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Role of macrophage colony-stimulating factor in polymicrobial sepsis according to studies using osteopetrotic (op/op)
Masahito Ogiku1, Hiroshi Kono, Kenichi Ishii
1First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
Background:
The specific purpose of this study was to investigate the role of macrophage colony-stimulating factor (M-CSF)-induced macrophages in mouse polymicrobial sepsis model.
Materials And Methods:
M-CSF deficient (op/op) mice and their littermate mice w ere subjected the cecal ligation and puncture (CLP). Survival was assessed for the following 7 d after the CLP operation, and histopathologic findings were evaluated 12h after CLP. After CLP, expression of inflammatory mediators in serum was assessed by enzyme immunosorbent assay (ELISA). Furthermore, isolated peritoneal macrophages were stimulated with lipopolysaccharide (LPS) (10μg/mL) for 4h, and cytokine concentration in the supernatant was then measured by ELISA. Moreover, phagocytosis of isolated macrophages was assessed using fluorescent rates beads. In another set of experiments, effects of neutralization antibodies against high mobility group box 1 (HMGB1) were investigated in CLP model.
Results:
Mortality was increased in op/op mice compared with op/? mice after CLP. Furthermore, serum HMGB1 levels were also significantly greater in op/op mice than op/? mice. Production of HMGB1 by isolated peritoneal macrophages was significantly greater in op/op mice than op/? mice. Furthermore, the phagocytosis index was significantly blunted in op/op mice compared with op/? mice. Importantly, treatment with neutralization antibodies against HMGB1 markedly prevented acute lung injury and mortality in op/op mice.
Conclusion:
Matured macrophages by M-CSF play pivotal role by scavenging endotoxin in inflammation. Furthermore, HMGB1 is involved in pathophysiology in polymicrobial sepsis, consistent with previous reports.
Insights
Macrophage colony-stimulating factor (M-CSF)-induced macrophages are crucial in combating polymicrobial sepsis by clearing endotoxins. Targeting high mobility group box 1 (HMGB1) can mitigate sepsis-induced lung injury and mortality.
Area of Science:
- Immunology
- Sepsis Pathophysiology
- Macrophage Biology
Background:
- Polymicrobial sepsis is a life-threatening condition with significant mortality.
- Macrophage colony-stimulating factor (M-CSF) plays a role in macrophage maturation and function.
- The specific role of M-CSF-induced macrophages in sepsis requires further elucidation.
Purpose of the Study:
- To investigate the role of M-CSF-induced macrophages in a mouse model of polymicrobial sepsis.
- To assess the impact of M-CSF deficiency on sepsis outcomes and inflammatory responses.
- To explore the involvement of high mobility group box 1 (HMGB1) in M-CSF-deficient sepsis.
Main Methods:
- Cecal ligation and puncture (CLP) model in M-CSF deficient (op/op) and wild-type mice.
- Assessment of survival, histopathology, serum inflammatory mediators (ELISA), and macrophage phagocytosis.
- In vitro stimulation of peritoneal macrophages with lipopolysaccharide (LPS).
- Evaluation of anti-HMGB1 neutralization antibody efficacy in the CLP model.
Main Results:
- M-CSF deficient mice exhibited increased mortality and acute lung injury post-CLP.
- Serum and macrophage-derived high mobility group box 1 (HMGB1) levels were elevated in M-CSF deficient mice.
- Impaired phagocytic capacity of macrophages was observed in M-CSF deficient mice.
- Anti-HMGB1 antibody treatment significantly reduced mortality and lung injury in M-CSF deficient mice.
Conclusions:
- M-CSF-induced macrophages are critical for endotoxin scavenging during sepsis.
- High mobility group box 1 (HMGB1) significantly contributes to the pathophysiology of polymicrobial sepsis.
- Targeting HMGB1 presents a potential therapeutic strategy for sepsis management.
