Exendin-4 Prevents oxLDL-Induced upregulation of TREM2 and attenuates foam cell formation and inflammation in Macrophages

Atherosclerosis (AS), a chronic inflammatory disease and a leading cause of cardiovascular morbidity and mortality. Macrophage-mediated lipid uptake and inflammation are central to plaque formation. TREM2, an immunoreceptor expressed in macrophages, has been reported to regulate lipid metabolism and inflammation, yet its role in atherosclerosis remains controversial. Exendin-4, a GLP-1 Receptor agonist with its known cardiovascular protective effects, may influence immune signaling beyond glycemic control. However, whether the effect of Exendin-4 mitigating AS and the relations with TREM2 and its downstream JAK2/STAT3 pathway are unknown. We aimed to investigate the role of the Exendin-4-TREM2-JAK2/STAT3 axis in foam cell formation and inflammation during AS progression. OxLDL was used to stimulate THP-1-derived macrophages, and apoE^-/- mice fed a high-fat diet were used to construct an in vivo AS model. TREM2 expression was manipulated using lentiviral vectors, and the role of JAK2 signaling was assessed with a specific inhibitor. We evaluated the effects of Exendin-4 on TREM2 expression, foam cell formation and inflammation. We found that lipid stimulation increased TREM2 expression and activated the JAK2/STAT3 pathway in macrophages, leading to enhanced foam cell formation and pro-inflammatory cytokine production. Also, TREM2 overexpression caused increasing levels of inflammatory cytokines and foam cells. Exendin-4 could alleviate AS progression under the anti-inflammatory and anti-foaming effects, with reducing TREM2 expressions. However, the inflammation and foam cell formation with JAK2/STAT3 pathway activation caused by TREM2 overexpression cannot be reversed by Exendin-4. All our findings indicate that Exendin-4 suppress foam cell formation and inflammatory responses, with inhibiting macrophage TREM2 expression up-regulation.

Atherosclerosis; Exendin-4; Foam cell; Inflammation; Macrophage; TREM2.