Proteomic and bioinformatic profiling of neutrophils in CLL reveals functional defects that predispose to bacterial infections.
Proteomic and bioinformatic profiling of neutrophils in CLL reveals functional defects that predispose to bacterial infections.
复制标题
DOI：
10.1182/bloodadvances.2020002949
复制
发表时间：
2021-03
期刊：
影响因子：
7.5
通讯作者：
Nirojah Subramaniam;Jenny Bottek;S. Thiebes;Kristina Zec;Matthias Kudla;Camille Soun;Elena de Dios Panal;Julia K. Lill;Aaron Pfennig;R. Herrmann;K. Bruderek;S. Rahmann;S. Brandau;P. Johansson;H. Reinhardt;J. Dürig;M. Seiffert;T. Bracht;B. Sitek;D. Engel
中科院分区：
文献类型：
--
作者：
Nirojah Subramaniam;Jenny Bottek;S. Thiebes;Kristina Zec;Matthias Kudla;Camille Soun;Elena de Dios Panal;Julia K. Lill;Aaron Pfennig;R. Herrmann;K. Bruderek;S. Rahmann;S. Brandau;P. Johansson;H. Reinhardt;J. Dürig;M. Seiffert;T. Bracht;B. Sitek;D. Engel
慢性淋巴细胞白血病（CLL）患者通常患有频繁和严重的细菌感染。虽然众所周知，中性粒细胞是促进早期防御的关键先天免疫细胞，但在CLL期间中性粒细胞的潜在表型和功能变化在很大程度上仍然难以捉摸。使用小鼠过继转移模型的CLL，我们证明加重细菌负荷的CLL荷小鼠尿路感染后，尿路致病性大肠杆菌。中性粒细胞蛋白质组的生物信息学分析显示，与干扰素信号相关的蛋白质表达增加，与颗粒组成和中性粒细胞迁移相关的蛋白质表达减少。功能实验证实了这些发现，显示髓过氧化物酶和酸化的中性粒细胞颗粒后，离体吞噬细菌的水平降低。途径富集分析表明，中性粒细胞募集的关键分子表达减少，中性粒细胞迁移到感染的膀胱显着减少。这些改变的中性粒细胞迁移特性也与CD62L和CXCR4表达减少相关，并与CLL患者感染发生率增加相关。总之，本研究通过蛋白质组学、生物信息学和功能分析描述了中性粒细胞的分子特征，这些分子特征与迁移能力降低有关，可能导致CLL患者细菌感染增加。
Patients with chronic lymphocytic leukemia (CLL) typically suffer from frequent and severe bacterial infections. Although it is well known that neutrophils are critical innate immune cells facilitating the early defense, the underlying phenotypical and functional changes in neutrophils during CLL remain largely elusive. Using a murine adoptive transfer model of CLL, we demonstrate aggravated bacterial burden in CLL-bearing mice upon a urinary tract infection with uropathogenic Escherichia coli. Bioinformatic analyses of the neutrophil proteome revealed increased expression of proteins associated with interferon signaling and decreased protein expression associated with granule composition and neutrophil migration. Functional experiments validated these findings by showing reduced levels of myeloperoxidase and acidification of neutrophil granules after ex vivo phagocytosis of bacteria. Pathway enrichment analysis indicated decreased expression of molecules critical for neutrophil recruitment, and migration of neutrophils into the infected urinary bladder was significantly reduced. These altered migratory properties of neutrophils were also associated with reduced expression of CD62L and CXCR4 and correlated with an increased incidence of infections in patients with CLL. In conclusion, this study describes a molecular signature of neutrophils through proteomic, bioinformatic, and functional analyses that are linked to a reduced migratory ability, potentially leading to increased bacterial infections in patients with CLL.