.
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DOI：
10.18632/oncotarget.7851
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发表时间：
2016-03-29
期刊：
影响因子：
--
通讯作者：
Mali RS
中科院分区：
文献类型：
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作者：
Kapur R;Shi J;Ghosh J;Munugalavadla V;Sims E;Martin H;Wei L;Mali RS
由于肥大细胞在调节免疫和自身免疫性疾病中的关键作用，了解肥大细胞的发育是至关重要的。在这里，我们展示了Rho激酶(ROCK)如何调节肥大细胞的发育，并可作为治疗过敏性疾病的靶点。ROCK1缺乏导致骨髓来源的肥大细胞(BMMC)对IL-3刺激的反应延迟成熟，以及对干细胞因子(SCF)刺激的反应减慢。此外，在ROCK1缺陷的BMMC中，整合素介导的黏附和迁移以及IgE介导的脱颗粒都受到损害。为了了解ROCK 1−/−BMMC肥大细胞发育改变的机制，我们分析了ROCK及其下游靶点包括LIMK(LIMK)的激活。我们观察到ROCK1缺陷的BMMCs在SCF刺激下ROCK、LIMK、AKT和ERK1/2的活性降低。此外，LIMK1或LIMK2的缺失也改变了BMMC的成熟和生长；LIMK1和LIMK2的联合缺失导致BMMC的成熟和生长进一步减少。在被动皮肤过敏反应模型中，ROCK1缺乏或用摇滚抑制剂法舒地尔治疗可保护小鼠免受IgE介导的攻击。我们的结果证实ROCK/LIMK通路是治疗肥大细胞相关变态反应性疾病的新靶点。
Understanding mast cell development is essential due to their critical role in regulating immunity and autoimmune diseases. Here, we show how Rho kinases (ROCK) regulate mast cell development and can function as therapeutic targets for treating allergic diseases. Rock1 deficiency results in delayed maturation of bone marrow derived mast cells (BMMCs) in response to IL-3 stimulation and reduced growth in response to stem cell factor (SCF) stimulation. Further, integrin-mediated adhesion and migration, and IgE-mediated degranulation are all impaired in Rock1-deficient BMMCs. To understand the mechanism behind altered mast cell development in Rock1−/− BMMCs, we analyzed the activation of ROCK and its downstream targets including LIM kinase (LIMK). We observed reduced activation of ROCK, LIMK, AKT and ERK1/2 in Rock1-deficient BMMCs in response to SCF stimulation. Further, loss of either Limk1 or Limk2 also demonstrated altered BMMC maturation and growth; combined deletion of both Limk1 and Limk2 resulted in further reduction in BMMC maturation and growth. In passive cutaneous anaphylaxis model, deficiency of Rock1 or treatment with ROCK inhibitor Fasudil protected mice against IgE-mediated challenge. Our results identify ROCK/LIMK pathway as a novel therapeutic target for treating allergic diseases involving mast cells.