Tertiary lymphoid structure (TLS) represents lymphocyte clusters in non-lymphoid organs. The formation and maintenance of TLS are dependent on follicular helper T (TFH) cells. However, the role of TFH cells during renal TLS formation and the renal fibrotic process has not been comprehensively elucidated in chronic kidney disease. Here, we detected the circulating TFH cells from 57 IgAN patients and found that the frequency of TFH cells was increased in IgA nephropathy patients with renal TLS and also increased in renal tissues from the ischemic-reperfusion-injury (IRI)-induced TLS model. The inducible T-cell co-stimulator (ICOS) is one of the surface marker molecules of TFH. Remarkably, the application of an ICOS-neutralizing antibody effectively prevented the upregulation of TFH cells and expression of its canonical functional mediator IL-21, and also reduced renal TLS formation and renal fibrosis in IRI mice in vivo. In the study of this mechanism, we found that recombinant IL-21 could directly promote renal fibrosis and the expression of p65. Furthermore, BAY 11-7085, a p65 selective inhibitor, could effectively alleviate the profibrotic effect induced by IL-21 stimulation. Our results together suggested that TFH cells contribute to TLS formation and renal fibrosis by IL-21. Targeting the ICOS-signaling pathway network could reduce TFH cell infiltration and alleviate renal fibrosis.

Recently, infertility has emerged as a significant and prevalent public health concern warranting considerable attention. Apoptosis, recognized as programmed cell death, constitutes a crucial process essential for the maintenance of normal spermatogenesis. Multiple investigations have illustrated that the dysregulated apoptosis of reproductive cells, encompassing spermatogonial stem cells, Sertoli cells, and Leydig cells, serves as a causative factor in male infertility. MicroRNAs represent a class of small RNA molecules that exert negative regulatory control over gene expression using direct interaction with messenger RNA transcripts. Previous studies have established that aberrant expression of miRNAs induces apoptosis in reproductive tissues, correlating with reproductive dysfunctions and infertility. In this review, we offer a comprehensive overview of miRNAs and their respective target genes implicated in the apoptotic process. As well, miRNAs are involved in multiple apoptotic signaling pathways, namely the PI3K/AKT, NOTCH, Wnt/β-catenin, and mTOR signaling cascades, exerting both negative and positive effects. We additionally elucidate the significant functions played by lncRNAs and circular RNAs as competing endogenous RNAs in the process of apoptosis within reproductive cells. We further illustrate that external factors, including silica nanoparticles, Cyclosporine A, and smoking, induce dysregulation of miRNAs, resulting in apoptosis within reproductive cells and subsequent male reproductive toxicity. Further, we discuss the implication of heat stress, hypoxia, and diabetes in reproductive cell apoptosis induced by miRNA dysregulation in male infertility. Finally, we demonstrate that the modulation of miRNAs via traditional and novel medicine could protect reproductive cells from apoptosis and be implemented as a therapeutic approach in male infertility.