Seitz Heather M, Camenisch Todd D, Lemke Greg, Earp H Shelton, Matsushima Glenn K
Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599, USA.
J Immunol. 2007 May 1;178(9):5635-42. doi: 10.4049/jimmunol.178.9.5635.
The clearance of apoptotic cells is important for regulating tissue homeostasis, inflammation, and autoimmune responses. The absence of receptor tyrosine kinases (Axl, Mertk, and Tyro3) results in widespread accumulation of apoptotic cells and autoantibody production in mice. In this report, we examine the function of the three family members in apoptotic cell clearance by different phagocytic cell types. Mertk elimination nearly abolished macrophage apoptotic cell phagocytosis; elimination of Axl, Tyro3, or both, reduced macrophage phagocytosis by approximately half, indicating that these also play a role. In contrast, apoptotic cell clearance in splenic and bone marrow-derived dendritic cells (DCs) is prolonged compared with macrophages and relied primarily on Axl and Tyro3. The slower ingestion may be due to lower DC expression of Axl and Tyro3 or absence of GAS6 expression, a known ligand for this receptor family. In vivo, phagocytosis of apoptotic material by retinal epithelial cells required Mertk. Unlike macrophages, there did not appear to be any role for Axl or Tyro3 in retinal homeostasis. Likewise, clearance of apoptotic thymocytes in vivo was dramatically reduced in mertk(kd) mice, but was normal in axl/tyro3(-/-) mice. Thus, cell and organ type specificity is clearly delineated, with DCs relying on Axl and Tyro3, retina and thymus requiring Mertk, and macrophages exhibiting an interaction that involves all three family members. Surprisingly, in macrophages, tyrosine phosphorylation of Mertk in response to apoptotic cells is markedly diminished from axl/tyro3(-/-) mice, suggesting that the interactions of these receptors by heterodimerization may be important in some cells.
凋亡细胞的清除对于调节组织稳态、炎症和自身免疫反应至关重要。缺乏受体酪氨酸激酶（Axl、Mertk和Tyro3）会导致小鼠体内凋亡细胞广泛积累和自身抗体产生。在本报告中，我们研究了这三个家族成员在不同吞噬细胞类型清除凋亡细胞中的功能。消除Mertk几乎完全消除了巨噬细胞对凋亡细胞的吞噬作用；消除Axl、Tyro3或两者，可使巨噬细胞吞噬作用降低约一半，表明它们也发挥作用。相比之下，脾脏和骨髓来源的树突状细胞（DCs）清除凋亡细胞的时间比巨噬细胞延长，且主要依赖Axl和Tyro3。摄取较慢可能是由于DCs中Axl和Tyro3的表达较低或缺乏该受体家族的已知配体GAS6的表达。在体内，视网膜上皮细胞对凋亡物质的吞噬需要Mertk。与巨噬细胞不同，Axl或Tyro3在视网膜稳态中似乎没有任何作用。同样，mertk(kd)小鼠体内凋亡胸腺细胞的清除显著减少，但axl/tyro3(-/-)小鼠体内清除正常。因此，细胞和器官类型的特异性清晰可辨，DCs依赖Axl和Tyro3，视网膜和胸腺需要Mertk，而巨噬细胞则表现出涉及所有三个家族成员的相互作用。令人惊讶的是，在巨噬细胞中，axl/tyro3(-/-)小鼠对凋亡细胞反应时Mertk的酪氨酸磷酸化明显减少，这表明这些受体通过异二聚化的相互作用在某些细胞中可能很重要。
