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Background: One of the causes of tubulointerstitial nephritis is viral infection, with innate immune responses affecting its pathogenesis. Toll-like receptor 3 (TLR3) recognizes viral infections and acts antivirally by activating signaling to produce inflammatory cytokines/chemokines, including C-C motif chemokine ligand 5 (CCL5) and interferon-β (IFN-β). Although cylindromatosis lysine 63 deubiquitinase (CYLD) is known to be associated with tubulointerstitial nephritis and renal function, its role in the antiviral innate immune response in tubular epithelial cells remains unknown. In this study, we investigated the association between CYLD and TLR3-mediated CCL5 production in cultured human renal proximal tubular epithelial cells (hRPTECs)., Methods and Results: Polyinosinic-polycytidylic acid (poly IC), a synthetic TLR3 ligand, was used to stimulate hRPTECs. mRNA expression was measured using reverse transcription-quantitative polymerase chain reaction. Protein expression was assayed using western blotting or an enzyme-linked immunosorbent assay. Knockdown of IFN-β, nuclear factor-kappa B (NF-κB) p65, and CYLD was performed by transfecting cells with specific small interfering RNAs. The intracellular localization of CYLD in hRPTECs was analyzed using immunofluorescence. Poly IC induced CCL5 expression in a time- and concentration-dependent manner, and knockdown of either IFN-β or p65 reduced poly IC-induced CCL5 expression. CYLD knockdown increased the poly IC-induced CCL5, phosphorylated IκB kinase α/β (IKK complex), and phosphorylated p65 expression. The CYLD protein was localized in the cytoplasm, and poly IC did not alter its expression., Conclusion: CYLD may prevent excessive inflammation due to an antiviral innate immune response by suppressing IKK complex and NF-κB activation downstream of TLR3 in hRPTECs., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). Repulsive guidance molecule a (RGMa) has been indicated to act as a bone morphogenetic protein (BMP) co‑receptor, enhancing BMP signalling activity. However, the role and downstream pathways of the BMP signalling pathway mediated by RGMa have yet to be fully elucidated. A recent study revealed that C‑C motif chemokine ligand 5 (CCL5) has a major role in the pathogenesis of MS via the recruitment of macrophages and T‑lymphocytes into the CNS. The present study aimed to evaluate whether RGMa regulates CCL5 via the BMP pathway in MS. The results demonstrated that RGMa regulated CCL5 expression in a BMP ligand‑dependent manner in experimental autoimmune encephalomyelitis (EAE) mice in vivo and in endothelial cells in vitro . First, specific inhibition of the expression of RGMa via RNA interference led to a significant reduction of the expression of RGMa and this was associated with a significant delay of EAE, an alleviated disease course and downregulation of CCL5 expression at both the protein and mRNA levels. Furthermore, exogenous noggin, an extracellular antagonist of BMP ligand, abolished the induction effect of RGMa on CCL5 in endothelial cells. Taken together, these results suggested that RGMa is an important regulator of MS and inflammatory mediators such as CCL5, and the present results should prove to be useful in terms of further elucidating the RGMa‑BMP receptor signalling pathway and the pathogenesis of RGMa on MS as far as the involvement of blood‑brain barrier permeability is concerned.

Objective: MicroRNA (miR)-147a acts as an inhibitory miRNA in many cancers. However, its potential roles in non-small-cell lung cancer (NSCLC) remain unclear., Methods: Levels of miR-147a and C-C motif chemokine ligand 5 (CCL5) were measured using a quantitative real-time PCR assay. Cell growth, migration, and invasion of NSCLC cells were assessed by colony formation, wound healing, and Transwell invasion assays, respectively. The role of miR-147a in the growth and metastatic ability of NSCLC in vivo was detected using a xenograft model and experimental lung metastasis model., Results: miR-147a was downregulated in NSCLC cell lines as well as in tissues. Gain-of-function and loss-of-function analyses demonstrated that upregulation of miR-147a decreased the aggressiveness of NSCLC cells in vitro . In addition, CCL5 was identified as a target of miR-147a. We also demonstrated the effect of miR-147a in the progression of NSCLC cells via targeting CCL5. Finally, the in vivo mouse xenograft model showed that miR-147a inhibited progression of NSCLC cells., Conclusions: Overall, expression of miR-147a was downregulated in NSCLC. Importantly, upregulation of miR-147a suppressed the growth and metastasis of NSCLC cells in vivo by targeting CCL5.

Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disorder with T cell-mediated immunological pathogenesis. C-C motif chemokine ligand 5 (CCL5) and its receptor C-C motif chemokine receptor 5 (CCR5) play important roles in the activation and recruitment of T cells. This study sought to explore the expression and biological functions of the CCL5-CCR5 axis in OLP. We examined the expression of the CCL5-CCR5 axis in the peripheral blood and oral tissue of healthy controls and patients with OLP using quantitative real-time PCR, Simple Western assays, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. In addition, we investigated the effects of the CCL5-CCR5 axis on the proliferation, apoptosis and migration of OLP T cells using Cell Counting Kit-8 (CCK8) assay, flow cytometry and transwell assay. We found that the expression of the CCL5-CCR5 axis was significantly elevated both in the peripheral blood and oral tissue of patients with OLP compared with healthy controls. CCL5 not only promoted OLP T-cell proliferation and migration but also inhibited OLP T-cell apoptosis. Moreover, CCR5 inhibition suppressed OLP T-cell proliferation and migration, whereas OLP T-cell apoptosis was promoted. In conclusion, our data suggest that the CCL5-CCR5 axis may be closely related to the inflammatory infiltration of T cells in OLP., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)