TLR7 activation by miR-21 promotes renal fibrosis by activating the pro-inflammatory signaling pathway in tubule epithelial cells

• Published in: Cell communication and signaling 2023-08, Vol.21 (1), p.1-215, Article 215
• Main Authors: Kim, Jeongwon, Ha, Sugyeong, Son, Minjung, Kim, Doyeon, Kim, Mi-Jeong, Kim, Bumseok, Kim, Donghwan, Chung, Hae Young, Chung, Ki Wung
• Format: Article
• Language: English
• Subjects: Cell culture; Chemokines; Epithelial cells; Experiments; Fibrosis; Hybridization; Inflammation; Kidney diseases; Kidneys; Macrophages; MicroRNAs; miR-21; miRNA; NF-κB protein; Physiology; Proteins; Renal fibrosis; Signal transduction; Therapeutic targets; TLR7; TLR7 protein; Toll-like receptors; Wound healing
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-023-01234-w

BackgroundToll-like receptor 7 (TLR7) is an endosomal TLR activated by single-stranded RNA, including endogenous microRNAs. Although TLR7 is known to promote inflammatory responses in pathophysiological conditions, its role in renal fibrosis has not been investigated. Here, we aim to investigate the inflammatory roles of TLR7 in kidney inflammation and fibrosis.MethodsTLR7 knockout mice (Tlr7 −/−) subjected to AD-induced kidney injury were utilized to examine the role of TLR7 in kidney fibrosis. To elucidate the role of TLR7 in renal epithelial cells, NRK52E rat renal tubule epithelial cells were employed.ResultsUnder fibrotic conditions induced by an adenine diet (AD), TLR7 was significantly increased in damaged tubule epithelial cells, where macrophages were highly infiltrated. TLR7 deficiency protected against AD-induced tubular damage, inflammation, and renal fibrosis. Under in vitro conditions, TLR7 activation increased NF-κB activity and induced chemokine expression, whereas TLR7 inhibition effectively blocked NF-κB activation. Furthermore, among the known TLR7 endogenous ligands, miR-21 was significantly upregulated in the tubular epithelial regions. In NRK52E cells, miR-21 treatment induced pro-inflammatory responses, which could be blocked by a TLR7 inhibitor. When the TLR7 inhibitor, M5049, was administered to the AD-induced renal fibrosis model, TLR7 inhibition significantly attenuated AD-induced renal inflammation and fibrosis.ConclusionsOverall, activation of TLR7 by endogenous miR-21 in renal epithelial cells contributes to inflammatory responses in a renal fibrosis model, suggesting a possible therapeutic target for the treatment of renal fibrosis.Video Abstract