SLE is a severe heterogeneous autoimmune disorder featured by the production of pathogenic autoantibodies, immune complex formation and deposition in several organs, severe innate and adaptive immune disorder and inflammation. The pathogenesis of SLE is complex and the treatment is still difficult, thus further exploring the novel mechanisms and treatment of SLE is necessary [37].
LIAS is an iron-sulfur cluster mitochondrial enzyme which produce Lipoic acid (LA), a powerful antioxidant. LA also acts as a coenzyme of two enzymes (pyruvate dehydrogenase complex and α-ketoglutarate dehydrogenase complex) implicated in energy metabolism in mitochondria [38]. Mitochondria is the main source of reactive oxygen species (ROS) and can provide energy to cell by oxidative phosphorylation and ATP synthesis [39]. Excessive oxidative stress was reported to act an essential role in the pathogenesis of SLE via enhancing inflammation, causing apoptotic cell death and destructing the immunological tolerance [40]. LIAS was found to associate with oxidative stress and inflammation, decreased LIAS expression in mice after LPS induction was accompanied by increased inflammatory response and leukocyte accumulation [41]. Overexpression of LIAS level in experimental atherosclerotic mice significantly increased the number of Tregs and reduced T-cell infiltration [42]. Therefore, LIAS may be involved in SLE progression.
After immune infiltration analyses, we noticed that LIAS expression was highly correlated with the infiltration of immune cells, such as iTreg cells, platelet, Th1 cells, Th2 cells, Tfh cells, NK cells, CD4 T cells, CD8 T cells, neutrophil, monocytes, macrophages and so on. Abundance of studies have reported that these cells were associated with the pathology and development of SLE [43–45]. Thus, we hypothesized that LIAS as an essential cuproptosis-mediated gene may involve in regulating the immune cells infiltration to lead to the occurrence and advancement of SLE.
The results of cell-cell interaction analysis revealed that CCL and ANNEXIN signaling pathways were different from LIAS-low and LIAS-high cells. It was reported that CCL3 participated in the inflammatory response by recruiting polymorphonuclear cells. This chemokine had been reported to communicate with CCR1, CCR4 and CCR5 receptors on target cells [46], the expression of CCL3 was elevated in pristin-induced model of SLE [47]. In addition, FISETIN was found to decrease expression of CCL3 and improve the condition of SLE in animal models [48]. CCL3 was also known as an inflammatory marker with differential expression among SLE subjects and other autoimmune diseases. The expression level of CCL3 was correlated with SLE activity and it showed significantly difference between patients with low SLE activity versus patients with moderate to high activity [49]. In addition, CCL2/MCP-1, CXCCL10/IP-10 and CCL19 were featured as the interferon-inducible genes, which might involve in interferon activity related with SLE disease activity [50, 51]. One study has reported CCL2 expression was elevated in both serum and urine of SLE subjects versus healthy controls, showing the influence of CCL2 in the development of SLE [52–54].
ANXA1 is a component of the annexin proteins superfamily, which is also termed as lipocortin 1, lipomodulin and macrocortin. ANXA1 is mainly located on the inner plasma membrane and within the cytoplasm of cells in innate and adaptive immunity, which would bind to acidic phospholipid in the presence of calcium ion [55]. Human and mouse neutrophils, macrophages and monocytes all displayed high level of cytoplasmic ANXA1 [56]. Moreover, ANXA1–FPR2 pathway could aid T cell activation and differentiation, evidence prompted the idea that ANXA1 had a potential role in regulating T cell receptor (TCR) signalling and its action is essential for proper T cell activation [57]. In a present case–control study, authors revealed various genetic associations between ANXA1, FPR1 and FPR2 expression and SLE susceptibility in the South Tunisian population [58]. Another study detected that both in-vitro and in‐vivo study, blocking the ANXA1–FPR2 pathway using monoclonal antibodies specific to annexin A1 was possibly due to down‐regulation of the activity of disease‐associated T and B cells in a SLE mouse model [59]. Therefore, we inferred that LIAS-mediated cuproptosis might involve in the CCL and ANNEXIN signaling pathways to regulate cell-cell interactions, finally lead to the occurrence and development of SLE.
In this study, we explored the expression levels, AUC value, immune infiltration analysis, and functional enrichment of LIAS-related subgroups by comprehensive bioinformatics technologies. Furthermore, the LIAS expression at a scRNA-seq level and its roles in regulating specific signaling pathways and cell-cell interactions were investigated. The above results have implicated that LIAS could be a novel biomarker for the diagnosis of SLE and LIAS-mediated cuproptosis might serve as an essential role in the development of SLE.