Ddb1-Cullin4-Associated-Factor 1 in Macrophages Restricts the Staphylococcus aureus-Induced Osteomyelitis

Yang Zong; Haojie Shan; Fuli Yin; Xin Ma; Chaolai Jiang; Nan Wang; Lihui Zhou; Yiwei Lin; Zubin Zhou; Xiaowei Yu

doi:10.2147/JIR.S307316

Ddb1-Cullin4-Associated-Factor 1 in Macrophages Restricts the Staphylococcus aureus-Induced Osteomyelitis

J Inflamm Res. 2021 Apr 28:14:1667-1676. doi: 10.2147/JIR.S307316. eCollection 2021.

Authors

Yang Zong^#¹, Haojie Shan^#¹, Fuli Yin¹, Xin Ma¹, Chaolai Jiang¹, Nan Wang², Lihui Zhou³, Yiwei Lin¹, Zubin Zhou¹, Xiaowei Yu¹

Affiliations

¹ Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China.
² Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China.
³ Department of Orthopaedic Surgery, Xiangshan First People's Hospital, Ningbo, Zhejiang, 315700, People's Republic of China.

^# Contributed equally.

Abstract

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 DCAF1^fl/flLyz2^cre/+ and DCAF1^fl/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.

Keywords: DCAF1; Staphylococcus aureus; inflammation; macrophages; osteomyelitis.