CD147 regulates the formation and function of immune synapses.

CD147 is a T cell activation-associated molecule which is closely involved in the formation of the immune synapse (IS). However, the precise role of CD147 in T cell activation and IS formation remains unclear. In the present study, we demonstrated that CD147 translocated to the IS upon T cell activation and was primarily distributed in the peripheral super molecular cluster (p-SMAC). The knock down of CD147 expression in T cells, but not in B cells, impaired IS formation. CD147 participated in IS formation between T cells and different types of antigen-presenting cells (APCs), including macrophages and dendritic cells. Ligation of CD147 with its monoclonal antibody (mAb) HAb18 effectively inhibited T cell activation and IL-2 secretion. CD98, a critical molecule interacting with CD147, was distributed in IS in a CD147-dependent way. Phosphorylation levels of T cell receptor (TCR) related molecules, like ZAP-70, ERK, and cJun, were down-regulated by CD147 ligation, which is crucial for the interaction of CD147 and TCR signaling transduction. CD147 is indispensable for the formation of immune synapses and plays an important role in the regulation of its function.

The immunomodulatory of interleukin-33 in rheumatoid arthritis: A systematic review.

Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease that primarily affects the joints and surrounding soft tissues, characterized by chronic inflammation and proliferation of the synovium. Various immune cells are involved in the pathophysiology of RA. The complex interplay of factors such as chronic inflammation, genetic susceptibility, dysregulation of serum antibody levels, among others, contribute to the complexity of the disease mechanism, disease activity, and treatment of RA. Recently, the cytokine storm leading to increased disease activity in RA has gained significant attention. Interleukin-33 (IL-33), a member of the IL-1 family, plays a crucial role in inflammation and immune regulation. ST2 (suppression of tumorigenicity 2 receptor), the receptor for IL-33, is widely expressed on the surface of various immune cells. When IL-33 binds to its receptor ST2, it activates downstream signaling pathways to exert immunoregulatory effects. In RA, IL-33 regulates the progression of the disease by modulating immune cells such as circulating monocytes, tissue-resident macrophages, synovial fibroblasts, mast cells, dendritic cells, neutrophils, T cells, B cells, endothelial cells, and others. We have summarized and analyzed these findings to elucidate the pathways through which IL-33 regulates RA. Furthermore, IL-33 has been detected in the synovium, serum, and synovial fluid of RA patients. Due to inconsistent research results, we conducted a meta-analysis on the association between serum IL-33, synovial fluid IL-33, and the risk of developing RA in patients. The pooled SMD was 1.29 (95% CI: 1.15-1.44), indicating that IL-33 promotes the onset and pathophysiological progression of RA. Therefore, IL-33 may serve as a biomarker for predicting the risk of developing RA and treatment outcomes. As existing drugs for RA still cannot address drug resistance in some patients, new therapeutic approaches are needed to alleviate the significant burden on RA patients and healthcare systems. In light of this, we analyzed the potential of targeting the IL-33/ST2-related signaling pathway to modulate immune cells associated with RA and alleviate inflammation. We also reviewed IL-33 and RA susceptibility-related single nucleotide polymorphisms, suggesting potential involvement of IL-33 and macrophage-related drug-resistant genes in RA resistance therapy. Our review elucidates the role of IL-33 in the pathophysiology of RA, offering new insights for the treatment of RA.

Inhibition of ferroptosis and iron accumulation alleviates pulmonary fibrosis in a bleomycin model.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease characterized by excessive proliferation of fibroblasts and excessive accumulation of extracellular matrix (ECM). Ferroptosis is a novel form of cell death characterized by the lethal accumulation of iron and lipid peroxidation, which is associated with many diseases. Our study addressed the potential role played by ferroptosis and iron accumulation in the progression of pulmonary fibrosis. We found that the inducers of pulmonary fibrosis and injury, namely, bleomycin (BLM) and lipopolysaccharide (LPS), induced ferroptosis of lung epithelial cells. Both the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) alleviated the symptoms of pulmonary fibrosis induced by bleomycin or LPS. TGF-ß stimulation upregulated the expression of transferrin receptor protein 1 (TFRC) in the human lung fibroblast cell line (MRC-5) and mouse primary lung fibroblasts, resulting in increased intracellular Fe2+, which promoted the transformation of fibroblasts into myofibroblasts. Mechanistically, TGF-ß enhanced the expression and nuclear localization of the transcriptional coactivator tafazzin (TAZ), which combined with the transcription factor TEA domain protein (TEAD)-4 to promote the transcription of TFRC. In addition, elevated Fe2+ failed to induce the ferroptosis of fibroblasts, which might be related to the regulation of iron export and lipid metabolism. Finally, we specifically knocked out TFRC expression in fibroblasts in mice, and compared with those in the control mice, the symptoms of pulmonary fibrosis were reduced in the knockout mice after bleomycin induction. Collectively, these findings suggest the therapeutic potential of ferroptosis inhibitors and iron chelators in treating pulmonary fibrosis.

