PDF(Pubmed)
Abstract：
Schistosomiasis is a neglected tropical disease caused by worms of the genus Schistosoma spp. The progression of disease results in intense tissue fibrosis and high mortality rate. After egg deposition by adult worms, the inflammatory response is characterized by the robust activation of type 2 immunity. Monocytes and macrophages play critical roles during schistosomiasis. Inflammatory Ly6Chigh monocytes are recruited from the blood to the inflammatory foci and differentiate into alternatively activated macrophages (AAMs), which promote tissue repair. The common chain of β2-integrins (CD18) regulates monocytopoiesis and mediates resistance to experimental schistosomiasis. There is still limited knowledge about mechanisms controlled by CD18 that impact monocyte development and effector cells such as macrophages during schistosomiasis. Here, we show that CD18low mice chronically infected with S. mansoni display monocyte progenitors with reduced proliferative capacity, resulting in the accumulation of the progenitor cell denominated proliferating-monocyte (pMo). Consequently, inflammatory Ly6Chigh and patrolling Ly6Clow monocytes are reduced in the bone marrow and blood. Mechanistically, low CD18 expression decreases Irf8 gene expression in pMo progenitor cells, whose encoded transcription factor regulates CSFR1 (CD115) expression on the cell surface. Furthermore, low CD18 expression affects the accumulation of inflammatory Ly6Chigh CD11b+ monocytes in the liver while the adoptive transference of these cells to infected-CD18low mice reduced the inflammatory infiltrate and fibrosis in the liver. Importantly, expression of Il4, Chil3l3 and Arg1 was downregulated, CD206+PD-L2+ AAMs were reduced and there were lower levels of IL-10 in the liver of CD18low mice chronically infected with S. mansoni. Overall, these findings suggest that CD18 controls the IRF8-CD115 axis on pMo progenitor cells, affecting their proliferation and maturation of monocytes. At the same time, CD18 is crucial for the appropriate polarization and function of AAMs and tissue repair during chronic schistosomiasis.
摘要：
血吸虫病是由血吸虫属蠕虫引起的一种被忽视的热带病。疾病的进展导致强烈的组织纤维化和高死亡率。卵被成虫沉积后，炎症反应的特征是2型免疫的强烈激活。单核细胞和巨噬细胞在血吸虫病过程中起关键作用。炎性Ly6Chigh单核细胞从血液中募集到炎症灶并分化为交替激活的巨噬细胞（AAM），促进组织修复。β2整合素（CD18）的共同链调节单核细胞生成并介导对实验性血吸虫病的抗性。关于CD18控制的影响血吸虫病过程中单核细胞发育和效应细胞如巨噬细胞的机制的知识仍然有限。这里,我们显示，CD18low小鼠慢性感染S.mansoni显示单核细胞祖细胞增殖能力降低，导致祖细胞称为增殖单核细胞（pMo）的积累。因此,炎性Ly6Chigh和巡逻Ly6Clow单核细胞在骨髓和血液中减少。机械上,低CD18表达降低pMo祖细胞中Irf8基因表达，其编码的转录因子调节CSFR1（CD115）在细胞表面的表达。此外，低CD18表达影响肝脏中炎性Ly6ChighCD11b+单核细胞的积累,而这些细胞过继转移至感染的CD18low小鼠减少了肝脏中的炎性浸润和纤维化。重要的是,Il4、Chil3l3和Arg1的表达下调，CD206+PD-L2+AAMs减少,并且在慢性感染S.mansoni的CD18low小鼠的肝脏中IL-10的水平较低。总的来说,这些发现表明CD18控制pMo祖细胞上的IRF8-CD115轴，影响单核细胞的增殖和成熟。同时,CD18对于慢性血吸虫病过程中AAM的适当极化和功能以及组织修复至关重要。
