Humoral regulation of iron metabolism by extracellular vesicles drives antibacterial response

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.

Heterogeneous dual-metal control ofSalmonellainfection

“…For example, in mice infected with invasive Salmonella , dietary iron overload exacerbates the infections ( 10 ), but the interpretation of this observation is complicated. Salmonella iron-uptake mutants and reporter strains seem support the idea that Salmonella’s replication is iron limitated (3, 5-7, 9, 11-17) . However, data on Salmonella mutants requiring micromolar iron concentrations might be irrelevant for wild-type Salmonella thriving on nanomolar iron ( 18 ).…”

The role and application of vesicles in triple-negative breast cancer: Opportunities and challenges

“…demonstrated the participation of EVs in the humoral coordination of bacterial infection. 178 EVs bind to circulating iron-containing proteins, regulate systemic iron metabolism, and prevent bacteria from obtaining iron, leading to bacteriostatic effects. 178 …”

“… 178 EVs bind to circulating iron-containing proteins, regulate systemic iron metabolism, and prevent bacteria from obtaining iron, leading to bacteriostatic effects. 178 …”

Bone marrow mesenchymal stem cell-derived exosomal microRNA-382 promotes osteogenesis in osteoblast via regulation of SLIT2

“…Accumulating evidence indicates that these features of hBMSCs are associated with extracellular vehicles secretion. Small extracellular vesicles (sEV) are extracellular vesicles generated by fusion with the cellular membrane of multi-vesicular bodies [10][11][12]. They are between 30 and 150 nm in diameter and contain abundant functional components such as proteins and microRNAs (miRNAs).…”