A groundbreaking study published in International Immunopharmacology has revealed that serum levels of High Mobility Group Box Protein-1 (HMGB-1), a multifunctional protein, could serve as a novel biomarker for diagnosing and monitoring systemic lupus erythematosus (SLE). HMGB-1, released during specific types of programmed cell death like ferroptosis and necroptosis, was found to be significantly elevated in SLE patients compared to healthy controls. This discovery sheds light on the potential of HMGB-1 to play a crucial role in the disease progression.
The study found that serum levels of HMGB-1, along with necroptosis markers receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL), and ferroptosis-related metabolites, were significantly elevated in SLE patients compared to healthy controls. These elevated levels were positively correlated with SLE disease activity. Furthermore, serum HMGB-1 showed a strong positive correlation with RIPK3/MLKL levels and ferroptosis metabolites. HMGB-1 levels were also associated with renal involvement and elevated antinuclear antibody (ANA) titers. In vitro experiments demonstrated that SLE serum and interferon γ (IFN-γ) treatment activated necroptosis and ferroptosis markers, leading to HMGB-1 release in both HEK293 and HK2 cells. Clinically, binary logistic analysis identified HMGB-1 as a significant independent risk factor for SLE.
HMGB-1, a member of the high-mobility group (HMG) family, was initially recognized as a ubiquitous nuclear protein capable of binding to both nuclear and cytoplasmic components. Under stress or during cell death, HMGB-1 is released into the extracellular space, where it acts as a damage-associated molecular pattern (DAMP). Various cell membrane proteins, including toll-like receptors 2/4 (TLR2/4) and the advanced glycosylation end product-specific receptor (AGER), have been identified as receptors for extracellular HMGB-1. Elevated levels of extracellular HMGB-1 drive acute and chronic inflammatory responses, contributing to the pathogenesis of various human diseases. Its binding activates the extracellular signal-regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, leading to the release of chemokines and cytokines
A study conducted by Hisham et al. revealed significantly elevated levels of HMGB1 in the SLE patients, along with a marginal association between the ‘C’ allele of HMGB1 and an increased risk of SLE. Although demographic differences between patients with and without lupus nephritis (LN) were not significant, notable distinctions were observed in musculoskeletal manifestations, SLEDAI scores, HMGB1 levels, and genotypes. Importantly, the C/T-T/T genotype was associated with a 3.5-fold increased risk of developing LN. The study concluded that measuring HMGB1 levels could be beneficial for diagnosing SLE and predicting LN, emphasizing the importance of HMGB1 gene variations in this context.
While this study marks a significant step forward in understanding the mechanisms behind SLE, further research is required to uncover the molecular functions of extracellular HMGB-1 in the disease.
References
- Zhao G, Wang X, Lei H, Ruan N, Yuan B, Tang S, Ni N, Zuo Z, Xun L, Luo M, Zhao Q, Qi J, Fu P. Serum HMGB-1 released by ferroptosis and necroptosis as a novel potential biomarker for systemic lupus erythematosus. Int Immunopharmacol. 2024 Oct 25;140:112886.
- Hisham FA, Tharwat S, Samra NE, Mostafa N, Nassar MK, El-Desoky MM. High mobility group box protein 1 (HMGB1) serum and urinary levels and gene polymorphism in Egyptian patients with systemic lupus erythematosus: A possible relation to lupus nephritis. Lupus. 2022 Dec;31(14):1777-1785.