MicroRNA-205-5b inhibits HMGB1 expression in LPS-induced sepsis

Abstract

Inflammatory cytokines belonging to high mobility group box (HMGB)1 play a key role in sepsis through yet unknown mechanisms. The inflammatory response is modulated by microRNAs (miRNAs or miRs) at multiple levels and is poorly understood. In this study, the regulation of HMGB1 by miRNAs was evaluated using 3-(2,4-dimethoxybenzylidene)anabaseine (GTS-21) to activate the cholinergic anti-inflammatory pathway (CAP) and decrease HMGB1 expression in RAW264.7 cells. Microarray-based miRNA expression profiling of RAW264.7 cells was used to screen target miRNAs through genetic screening, GO analysis and hierarchical clustering. The expression of miRNA targets in the serum, colon, spleen, livers and lungs of BALB/c mice was quantified by RT-qPCR. Serum protein levels were quantified by ELISA. Western blot analysis and RT-qPCR were used for verification in vitro. Using miRNA array analysis, we screened 3 miRNAs (miR‑205‑5b, miR‑196a and miR‑193b). Animal experiments with miR‑205‑5b indicated its high degree of expression in the serum, colon, spleen, liver and lungs following the downregulation of HMGB1 in the tissues. RAW264.7 cells transfected with miR‑205‑5b mimics downregulated HMGB1 protein expression, suggesting translational regulation. HMGB1 expression negatively correlated with miR‑205‑5b expression in LPS-induced sepsis. By contrast, HMGB1 expression in LPS-stimulated RAW264.7 cells was increased following transfection with miR‑205‑5b inhibitor. miR‑205‑5b is a critical mediator of cholinergic anti-inflammatory activity in late sepsis. The upregulation of miR‑205‑5b as a potential therapeutic target for the treatment of inflammatory diseases is a possible novel therapeutic strategy against late sepsis. The mechanisms involved include the by post-transcriptional suppression of HMGB1 in cells and tissues.

The involvement of regulatory non-coding RNAs in sepsis: a systematic review

“…Overexpression of miR-15a/16 in the LPS-treated murine macrophage RAW264.7 downregulated the expression of Toll-like receptor (TLR)4 and IL-1 receptor-associated kinase 1 (IRAK1), contributing to immunosuppressive phenotypes [53, 61]. Similarly, expression of miR-205-5b alleviates the expression of high mobility group box 1 (HMGB1) [62]. …”

Effects of nebulized N­‐acetylcystein on the expression of HMGB1 and RAGE in rats with hyperoxia‐­induced lung injury

“…HMGB1 is a nuclear transcription factor and it is also a late inflammatory mediator in the pathogenesis of sepsis and ARDS. HMGB1 mRNA is highly expressed in sepsis and mechanical ventilation‐induced lung injury in vivo (Wolfson, Mapes, & Garcia, ; Zhou, Wang, Li, LI, & SANG, ). Extracellular HMGB1 is mainly used as proinflammatory factors, involved in promoting inflammatory reactions, leukocyte aggregation, and other physiological processes, which can aggravate the progression of sepsis and acute lung injury (Entezari et al, ).…”

High-throughput and multi-dimensional omics approach uncovers a huaxian capsule to ameliorate the dysregulated expression profiling of severe sepsis rats

“…29 Another group showed that the upregulation of miR-205-5b is a potential therapeutic target for the treatment of sepsis. 30 A variety of miRNAs such as miR-150, miR-15a/16, miR-132, miR-122, and miR-27a as biomarkers, were described in the context of sepsis. [31][32][33][34][35][36] Importantly, our results demonstrated differential expression of 36 upregulated and 20 downregulated miRNAs in HXC treatment group compared with SS rats.…”

“…Zhou et al had showed that the upregulation of MicroRNA-205-5b as a potential therapeutic target for the treatment of sepsis. 26 Some evidence recently showed that the abnormal expression of miRNA is closely related with the occurrence and development of diseases. Therefore, the present study using high-throughput microRNA and metabolome expression proling method was conducted to investigate the metabolic mechanisms of HXC exerting its therapeutic effect in a model of SS.…”