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Ddb1-Cullin4-Associated-Factor 1 in Macrophages Restricts the Staphylococcus aureus-Induced Osteomyelitis
Yang Zong1, Haojie Shan1, Fuli Yin1
1Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China.
Introduction:
Ddb1-cullin4-associated-factor 1 (DCAF1) is known to regulate protein ubiquitination, while the roles of DCAF1 in osteomyelitis remain unknown. This study aims to investigate the effects of DCAF1 deficiency in macrophages on osteomyelitis and elucidate the molecular mechanism.
Methods:
Staphylococcus aureus-induced mouse model of osteomyelitis was established on the DCAF1fl/flLyz2cre/+ and DCAF1fl/flLyz2+/+ (control) mice. Flow cytometry was conducted to analyze the populations of adaptive and innate immune cells. Lipopolysaccharides (LPS)-induced bone marrow-derived macrophages (BMDMs) were established. qRT-PCR and immunoblot analysis were used to determine the levels of inflammation-related biomarkers. ELISA was used to determine the release of inflammatory cytokines including IL-1β, IL-6, and TNF.
Results:
The populations of immune cells in the bone marrow and spleen were not affected due to DCAF1 deficiency in macrophages. DCAF1 suppressed inflammatory cytokines in LPS-induced BMDMs. Additionally, DCAF1 deficiency in macrophages induced severe symptoms including less bacterial load in the femur, cortical bone loss, and reactive bone formation. Mechanistic study revealed that DCAF1 deficiency induced p38 hyperactivation.
Discussion:
DCAF1 in macrophages suppressed the Staphylococcus aureus-induced mouse model of osteomyelitis.
Insights
DDB1-cullin4-associated-factor 1 (DCAF1) deficiency in macrophages worsens Staphylococcus aureus osteomyelitis by increasing inflammatory cytokines and p38 hyperactivation, indicating DCAF1
Area of Science:
- Immunology
- Molecular Biology
- Bone Biology
Background:
- DDB1-cullin4-associated-factor 1 (DCAF1) regulates protein ubiquitination.
- The role of DCAF1 in osteomyelitis is currently unknown.
- This study investigates DCAF1's function in macrophages during osteomyelitis.
Purpose of the Study:
- To determine the effect of DCAF1 deficiency in macrophages on osteomyelitis.
- To elucidate the molecular mechanisms underlying DCAF1's role in osteomyelitis.
Main Methods:
- Established a Staphylococcus aureus-induced mouse model of osteomyelitis using DCAF1 conditional knockout mice.
- Analyzed immune cell populations via flow cytometry.
- Investigated inflammatory markers and cytokine release (IL-1β, IL-6, TNF) in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs) using qRT-PCR, immunoblot, and ELISA.
- Assessed p38 pathway activation.
Main Results:
- DCAF1 deficiency in macrophages did not alter immune cell populations.
- DCAF1 suppressed inflammatory cytokine production in LPS-induced BMDMs.
- DCAF1 deficiency exacerbated osteomyelitis, leading to reduced bacterial load, significant cortical bone loss, and increased reactive bone formation.
- Mechanistically, DCAF1 deficiency resulted in p38 hyperactivation.
Conclusions:
- DCAF1 in macrophages plays a protective role by suppressing Staphylococcus aureus-induced osteomyelitis.
- DCAF1 deficiency promotes inflammation and bone destruction through p38 pathway activation.
