Journal Article

DPP4 inhibition curbs systemic inflammation

Brabenec, Laura, Meybohm, Patrick, Wagner, Nana-Maria, Klotz, Luisa, Rossaint, Jan, Cursiefen, Christina, Roth, Johannes, Beulen, Rebekka, Hellenthal, Katharina E. M., Hollmann, Katharina, Burkard, Philipp, Schughart, Klaus, Wirth, Timo, Lehmann, Martin, Kintrup, Sebastian

2025

Overview

Background Systemic inflammation is a critical clinical condition regularly observed in the context of surgery-induced trauma or infection. Systemic inflammation induces an ubiquitous activation of the vasculature and vascular dysfunction related to organ damage and adverse outcomes. The dipeptidyl peptidase-4 (DPP4) modulates the receptor preferences and activity of a multitude of humoral substrates mediating the systemic inflammatory response. We here determined whether DPP4 inhibition is a means to beneficially modulate systemic inflammatory responses affecting vascular and organ integrity. Methods In cardiac surgery patients medicated with DPP4 inhibitors, we used a systems biology approach for in-depth characterization of the perioperative immune response and assessment of macro- and microvascular dynamics compared to control patients. In parallel, we mechanistically evaluated the efficacy of DPP4 inhibition on modulating immune responses, capillary leakage, vasoplegia and endothelial transcriptomic profiles in mice with severe systemic inflammation. Results Preoperative oral intake of the DPP4 inhibitor sitagliptin modulated innate and adaptive immune phenotypes and was associated with augmented microvascluar integrity, reduced vasoplegia and improved clinical parameters of capillary leakage in patients undergoing cardiac surgery. In mice, DPP4 inhibition curbed the inflammatory response to a polymicrobial sepsis resulting in a massive reduction in endothelial gene activation assoicated with preserved vascular barrier function, augmented vasopressor responses and organ integrity. Conclusions We conclude that DPP4 inhibition may be a safe and potent means to curb immune responses to surgery or infection, resulting in a preservation of vascular integrity that translates into organ protection and improved clinical outcomes. Trial registration https://www.clinicaltrials.gov ; Unique identifier: NCT05725798, study start: 2022-02-01. Graphical abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Aged / Animals / Cardiac patients / Critical Care Medicine / Cytokines / Design of experiments / Diabetes / Dipeptidyl Peptidase 4 / Dipeptidyl-Peptidase IV Inhibitors - pharmacology / Dipeptidyl-Peptidase IV Inhibitors - therapeutic use / Edema / Emergency Medicine / Endothelium / Ethylenediaminetetraacetic acid / Female / Flow cytometry / Flow velocity / Health aspects / Heart surgery / Humans / Immune response / Infection / Inflammation / Inflammation - drug therapy / Intensive / Intensive care / Male / Medicine / Medicine & Public Health / Mice / Microscopy / Middle Aged / Oxidative stress / Patients / Sepsis / Sitagliptin / Sitagliptin Phosphate - pharmacology / Sitagliptin Phosphate - therapeutic use / Software / Tumor necrosis factor-TNF / Type 2 diabetes