Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system
Negative regulation of phagocytosis in macrophages by the CD47-SHPS-1 system
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DOI：
10.4049/jimmunol.174.4.2004
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发表时间：
2005-02-15
影响因子：
4.4
通讯作者：
Matozaki, T
中科院分区：
文献类型：
--
作者：
Okazawa, H;Motegi, SI;Matozaki, T
含Src同源2结构域的蛋白酪氨酸磷酸酶（SHP）底物-1（SHPS-1）是一种主要在巨噬细胞中表达的跨膜蛋白。其细胞外区域与在相邻细胞表面上表达的跨膜配体CD 47相互作用，并且其细胞质区域结合蛋白酪氨酸磷酸酶SHP-1和SHP-2。来自表达缺少大部分胞质区域的突变SHPS-1蛋白的小鼠的腹腔巨噬细胞对IgG或补体调理的RBC的吞噬作用与明显的相比显著增强。野生型巨噬细胞。无论是用CD 47缺陷型RBC作为吞噬目标，还是在存在SHPS-L的阻断性Ab的情况下，都没有观察到这种作用。通过RNA干扰从野生型巨噬细胞中消耗SHPS-1也促进了Fc γ R介导的野生型RBC的吞噬作用。通过RBC上的CD 47连接巨噬细胞上的SHPS-I促进SHPS-I的酪氨酸磷酸化及其与SHP-1的缔合，而响应于Fc γ R的交联，SHPS-I的酪氨酸磷酸化显著降低。使用PI 3 K或Syk抑制剂（但不使用MEK或Src家族激酶抑制剂）治疗，消除了SHPS-1突变小鼠巨噬细胞中FcgammaR介导的吞噬作用的明显增强。相反，FcgammaR介导的Syk、Cbl或FcR γ亚基的酪氨酸磷酸化在野生型和SHPS-I突变小鼠的巨噬细胞中是相似的。这些结果表明，通过CD 47连接巨噬细胞上的SHPS-1促进了SHPS-1的酪氨酸磷酸化，从而防止了Fc γ R介导的SHPS-1-SHP-1复合物的破坏，导致吞噬作用的抑制。SHPS-1-SHP-1复合物对吞噬作用的抑制可以在Syk或PI 3 K信号传导水平上介导。
Src homology 2 domain-containing protein tyrosine phosphatase (SHP) substrate-1 (SHPS-1) is a transmembrane protein that is expressed predominantly in macrophages. Its extracellular region interacts with the transmembrane ligand CD47 expressed on the surface of adjacent cells, and its cytoplasmic region binds the protein tyrosine phosphatases SHP-1 and SUP-2. Phagocytosis of IgG- or complement-opsonized RBCs by peritoneal macrophages derived from mice that express a mutant SHPS-1 protein that lacks most of the cytoplasmic region was markedly enhanced compared with that apparent. with wild-type macrophages. This effect was not observed either with CD47-deficient RBCs as the phagocytic tat-get or in the presence of blocking Abs to SHPS-L Depletion of SHPS-1 from wild-type macrophages by RNA interference also promoted FcgammaR-mediated phagocytosis of wild-type RBCs. Ligation of SHPS-I on macrophages; by CD47 on RBCs promoted tyrosine phosphorylation of SHPS-I and its association with SHP-1, whereas tyrosine phosphorylation of SHPS-1 was markedly reduced in response to cross-linking of FcgammaRs. Treatment with inhibitors of PI3K or of Syk, but not with those of MEK or Src family kinases, abolished the enhancement of FcgammaR-mediated phagocytosis apparent in macrophages from SHPS-1 mutant mice. In contrast, FcgammaR-mediated tyrosine phosphorylation of Syk, Cbl, or the gamma subunit of FcR was similar in macrophages from wild-type and SHPS-I mutant mice. These results suggest that ligation of SHPS-1 on macrophages by CD47 promotes the tyrosine phosphorylation of SHPS-1 and thereby prevents the FcgammaR-mediated disruption of the SHPS-1-SHP-1 complex, resulting in inhibition of phagocytosis. The inhibition of phagocytosis by the SHPS-1-SHP-1 complex may be mediated at the level of Syk or PI3K signaling.