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Updated: Dec 2, 2025
Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
CRIg+ Macrophages Prevent Gut Microbial DNA-Containing Extracellular Vesicle-Induced Tissue Inflammation and Insulin
Zhenlong Luo1, Yudong Ji2, Hong Gao3
1Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, California; Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Background & Aims:
Liver CRIg+ (complement receptor of the immunoglobulin superfamily) macrophages play a critical role in filtering bacteria and their products from circulation. Translocation of microbiota-derived products from an impaired gut barrier contributes to the development of obesity-associated tissue inflammation and insulin resistance. However, the critical role of CRIg+ macrophages in clearing microbiota-derived products from the bloodstream in the context of obesity is largely unknown.
Methods:
We performed studies with CRIg-/-, C3-/-, cGAS-/-, and their wild-type littermate mice. The CRIg+ macrophage population and bacterial DNA abundance were examined in both mouse and human liver by either flow cytometric or immunohistochemistry analysis. Gut microbial DNA-containing extracellular vesicles (mEVs) were adoptively transferred into CRIg-/-, C3-/-, or wild-type mice, and tissue inflammation and insulin sensitivity were measured in these mice. After coculture with gut mEVs, cellular insulin responses and cGAS/STING-mediated inflammatory responses were evaluated.
Results:
Gut mEVs can reach metabolic tissues in obesity. Liver CRIg+ macrophages efficiently clear mEVs from the bloodstream through a C3-dependent opsonization mechanism, whereas obesity elicits a marked reduction in the CRIg+ macrophage population. Depletion of CRIg+ cells results in the spread of mEVs into distant metabolic tissues, subsequently exacerbating tissue inflammation and metabolic disorders. Additionally, in vitro treatment of obese mEVs directly triggers inflammation and insulin resistance of insulin target cells. Depletion of microbial DNA blunts the pathogenic effects of intestinal EVs. Furthermore, the cGAS/STING pathway is crucial for microbial DNA-mediated inflammatory responses.
Conclusions:
Deficiency of CRIg+ macrophages and leakage of intestinal EVs containing microbial DNA contribute to the development of obesity-associated tissue inflammation and metabolic diseases.
Insights
Liver macrophages expressing complement receptor of the immunoglobulin superfamily (CRIg) clear microbial products. Obesity reduces these cells, leading to inflammation and insulin resistance due to gut microbial extracellular vesicles.
Area of Science:
- Immunology
- Metabolic Diseases
- Microbiome Research
Background:
- Liver CRIg+ macrophages filter circulating bacteria and their products.
- Gut barrier dysfunction in obesity allows microbial products to cause inflammation and insulin resistance.
- The role of CRIg+ macrophages in clearing microbial products during obesity is unclear.
Purpose of the Study:
- Investigate the role of CRIg+ macrophages in clearing gut microbial extracellular vesicles (mEVs) in obesity.
- Determine the mechanisms by which mEVs contribute to obesity-associated inflammation and insulin resistance.
- Elucidate the involvement of the cGAS/STING pathway in mEV-induced inflammation.
Main Methods:
- Utilized C57BL/6 mice lacking CRIg, C3, or cGAS, alongside wild-type littermates.
- Quantified CRIg+ macrophage populations and bacterial DNA in mouse and human liver tissues.
- Adoptively transferred gut mEVs into mice and assessed tissue inflammation and insulin sensitivity.
- Evaluated cellular insulin and inflammatory responses to mEVs in vitro, including cGAS/STING pathway activation.
Main Results:
- Obese mice exhibit reduced liver CRIg+ macrophage populations.
- Liver CRIg+ macrophages clear mEVs via C3-dependent opsonization.
- Depletion of CRIg+ macrophages allows mEVs to spread, exacerbating tissue inflammation and metabolic dysfunction.
- Microbial DNA within mEVs triggers inflammation and insulin resistance through the cGAS/STING pathway.
Conclusions:
- Reduced CRIg+ macrophage function and gut barrier leakage of microbial DNA-containing EVs drive obesity-associated inflammation and metabolic disease.
- Targeting CRIg+ macrophages or microbial DNA may offer therapeutic strategies for obesity-related complications.
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