Humoral regulation of iron metabolism by extracellular vesicles drives antibacterial response
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Abstract
Abstract Immediate iron restriction by the host is a critical process to protect against bacterial infections. Although the cell-dependent iron sequestration mechanism in liver or spleen has been identified, it is still unclear that whether the host launched humoral regulation mechanism to promptly acquire iron that widely distributes throughout body fluids. Here, we showed that after bacterial invasion, host immediately releases nanosized exosomes to capture circulating iron-containing proteins, which is required for prompt systemic iron sequestration and antibacterial defense. Mechanistically, in a sepsis model, we found that Salmonella Typhimurium induces endoplasmic reticulum stress in macrophages and activates inositol requiring enzyme 1α (IRE1α) signaling, triggering lysosomal dysfunction and promoting exosome release. These exosomes bearing transferrin receptors, CD163 and CD91 bind multiple iron-containing proteins, prevent bacteria from iron acquisition, and recycle them to tissue-resident macrophages, ultimately sequestering iron and protecting against infection. Our findings reveal a previously unknown humoral regulation mechanism of iron metabolism during bacterial infection, and suggest the release and circulation of extracellular vesicles could be an important way to promptly regulate systemic ion metabolism.
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- Authors
- Kuang, H., Dou, G., Cheng, L., Wang, X., Xu, H., Liu, X., Ding, F., Yang, X., Liu, S., Bao, L., Liu, H., Liu, Y., Li, B., Jin, Y., & Liu, S.
- Affiliations
- Air Force Medical University (CN)
- China Medical University (CN)
- Southern Medical University (CN)
- Corresponding author
- Liu, Siying
- Jin, Yan
- Liu, Shiyu
- ORCID
- Venue
- Nature Metabolism
- Published
- 2023-01-19
- Volume
- 5
- Issue
- 1
- Pages
- 111-128
- ISSN
- 2522-5812 (ISSN-L)
- OpenAlex
- W4317500242
- Cited by
- 53
- References
- 12
- Citations by year
- 2026: 18 · 2025: 13 · 2024: 14 · 2023: 8
- FWCI
- 10.41
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (3180017, 81991504, 82170925)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- extracellular vesicles, iron metabolism, humoral immunity, macrophages, Salmonella typhimurium, sepsis, endoplasmic reticulum stress, IRE1α signaling, lysosomal dysfunction, iron acquisition, iron sequestration, antibacterial response, host defense against infection
- MeSH terms
- Extracellular Vesicles, Animals, Anti-Bacterial Agents, Female, Iron, Salmonella Infections, Animal, Salmonella typhimurium, Mice
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