Deficiency of Myeloid PP4 in mice exacerbates Neutrophil hyperactivation during Sepsis

We previously demonstrated that serine/threonine phosphatase PP4 functions as a negative regulator of innate immunity, prevents hyperactivation of Toll-like receptors (TLRs) signaling in sepsis. Because the recruitment of monocytes to sites of inflammation is critical for host defense, we then explored the role of PP4 in myeloid lineage cells. Mice without PP4 only in myeloid cells were more susceptible to sepsis due to serious tissue damage. Importantly, CLP induced myeloid PP4 deficiency mice produced significantly more proinflammatory cytokines and chemokines, which contributed to dysregulated neutrophil recruitment. Neutrophils isolated from mice without PP4 showed an increase in NETs formation in response to subsequent RANTES stimulation. Mechanistically, PP4 regulated RANTES production via TBK1/IRF3 axis in macrophages. Finally, RNA-seq analysis of the livers obtained from myeloid PP4 deficiency mice relative to wildtype controls identified 1849 differentially expressed genes. Of these, 628 were upregulated and 1221 were downregulated. Moreover, 25 significantly enriched GO terms and 1 significantly enriched KEGG pathways were identified, involving multicellular organismal homeostasis, regulation of phosphorylation and inflammation response, and cytokine-cytokine receptor interaction, which might also play roles in the process of sepsis. Thus, our data provide a remarkable new resource of regulatory pathways for understanding PP4 function at the organism level.