surface components and DKK1 signalling via LRP6 promote migration and longevity of neutrophils in the infection site.

Background: 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.

Results: 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.

Conclusion: 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.