Guanjun Dong

Toll-like receptors (TLRs) play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE) by regulating the activation and differentiation of immune cells. Oleic acid (OA), the predominant monounsaturated fatty acid found in adipose tissue, is known to regulate various biological processes. However, the regulatory role of OA in TLR signaling pathways activation and SLE pathogenesis remains unclear. In this study, we reveal that OA treatment significantly alleviates symptoms in both MRL/lpr mice and imiquimod (IMQ)-induced lupus model mice, as evidenced by reduced splenomegaly, decreased anti-dsDNA antibody levels, ameliorated renal pathological damage, and diminished glomerular deposits of IgG and IgM. Notably, OA treatment not only suppresses the activation of immune cells, including B cells, macrophages, dendritic cells, and T cells, but also inhibits the differentiation of B cells and T cells in vivo. Importantly, OA effectively inhibits TLRs-mediated activation of immune cells by blocking the MAPK pathway and NF-κB pathway. Mechanistically, OA promotes IL-10 expression in B cells by activating STAT3, and IL-10 can significantly inhibit the activation of TLR pathways. Collectively, our findings reveal that OA mitigates lupus pathogenesis by targeting TLR pathways through the STAT3/IL-10 axis, indicating that OA may be a promising treatment candidate for SLE.

Cancer continues to pose significant risks to public health globally due to incomplete therapeutic conquests even though significant advances have been achieved in the field of oncology. Therefore, understanding the molecular mechanisms driving tumorigenesis and progression is critical for developing novel treatment strategies to achieve effective cancer treatment. Norrin, the secreted cystine-knot protein originally recognized for its functional role in retinal vascular development an neuronal protection, is now implicated in oncogenic processes. This review synthesizes the existing evidence on Norrin’s involvement in tumors, highlighting its aberrant expression across multiple malignancies and its functional role in cancer cell proliferation, migration, invasion, and tumor-associated angiogenesis. The compelling data reported in this review suggest that dysregulated Norrin signaling promotes oncogenesis in various cancer types. Furthermore, the mechanistic basis of Norrin’s tumorigenic effect is discussed, and the therapeutic potential of targeting Norrin is evaluated to provide novel insights for future diagnostic and therapeutic development in oncology.

The abnormal activation and differentiation of B cells play an important role in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). Alpha-ketoglutarate (α-KG), a key metabolite in the tricarboxylic acid cycle, has been shown to be involved in the pathogenesis of many diseases by regulating the immune response. However, the role of α-KG in the pathogenesis of SLE, as well as the activation and differentiation of B cells, remains unclear. In this study, we used organic acid-targeted metabolomics to analyze the changes in the levels of 100 organic acids in the serum of SLE patients and healthy controls, and found a significant increase in the α-KG level in SLE patients compared to that in healthy controls. Notably, α-KG significantly could inhibit the activation and differentiation of B cells and alleviate disease progression in lupus-prone mice. Mechanistically, RNA-seq revealed that α-KG upregulated the expression of ENTPD1, which encodes an important immune checkpoint molecule CD39; B-cell-specific loss of ENTPD1 could significantly promote the Toll-like receptors-mediated activation and differentiation of B cells and aggravate the disease conditions of lupus-prone mice. The findings of our study demonstrate that α-KG alleviates the pathogenesis of lupus and inhibits the activation and differentiation of B cells by increasing the expression of CD39. Our findings laid a theoretical foundation for understanding the pathogenesis of SLE. Based on our study, α-KG might be further examined as a drug for the effective treatment of SLE.

The interleukin 17 (IL-17) family of cytokines has emerged as a critical player in autoimmune disease, including systemic lupus erythematosus (SLE). However, the role of IL-17B, a poorly understood cytokine, in the pathogenesis of SLE is still not known. In this study, we investigated the role of IL-17B in the activation and differentiation of B cells, and the pathogenesis of SLE. Intriguingly, IL-17B deficiency aggravated disease in lupus-prone mice and promoted the activation of B cells and the differentiation of germinal center B cells and plasma cells, while recombinant mouse IL-17B (rmIL-17B) significantly alleviated disease in lupus-prone mice. Mechanistically, rmIL-17B inhibited the activation of the Toll-like receptor and interferon pathways in B cells by downregulating fatty acid synthase–mediated (FASN-mediated) lipid metabolism. Loss of FASN significantly alleviated the disease in lupus-prone mice and inhibited the activation and differentiation of B cells. In addition, B cells had greater FASN expression and lower IL-17RB levels in patients with SLE than in healthy controls. Our study describes the role of IL-17B in regulating B cell activation and differentiation, and alleviating the onset of SLE. These findings will lay a theoretical foundation for further understanding of the pathogenesis of SLE.

