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Plasma levels of DPP4 activity and sDPP4 are dissociated from inflammation in mice and humans
Laurie L Baggio1, Elodie M Varin1, Jacqueline A Koehler1
1Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON, Canada.
Abstract:
Dipeptidyl peptidase-4 (DPP4) modulates inflammation by enzymatic cleavage of immunoregulatory peptides and through its soluble form (sDPP4) that directly engages immune cells. Here we examine whether reduction of DPP4 activity alters inflammation. Prolonged DPP4 inhibition increases plasma levels of sDPP4, and induces sDPP4 expression in lymphocyte-enriched organs in mice. Bone marrow transplantation experiments identify hematopoietic cells as the predominant source of plasma sDPP4 following catalytic DPP4 inhibition. Surprisingly, systemic DPP4 inhibition increases plasma levels of inflammatory markers in regular chow-fed but not in high fat-fed mice. Plasma levels of sDPP4 and biomarkers of inflammation are lower in metformin-treated subjects with type 2 diabetes (T2D) and cardiovascular disease, yet exhibit considerable inter-individual variation. Sitagliptin therapy for 12 months reduces DPP4 activity yet does not increase markers of inflammation or levels of sDPP4. Collectively our findings dissociate levels of DPP4 enzyme activity, sDPP4 and biomarkers of inflammation in mice and humans.
Insights
Dipeptidyl peptidase-4 (DPP4) inhibition increases soluble DPP4 and inflammation markers in mice, but not in humans treated with sitagliptin. DPP4 activity, soluble DPP4, and inflammation markers are dissociated.
Area of Science:
- Immunology
- Endocrinology
- Pharmacology
Background:
- Dipeptidyl peptidase-4 (DPP4) influences inflammation via peptide cleavage and soluble DPP4 (sDPP4) interactions.
- The relationship between DPP4 activity, sDPP4 levels, and inflammation requires further elucidation.
Purpose of the Study:
- To investigate how reducing DPP4 activity impacts inflammation in preclinical and clinical settings.
- To determine the source of plasma sDPP4 following DPP4 inhibition.
- To assess the dissociation between DPP4 activity, sDPP4, and inflammatory markers.
Main Methods:
- Systemic DPP4 inhibition in mice on different diets.
- Bone marrow transplantation in mice to identify sDPP4 source.
- Analysis of plasma sDPP4 and inflammatory markers in metformin-treated type 2 diabetes patients.
- Evaluation of sitagliptin therapy effects on DPP4 activity, sDPP4, and inflammation markers.
Main Results:
- Prolonged DPP4 inhibition increased sDPP4 and inflammatory markers in regular chow-fed mice, but not high-fat-fed mice.
- Hematopoietic cells were identified as the primary source of plasma sDPP4 after DPP4 inhibition.
- Metformin-treated patients showed lower sDPP4 and inflammation markers, with significant inter-individual variability.
- Sitagliptin treatment for 12 months reduced DPP4 activity without increasing inflammation markers or sDPP4 levels.
Conclusions:
- DPP4 enzyme activity, sDPP4 levels, and inflammation biomarkers are not consistently correlated in mice or humans.
- Dietary factors may influence the inflammatory response to DPP4 inhibition.
- Clinical DPP4 inhibition with sitagliptin does not appear to exacerbate inflammation.
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