Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, NE, United States.
Department of Molecular Microbiology, Washington University School of Medicine in St Louis, St. Louis, MO, United States.
Front Immunol. 2024 Oct 22;15:1473133. doi: 10.3389/fimmu.2024.1473133. eCollection 2024.
Host-related factors highly regulate the increased circulation of neutrophils during infection. Platelet-derived Dickkopf-1 (DKK1) is established as a high-affinity ligand to LRP6. Recently, we demonstrated that DKK1 upregulates leukocyte-platelet aggregation, infiltration of neutrophils to the draining lymph node and Th2 differentiation during infection, suggesting the potential involvement of the DKK1-LRP6 signalling pathway in neutrophil migration in infectious diseases.
In this study, we further explored the potential role of DKK1-LRP6 signalling in the migration and longevity of activated neutrophils in the infection site using BALB/c mice with PMNs deficient in LRP6 (LRP6) or BALB/c mice deficient in both PMN LRP6 and platelet DKK1 (LRP6 DKK1). Relative to the infected wild-type BALB/c mice, reduced neutrophil activation at the infection site of LRP6 or LRP6 DKK1 mice was noted. The neutrophils obtained from either infected LRP6 or LRP6 DKK1 mice additionally showed a high level of apoptosis. Notably, the level of LRP6 expressing neutrophils was elevated in infected BALB/c mice. Relative to infected BALB/c mice, a significant reduction in parasite load was observed in both LRP6 and LRP6 DKK1 infected mice. Notably, DKK1 levels were comparable in the LRP6 and BALB/c mice in response to infection, indicating that PMN activation is the major pathway for DKK1 in promoting parasitemia. Parasite-specific components also play a crucial role in modulating neutrophil circulation in disease. Thus, we further determine the contribution of membrane components in the migration of neutrophils to the infection site using null mutants deficient in LPG synthesis ( ) or lacking all ether phospholipids (plasmalogens, LPG, and GIPLs) synthesis ( ). Relative to the WT controls, parasite-infected mice showed a sustained decrease in neutrophils and neutrophil-platelet aggregates (for at least 14 days PI), while neutrophils returned to normal in parasite-infected mice after day 3 PI.
Our results suggest that DKK1 signalling and pathogen-associated molecular patterns appear to regulate the migration and sustenance of viable activated neutrophils in the infection site resulting in chronic type 2 cell-mediated inflammation.
宿主相关因素高度调节感染期间中性粒细胞的循环增加。血小板衍生的 Dickkopf-1（DKK1）被确立为 LRP6 的高亲和力配体。最近，我们证明 DKK1 上调白细胞-血小板聚集、中性粒细胞浸润引流淋巴结和 Th2 分化在感染过程中，提示 DKK1-LRP6 信号通路可能参与感染性疾病中性粒细胞的迁移。
在这项研究中，我们使用 LRP6 缺陷型 PMN 的 BALB/c 小鼠（LRP6）或同时缺乏 PMN LRP6 和血小板 DKK1 的 BALB/c 小鼠（LRP6 DKK1）进一步探讨了 DKK1-LRP6 信号在感染部位激活的中性粒细胞迁移和寿命中的潜在作用。与感染野生型 BALB/c 小鼠相比，LRP6 或 LRP6 DKK1 小鼠感染部位中性粒细胞的激活减少。从感染的 LRP6 或 LRP6 DKK1 小鼠获得的中性粒细胞也表现出高水平的凋亡。值得注意的是，感染 BALB/c 小鼠中表达 LRP6 的中性粒细胞水平升高。与感染 BALB/c 小鼠相比，LRP6 和 LRP6 DKK1 感染小鼠的寄生虫载量均显著降低。值得注意的是，感染后 LRP6 和 BALB/c 小鼠的 DKK1 水平相当，表明 PMN 激活是 DKK1 促进寄生虫血症的主要途径。寄生虫特异性成分在调节疾病中性粒细胞循环中也起着至关重要的作用。因此，我们使用缺乏 LPG 合成（）或缺乏所有醚磷脂（质体、LPG 和 GIPL）合成（）的缺失突变体进一步确定膜成分在中性粒细胞向感染部位迁移中的作用。与 WT 对照相比，寄生虫感染小鼠的中性粒细胞和中性粒细胞-血小板聚集体持续减少（至少 14 天 PI），而寄生虫感染小鼠在 3 天 PI 后中性粒细胞恢复正常。
我们的结果表明，DKK1 信号和病原体相关分子模式似乎调节感染部位存活激活的中性粒细胞的迁移和维持，导致慢性 2 型细胞介导的炎症。
