City of Hope Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1450 E. Duarte Road, Duarte, CA 91010, USA.
Immunity. 2010 Oct 29;33(4):620-31. doi: 10.1016/j.immuni.2010.10.009.
Although carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) is an activation marker for neutrophils and delays neutrophil apoptosis, the role of CEACAM1 in granulopoiesis and neutrophil-dependent host immune responses has not been investigated. CEACAM1 expression correlated with granulocytic differentiation, and Ceacam1(-/-) mice developed neutrophilia because of loss of the Src-homology-phosphatase-1 (SHP-1)-dependent inhibition of granulocyte colony-stimulating factor receptor (G-CSFR) signal transducer and activator of transcription (Stat3) pathway provided by CEACAM1. Moreover, Ceacam1(-/-) mice were hypersensitive to Listeria Monocytogenes (LM) infection with an accelerated mortality. Reintroduction of CEACAM1 into Ceacam1(-/-) bone marrow restored normal granulopoiesis and host sensitivity to LM infection, while mutation of its immunoreceptor tyrosine-based inhibitory motifs (ITIMs) abrogated this restoration. shRNA-mediated reduction of Stat3 amounts rescued normal granulopoiesis, attenuating host sensitivity to LM infection in Ceacam1(-/-) mice. Thus, CEACAM1 acted as a coinhibitory receptor for G-CSFR regulating granulopoiesis and host innate immune response to bacterial infections.
虽然癌胚抗原相关细胞黏附分子-1（CEACAM1）是中性粒细胞的激活标志物，可延迟中性粒细胞凋亡，但 CEACAM1 在粒细胞生成和中性粒细胞依赖的宿主免疫反应中的作用尚未被研究。CEACAM1 的表达与粒细胞分化相关，由于 CEACAM1 缺失了 Src 同源性磷酸酶-1（SHP-1）对粒细胞集落刺激因子受体（G-CSFR）信号转导子和转录激活子 3（Stat3）通路的抑制作用，Ceacam1(-/-) 小鼠发展为中性粒细胞增多症。此外，Ceacam1(-/-) 小鼠对李斯特菌（LM）感染高度敏感，死亡率加速。将 CEACAM1 重新引入 Ceacam1(-/-) 骨髓中可恢复正常的粒细胞生成和宿主对 LM 感染的敏感性，而其免疫受体酪氨酸抑制基序（ITIMs）的突变则消除了这种恢复。shRNA 介导的 Stat3 水平降低可挽救正常的粒细胞生成，减轻 Ceacam1(-/-) 小鼠对 LM 感染的宿主敏感性。因此，CEACAM1 作为 G-CSFR 的共抑制受体，调节粒细胞生成和宿主对细菌感染的固有免疫反应。
