Apolipoprotein E deficiency potentiates macrophage against Staphylococcus aureus in mice with osteomyelitis via regulating cholesterol metabolism.

Introduction: Staphylococcus aureus (S. aureus) osteomyelitis causes a variety of metabolism disorders in microenvironment and cells. Defining the changes in cholesterol metabolism and identifying key factors involved in cholesterol metabolism disorders during S. aureus osteomyelitis is crucial to understanding the mechanisms of S. aureus osteomyelitis and is important in designing host-directed therapeutic strategies. Methods: In this study, we conducted in vitro and in vivo experiments to define the effects of S. aureus osteomyelitis on cholesterol metabolism, as well as the role of Apolipoprotein E (ApoE) in regulating cholesterol metabolism by macrophages during S. aureus osteomyelitis. Results: The data from GSE166522 showed that cholesterol metabolism disorder was induced by S. aureus osteomyelitis. Loss of cholesterol from macrophage obtained from mice with S. aureus osteomyelitis was detected by liquid chromatography-tandem mass spectrometry(LC-MS/MS), which is consistent with Filipin III staining results. Changes in intracellular cholesterol content influenced bactericidal capacity of macrophage. Subsequently, it was proven by gene set enrichment analysis and qPCR, that ApoE played a key role in developing cholesterol metabolism disorder in S. aureus osteomyelitis. ApoE deficiency in macrophages resulted in increased resistance to S. aureus. ApoE-deficient mice manifested abated bone destruction and decreased bacteria load. Moreover, the combination of transcriptional analysis, qPCR, and killing assay showed that ApoE deficiency led to enhanced cholesterol biosynthesis in macrophage, ameliorating anti-infection ability. Conclusion: We identified a previously unrecognized role of ApoE in S. aureus osteomyelitis from the perspective of metabolic reprogramming. Hence, during treating S. aureus osteomyelitis, considering cholesterol metabolism as a potential therapeutic target presents a new research direction.

The effect of Staphylococcus aureus on innate and adaptive immunity and potential immunotherapy for S. aureus-induced osteomyelitis.

Osteomyelitis is a chronic inflammatory bone disease caused by infection of open fractures or post-operative implants. Particularly in patients with open fractures, the risk of osteomyelitis is greatly increased as the soft tissue damage and bacterial infection are often more severe. Staphylococcus aureus, one of the most common pathogens of osteomyelitis, disrupts the immune response through multiple mechanisms, such as biofilm formation, virulence factor secretion, and metabolic pattern alteration, which attenuates the effectiveness of antibiotics and surgical debridement toward osteomyelitis. In osteomyelitis, immune cells such as neutrophils, macrophages and T cells are activated in response to pathogenic bacteria invasion with excessive inflammatory factor secretion, immune checkpoint overexpression, and downregulation of immune pathway transcription factors, which enhances osteoclastogenesis and results in bone destruction. Therefore, the study of the mechanisms of abnormal immunity will be a new breakthrough in the treatment of osteomyelitis.

The Effect of Diabetes Mellitus on the Neurological Function of Patients with Cervical Spondylotic Myelopathy.

OBJECTIVE: To evaluate the clinical value of diabetes mellitus for diagnosis and postoperative prognosis in patients with cervical spondylotic myelopathy undergoing anterior decompression and fusion. METHODS: A total of 84 Patients (50 males and 34 females) who underwent anterior decompression and fusion were reviewed in this single-center retrospective study. The patients were divided into two groups (44 patients in the diabetes mellitus group and 40 in the non-diabetic group). Clinical manifestations were evaluated, including characteristics baseline, clinical tests, MRI information, clinical scores, and complications. The predictive effect of diabetes mellitus on clinical scores were assessed via the receiver operating characteristic curve. The correlation between the severity of diabetes mellitus and neurological function recovery was estimated using the Pearson correlation coefficient. RESULTS: Patients with diabetes mellitus exhibited a higher ratio of hyperintensity of the spinal cord (P < 0.05) and worse preoperative clinical scores and neurological recovery (all P < 0.05). Receiver operating characteristic curve results indicated that diabetes mellitus could serve as a good indicator for preoperative evaluation of the Japanese Orthopedic Association (JOA) score (area under curve [AUC] = 0.639), visual analogue score (AUC = 0.642), and Nurick score (AUC = 0.740). In addition, analysis of JOA in isolation suggested that diabetes mellitus correlated closely with the sensory function in the upper and lower limbs (both P < 0.01). The Receiver operating characteristic curve also demonstrated that diabetes mellitus as a clinical test had a reasonable specificity for sensory function in the upper (AUC = 0.654) and lower limbs (AUC = 0.671). Both the level of HbA1c and the duration of diabetes mellitus were negatively correlated with the recovery rate of the JOA score. There was no significant difference between the perioperative complications between the two groups (P > 0.05). CONCLUSION: This present study revealed that the neurological impairment caused by diabetes mellitus in patients undergoing anterior decompression and fusion does not only affect postoperative functional recovery but also interferes with the preoperative clinical manifestations, especially the sensory function in the upper and lower limbs.