PP4 modulates macrophage-neutrophil crosstalk to restrict CCL5 -driven NETosis in sepsis - PubMed
19 days ago
- #NETosis
- #sepsis
- #immune response
- Sepsis is a life-threatening condition caused by a dysregulated immune response to infection, leading to high mortality.
- PP4 expression is reduced in myeloid cells during fatal human sepsis, suggesting a protective role.
- Myeloid cell-specific PP4 knockout mice showed increased sepsis susceptibility and severe tissue damage.
- PP4 modulates macrophage-neutrophil crosstalk, with its loss leading to dysregulated CCL5/CCR5 signaling and excessive neutrophil activation.
- Elevated CCL5 from macrophages enhances NETosis, ROS production, and elastase activity via CCR5 in neutrophils.
- PP4 dephosphorylates TBK1, inactivating IRF3 and suppressing CCL5 production in macrophages.
- ERK1/2 phosphorylation increases CCR5 expression in PP4-deficient neutrophils, amplifying NETosis.
- Wild-type PP4 transfection reduces CCR5 expression and limits ROS and NETs formation in neutrophils.
- PP4 is identified as a critical regulator of CCL5/CCR5-driven NETosis, offering a potential therapeutic target for sepsis.