[A mouse model of spondyloarthritis induced by human cartilage proteglycan].

Objective To develop a model of spondyloarthritis (SpA) in mice, and analyze their clinical manifestations, radiological and histological features, and inflammatory cytokines expression levels. Methods Fourteen-week-old female BALB/c mice were immunized by intraperitoneal injection of human cartilage proteoglycan (PG), with their peripheral joints observed and scored 3 times a week. 45 weeks after immunization, micro-computed tomography (micro-CT) was used to scan the axial and peripheral joints, and bone mineral density (BMD) and bone volume/total volume (BV/TV) of the vertebral body were analyzed. The pathological changes of the axial and peripheral joints were evaluated by HE and Safranin-Fast Green staining. The levels of tumor necrosis factor alpha (TNF-α) and interleukin 17A (IL-17A) in serum were tested by ELISA. Results 30% (6/20) of PG-induced SpA (PGISpA) mice exhibited peripheral joint swelling and joint stiffness. Micro-CT showed reduced BMD and BV/TV of the vertebral body and new bone formation in sacroiliac and spinal joints in PGISpA compared with the control. Histological staining showed inflammatory cell infiltration and abnormal proliferation of synovial cells and chondrocytes in the peripheral joints. It also observed chondrocytes proliferation in the sacroiliac joints, and increased chondrocytes and osteoblasts in the spinal joints in PGISpA mice. TNF-α and IL-17A increased at week 20 after induction and TNF-α decreased at week 45 in the serum of induced mice, while IL-17A continued to increase. Conclusion The established model of PGISpA showed similar imaging and pathological features to those of human SpA, suggesting a role of IL-17A in the pathogenesis. This model, together with its research platform, can serve as the cornerstone for SpA and model animal studies.

A20 regulates the therapeutic effect of anti-PD-1 immunotherapy in melanoma.

BACKGROUND: The therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive. METHODS: The association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism. RESULTS: We first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8+T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8+T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1+CD8+T cells to tumor burden. CONCLUSIONS: Together, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade.

The risk of circulating angiogenic T cells and subsets in patients with systemic sclerosis.

To ascertain the number and percentage of angiogenic T (Tang) cell subsets by flow cytometry in systemic sclerosis (SSc), and their relation with specific clinical features. Thirty SSc patients and 15 healthy controls (HCs) were included. Luminex was performed to analyze the levels of interleukin (IL)-17A, vascular endothelial growth factor (VEGF), tumor necrosis factor-α, and vascular cell adhesion molecule (VCAM). The ratio of circulating CD3 + CD31 + CXCR4 + T (CD3 + Tang) cells and CD8+ CD31 + CXCR4 + T (CD8+ Tang) cells in SSc patients was enlarger than in HCs, while CD4 + CD31 + CXCR4 + T cells (CD4 + Tang) exhibited no difference between SSc patients and HCs. The number and percentage of Tang cells were higher in SSc patients with pulmonary artery hypertension (PAH) than in non-PAH SSc patients and HCs. The ratios of Tang cell subsets in nucleolar pattern-positive SSc patients were markedly raised as compared with their negative ones and HCs. Additionally, the percentage of circulating CD3 + Tang cells was positively associated with VEGF serum levels in SSc patients. Meanwhile, the rate of CD8+ tang cells might have been emphatically corresponded to VEGF and VCAM serum levels in SSc patients. These results imply that the increase in Tang cells in peripheral blood are associated with immunoregulatory disturbances in SSc patients.