Toll-like receptors (TLRs), especially TLR7, play an important role in systemic lupus erythematosus (SLE) pathogenesis. However, the regulatory mechanism underlying the abnormal activation of TLR pathways in patients with SLE has not been elucidated. Notably, accumulating evidence indicates that myeloid-derived suppressor cells (MDSCs) are important regulators of inflammation and autoimmune diseases. Compared with healthy control subjects, patients with SLE have a greater proportion of MDSCs among peripheral blood mononuclear cells (PBMCs); however, the effect of MDSCs on TLR7 pathway activation has not been determined. In the present study, lupus MDSCs significantly promoted TLR7 pathway activation in macrophages and dendritic cells (DCs), exacerbating the imiquimod-induced lupus model. RNA-sequencing analysis revealed significant overexpression of S100 calcium-binding protein A8 (S100A8) and S100A9 in MDSCs from diseased MRL/lpr mice. In vitro and in vivo studies demonstrated that S100A8/9 effectively promoted TLR7 pathway activation and that S100A8/9 deficiency reversed the promoting effect of MDSCs on TLR7 pathway activation in lupus. Mechanistically, MDSC-derived S100A8/9 upregulated interferon gamma (IFN-γ) secretion by macrophages and IFN-γ subsequently promoted TLR7 pathway activation in an autocrine manner. Taken together, these findings suggest that lupus MDSCs promote TLR7 pathway activation and lupus pathogenesis through the S100A8/9-IFN-γ axis. Our study identified an important target for SLE therapy.

Fatty acid metabolism, particularly fatty acid synthesis, is a very important cellular physiological process in which nutrients are used for energy storage and biofilm synthesis. As a key enzyme in the fatty acid metabolism, fatty acid synthase (FASN) is receiving increasing attention. Although previous studies on FASN have mainly focused on various malignancies, many studies have recently reported that FASN regulates the survival, differentiation, and function of various immune cells, and subsequently participates in the occurrence and development of immune-related diseases. However, few studies to date systematically summarized the function and molecular mechanisms of FASN in immune cell biology and related diseases. In this review, we discuss the regulatory effect of FASN on immune cells, and the progress in research on the implications of FASN in immune-related diseases. Understanding the function of FASN in immune cell biology and related diseases can offer insights into novel treatment strategies for clinical diseases.

Endotoxin shock remains one of the major causes of mortality worldwide. Pyruvate dehydrogenase kinase (PDK) 2 is an important regulatory enzyme involved in glucose metabolism. The purpose of this study was to determine the regulatory effect of PDK2 on LPS-induced endotoxin shock and explore the mechanisms in vivo and in vitro. Here, we showed that PDK2 contributed to Toll-like receptor (TLR)-mediated inflammation. Lipopolysaccharide (LPS) activation of TLR4 pathways resulted in PDK2 upregulation in macrophages and dendritic cells (DCs). PDK2 overexpression enhanced TLR4 signaling pathway activation, whereas downregulating PDK2 expression inhibited TLR4 signaling pathway activation. Pharmacological inhibition of PDK2 significantly decreased the mortality rate and alleviated pathological injury in the lungs and livers of LPS-challenged mice, while significantly suppressing proinflammatory cytokine production. Thus, we confirmed that PDK2 is involved in LPS-induced endotoxin shock by modulating TLR4-mitogen-activated protein kinase signaling and inducing the production of proinflammatory cytokines in macrophages and DCs. Our findings highlight the importance of PDK2 as a novel target to treat septic shock.

Toll-like receptors (TLRs) are the first line of defense in the immune system, whose activation plays a key role in the pathogenesis of inflammation and autoimmunity. TLRs can activate a variety of immune cells such as macrophages and dendritic cells, which produce proinflammatory cytokines, chemokines, and co-stimulatory molecules that lead to the development of inflammation and autoimmune diseases. As a nonreceptor tyrosine kinase, ACK1 is involved in multiple signaling pathways and physiological processes. However, the roles of ACK1 in the activation of TLR pathways and in the pathogenesis of inflammation and autoimmune diseases have not yet been reported. We found that the expression of ACK1 could be upregulated by TLR pathways in vivo and in vitro. Intriguingly, overexpression of ACK1 significantly promoted the activation of TLR4, TLR7, and TLR9 pathways, while knockdown of ACK1 or the use of the ACK1 inhibitor AIM-100 significantly inhibited the activation of TLR4, TLR7, and TLR9 pathways. In vivo studies showed that the inhibition of ACK1 activity by AIM-100 could significantly protect mice from the TLR4 agonist lipopolysaccharide (LPS)-mediated endotoxin shock and alleviate the condition of imiquimod-mediated lupus-prone mice and MRL/lpr mice. In summary, ACK1 participates in TLR-mediated inflammation and autoimmunity and has great potential in controlling inflammation and alleviating autoimmune diseases.