Crosstalk between circulating DPP3 and immune cells in the context of cardio-systemic stress.

Dipeptidylpeptidase 3 (DPP3) is a ubiquitous intracellular peptidase recently identified in the circulation (cDPP3) as a biomarker and therapeutic target in circulatory failure. The source and mechanism of DPP3 release remain unclear. Based on increased DPP3 expression in the bone marrow compartment under stress conditions, we aimed to assess bone marrow's contribution to DPP3 release. WT bone marrow was transplanted into irradiated DPP3-knockout (KO) mice, generating KO(BM WT) mice, which recovered 44% of baseline cDPP3 activity. In stressed KO(BM WT) mice, cDPP3 increase was comparable to stressed WT mice. DPP3 injection in WT mice induced cardiac neutrophil infiltration. Extracellular vesicles from plasma and bone marrow carried only a minimal fraction of DPP3, indicating mainly soluble release. These results reveal bone marrow-derived cells as a main driver of cDPP3 release under stress and provide a foundation to optimize its use as a biomarker and therapeutic target.