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Updated: Sep 30, 2025
Investigation of Macrophage Polarization Using Bone Marrow Derived Macrophages
Published on: June 23, 2013
IL-4 polarized human macrophage exosomes control cardiometabolic inflammation and diabetes in obesity
Tuan Anh Phu1, Martin Ng1, Ngan K Vu1
1Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA; Northern California Institute for Research and Education, San Francisco, CA 94121, USA.
Abstract:
Cardiometabolic disease is an increasing cause of morbidity and death in society. While M1-like macrophages contribute to metabolic inflammation and insulin resistance, those polarized to an M2-like phenotype exert protective properties. Building on our observations reporting M2-like macrophage exosomes in atherosclerosis control, we tested whether they could serve to control inflammation in the liver and adipose tissue of obese mice. In thinking of clinical translation, we studied human THP-1 macrophages exposed to interleukin (IL)-4 as a source of exosomes (THP1-IL4-exo). Our findings show that THP1-IL4-exo polarized primary macrophages to an anti-inflammatory phenotype and reprogramed their energy metabolism by increasing levels of microRNA-21/99a/146b/378a (miR-21/99a/146b/378a) while reducing miR-33. This increased lipophagy, mitochondrial activity, and oxidative phosphorylation (OXPHOS). THP1-IL4-exo exerted a similar regulation of these miRs in cultured 3T3-L1 adipocytes. This enhanced insulin-dependent glucose uptake through increased peroxisome proliferator activated receptor gamma (PPARγ)-driven expression of GLUT4. It also increased levels of UCP1 and OXPHOS activity, which promoted lipophagy, mitochondrial activity, and beiging of 3T3-L1 adipocytes. Intraperitoneal infusions of THP1-IL4-exo into obese wild-type and Ldlr-/- mice fed a Western high-fat diet reduced hematopoiesis and myelopoiesis, and favorably reprogramed inflammatory signaling and metabolism in circulating Ly6Chi monocytes. This also reduced leukocyte numbers and inflammatory activity in the circulation, aorta, adipose tissue, and the liver. Such treatments reduced hepatic steatosis and increased the beiging of white adipose tissue as revealed by increased UCP1 expression and OXPHOS activity that normalized blood insulin levels and improved glucose tolerance. Our findings support THP1-IL4-exo as a therapeutic approach to control cardiometabolic disease and diabetes in obesity.
Insights
M2-like macrophage exosomes (THP1-IL4-exo) combat obesity-related cardiometabolic disease. These exosomes reduce inflammation and improve metabolism in liver and adipose tissue, offering a potential therapeutic strategy for diabetes.
Area of Science:
- Immunology and Metabolism
- Cell Biology
- Molecular Biology
Background:
- Cardiometabolic disease, including insulin resistance and inflammation, is a growing health concern.
- M1-like macrophages promote inflammation, while M2-like macrophages offer protective effects.
- Previous research indicated M2-like macrophage exosomes can control atherosclerosis.
Purpose of the Study:
- To investigate the potential of M2-like macrophage exosomes (THP1-IL4-exo) in controlling inflammation and metabolic dysfunction in obesity.
- To explore the therapeutic applications of THP1-IL4-exo for cardiometabolic diseases.
Main Methods:
- THP-1 macrophages were treated with interleukin-4 (IL-4) to generate exosomes (THP1-IL4-exo).
- The effects of THP1-IL4-exo on primary macrophages and 3T3-L1 adipocytes were analyzed, focusing on microRNA profiles, lipophagy, mitochondrial activity, and glucose uptake.
- Obese mice (wild-type and Ldlr-/-) were treated with THP1-IL4-exo, and their metabolic and inflammatory markers were assessed in circulation, adipose tissue, liver, and aorta.
Main Results:
- THP1-IL4-exo induced an anti-inflammatory macrophage phenotype and reprogramed cellular metabolism by altering microRNA levels (increasing miR-21/99a/146b/378a, decreasing miR-33).
- Exosomes enhanced lipophagy, mitochondrial activity, oxidative phosphorylation (OXPHOS), and insulin-dependent glucose uptake in adipocytes.
- In obese mice, THP1-IL4-exo treatment reduced myelopoiesis, modulated inflammatory signaling in monocytes, decreased leukocyte counts, and alleviated hepatic steatosis and inflammation.
Conclusions:
- THP1-IL4-exo treatment improved metabolic parameters, including insulin sensitivity and glucose tolerance, in obese mice.
- Exosomes promoted adipose tissue beiging, indicated by increased UCP1 expression and OXPHOS activity.
- THP1-IL4-exo demonstrates significant therapeutic potential for managing obesity-associated cardiometabolic disease and diabetes.
