Oxidized LDL upregulates macrophage DPP4 expression via TLR4/TRIF/CD36 pathways

Abstract

Background We and others have shown that dipeptidyl peptidase-IV (DPP4) expression is increased in obesity/atherosclerosis and is positively correlated with atherosclerotic burden. However, the mechanism by which DPP4 expression is regulated in obesity remains unclear. In this study, we investigated the pathways regulating the expression of DPP4 on macrophages. Methods Flowsight® Imaging Flow Cytometry was employed for the detection of DPP4 and immunophenotyping. DPP4 enzymatic activity was measured by a DPPIV-Glo™ Protease Assay kit. Findings Human monocytes expressed a moderate level of membrane-bound DPP4. Obese patients with body mass index (BMI) ≥ 30 had a higher level of monocyte DPP4 expression, in parallel with higher levels of HOMA-IR, blood glucose, triglycerides, and non-HDL cholesterol, compared to those in the non-obese (BMI < 30) patients. Oxidized low-density lipoprotein (oxLDL), but not native LDL, up-regulated DPP4 expression on macrophages with a preferential increase in CD36 + cells. OxLDL mediated DPP4 up-regulation was considerably diminished by Toll-like receptor-4 (TLR4) knockdown and CD36 deficiency. TRIF deficiency, but not MyD88 deficiency, attenuated oxLDL-induced DPP4 increase. Interpretation Our study suggests a key role for oxLDL and downstream CD36/TLR4/TRIF in regulating DPP4 expression. Increased DPP4 in response to oxidized lipids may represent an integrated mechanism linking post-prandial glucose metabolism to lipoprotein abnormality-potentiated atherosclerosis.

No Evidence for Human Monocyte-Derived Macrophage Infection and Antibody-Mediated Enhancement of SARS-CoV-2 Infection

“…It is also in agreement with previous reports describing the infection of alveolar macrophages by HCoV-229E (Funk et al, 2012). The cellular receptor for MERS-CoV dipeptidyl peptidase-IV (DPP4 also known as CD26) is expressed at low levels by human monocytes and macrophages of healthy donors (Wang et al, 2013;Zhong et al, 2013;Rao et al, 2018;Rao et al, 2019), which could explain MERS-CoV infection of hMDM in our experiments.…”

Assessment of the Effect of Short-Term Combined High-Intensity Interval Training on TLR4, NF-κB and IRF3 Expression in Young Overweight and Obese Girls

“…The postprandial metabolism was possibly impaired by circulating oxidized lipids through the TLR4 pathway [38]. Increasing the levels of TLR4 signaling products contributes to the pathogenesis of immunometabolic disorders like atherosclerosis and IR, which are aggravated by dyslipidemia, suggesting that dyslipidemia acts as a critical parameter in meta-inflammation progression [2].…”

DPP4 Inhibitor Attenuates Severe Acute Pancreatitis-Associated Intestinal Inflammation via Nrf2 Signaling

“…DPP4 expression in the intestine is the highest among that of all organs, speculated to be widely distributed in the intestinal tract and closely related to the occurrence and development of various intestinal diseases. Recently, DPP4 expression is reportedly upregulated in some inflammatory diseases such as inflammatory bowel disease, atherosclerosis, obesity, and multiple sclerosis, suggesting its involvement in the pathogenesis of inflammation [8–10]. In our previous experiments, DPP4 in the intestinal tract was demonstrated to be significantly increased in the SAP mouse model and could be inhibited by the DPP4 inhibitor (DPP4i) sitagliptin.…”