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The discovery of toll-like receptors (TLRs) and the subsequent recognition that endogenous nucleic acids (NAs) could serve as TLR ligands have led to essential insights into mechanisms of healthy immune responses as well as pathogenic mechanisms relevant to systemic autoimmune and inflammatory diseases. In systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis, NA-containing immune complexes serve as TLR ligands, with distinct implications depending on the additional immune stimuli available. Plasmacytoid dendritic cells (pDCs), the robust producers of type I interferon (IFN-I), are providing critical insights relevant to TLR-mediated healthy immune responses and tissue repair, as well as generation of inflammation, autoimmunity and fibrosis, processes central to the pathogenesis of many autoimmune diseases. In this review, we describe recent data characterizing the role of platelets and NA-binding chemokines in modulation of TLR signaling in pDCs, as well as implications for how the IFN-I products of pDCs contribute to the generation of inflammation and wound healing responses by monocyte/macrophages. Chemokine modulators of TLR-mediated B cell tolerance mechanisms and interactions between TLR signaling and metabolic pathways are also considered. The modulators of TLR signaling and their contribution to the pathogenesis of systemic autoimmune diseases suggest new opportunities for identification of novel therapeutic targets., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The age-associated functional decline of the kidney is accompanied by structural changes including glomerular sclerosis and interstitial fibrosis. Aging kidneys also exhibit increased vulnerability in stressful environmental conditions. In this study, we assessed the differences in responses between young and aged animals to folic acid (FA)-induced renal fibrosis. To monitor the effects of aging on FA-induced kidney fibrosis, we administered FA (250 mg/kg) to young (6-month old) and aged (20-month old) rats. The development of severe fibrosis was only detected in aged rat kidneys, which was accompanied by increased kidney injury and inflammation. Furthermore, we found that FA-treated aged rats had significantly lower farnesoid X receptor (FXR) expression in the tubular epithelial cells than the rats not treated with FA. Interestingly, the extent of inflammation was severe in the kidneys of aged rat, where the FXR expression was low. To explore the role of FXR in kidney inflammation, in vitro studies were performed using NRK52E kidney tubule epithelial cells. NF-κB activation by lipopolysaccharide treatment induces chemokine production in NRK52E cells. The activation of FXR by obeticholic acid significantly reduced the transcriptional activity of NF-κB and chemokine production. In contrast, FXR knockdown increased LPS-induced chemokine production in NRK52E cells. Finally, FXR-knockout mice that were administered FA showed increased inflammation and severe fibrosis. In summary, we demonstrated that diminished FXR expression in the epithelial cells of the renal tubules exacerbated the fibrotic response in aged rat kidneys by upregulating pro-inflammatory NF-κB activation. [ABSTRACT FROM AUTHOR]

Circular ribonucleic acids (circRNAs) are a class of long non-coding RNA that were once regarded as non-functional transcription byproducts. However, recent studies suggested that circRNAs may exhibit important regulatory roles in many critical biological pathways and disease pathologies. These studies have identified significantly differential expression profiles of circRNAs upon changes in physiological and pathological conditions of eukaryotic cells. Importantly, a substantial number of studies have suggested that circRNAs may play critical roles in organ injuries. This review aims to provide a summary of recent studies on circRNAs in organ injuries with respect to (1) changes in circRNAs expression patterns, (2) main mechanism axi(e)s, (3) therapeutic implications and (4) future study prospective. With the increasing attention to this research area and the advancement in high-throughput nucleic acid sequencing techniques, our knowledge of circRNAs may bring fruitful outcomes from basic and clinical research. [ABSTRACT FROM AUTHOR]