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Effect of CCL2 antisense oligodeoxynucleotides on bacterial translocation and subsequent sepsis in severely burned
Kenji Shigematsu1, Mari Kogiso, Makiko Kobayashi
1Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77555-0435, USA.
Abstract:
Severely burned mice are susceptible to sepsis stemming from Enterococcus faecalis translocation due to the impaired generation of M1 macrophages (M1MΦs) in local translocation sites. In our previous studies, CCL2 has been characterized as a major effector molecule on the burn-associated generation of M2MΦs, an inhibitor cell type for resident MΦ conversion into M1MΦs. In this study, we tried to protect burned mice orally infected with E. faecalis utilizing CCL2 antisense oligodeoxynucleotides (ODNs). We show that M2MΦs in mesenteric lymph nodes (MLNs) were not demonstrated in burned mice treated with CCL2 antisense ODNs. M1MΦs were not induced by heat-killed E. faecalis from resident MΦs transwell-cultured with mesenteric lymph node macrophages (MLN-MΦs) from burned mice, while M1MΦs were induced by the same antigen from resident MΦs transwell-cultured with MΦs which were isolated from burned mice treated with CCL2 antisense ODNs. Bacterial growth in MLNs was shown in burned mice orally infected with a lethal dose of E. faecalis. However, after the same infection, sepsis did not develop in burned mice treated with CCL2 antisense ODNs. These results indicate that bacterial translocation and subsequent sepsis are controlled in burned mice orally infected with a lethal dose of E. faecalis by gene therapy utilizing CCL2 antisense ODNs.
Insights
Gene therapy using CCL2 antisense oligodeoxynucleotides prevents Enterococcus faecalis sepsis in burned mice. This approach inhibits M2 macrophage generation, promoting M1 macrophage function and controlling bacterial translocation.
Area of Science:
- Immunology
- Microbiology
- Gene Therapy
Background:
- Severely burned mice are prone to sepsis from Enterococcus faecalis due to impaired M1 macrophage generation.
- CCL2 drives M2 macrophage accumulation, which inhibits the conversion of resident macrophages into M1 macrophages.
Purpose of the Study:
- To investigate the efficacy of CCL2 antisense oligodeoxynucleotides (ODNs) in protecting burned mice against E. faecalis infection.
- To determine if CCL2 inhibition can restore M1 macrophage function and prevent sepsis.
Main Methods:
- Burned mice were orally infected with E. faecalis and treated with CCL2 antisense ODNs.
- Macrophage populations (M1 and M2) in mesenteric lymph nodes (MLNs) were analyzed.
- In vitro studies assessed M1 macrophage induction using transwell cultures.
- Bacterial growth and sepsis development were monitored.
Main Results:
- CCL2 antisense ODN treatment prevented M2 macrophage accumulation in MLNs of burned mice.
- M1 macrophage induction was restored in vitro when using macrophages from ODN-treated mice.
- Bacterial translocation and sepsis were significantly reduced in burned mice treated with CCL2 antisense ODNs.
- Oral E. faecalis infection led to sepsis in untreated burned mice, but not in ODN-treated mice.
Conclusions:
- CCL2 antisense ODNs effectively control bacterial translocation and prevent sepsis in burned mice orally infected with E. faecalis.
- This gene therapy approach restores macrophage function, shifting the balance towards protective M1 macrophages.
- Targeting CCL2 offers a promising strategy for managing post-burn infections.
