MiR-146a Ameliorates Hemoglobin-Induced Microglial Inflammatory Response via TLR4/IRAK1/TRAF6 Associated Pathways

Abstract

Microglial activation and sustained inflammation in the brain can lead to neuronal damage. Hence, limiting microglial activation and brain inflammation is a good therapeutic strategy for inflammatory-associated central nervous disease. MiR-146a is a promising therapeutic microRNA, since it can negatively regulate the inflammatory response. We thus investigated the expression changes of miR-146a after experimental induction of a subarachnoid hemorrhage (SAH) in vivo and in vitro, and we assessed the anti-inflammatory effects of miR-146a in microglial cells in vitro. Primary microglial cells were preincubated with miR-146a before hemoglobin (Hb) treatment. The results indicated that miR-146a decreased gene expression of Hb-induced pro-inflammatory cytokines (TNF-α and IL-1β) and phenotype-related genes (iNOS and CD86) through IRAK1/TRAF6/NF-κB or MAPK signaling pathways, suggesting its pro-resolution activity in microglia. However, contrary to the LPS-induced microglia or macrophage activation model, we did not observe an elevation in miR-146a after activation. Overall, our findings demonstrated that miR-146a was involved in the regulation of brain inflammation and could be considered a novel therapeutic agent for treating brain inflammation.

miRNA-146a and miRNA-202-3p Attenuate Inflammatory Response by Inhibiting TLR4, IRAK1, and TRAF6 Expressions in Rats following Spinal Cord Injury

“…In our study, we found that upregulation of miRNA-146a could inhibit expressions of TLR4, IRAK1, and TRAF6 at mRNA and protein levels. Consistent with our results, Liu et al demonstrated that miR-146 could attenuate microglial inflammatory response through TLR4/ IRAK1/TRAF6-related pathways [30]. Additionally, the TLR4/IRAK1/TRAF6 axis was revealed in our work, as 11 Journal of Nanomaterials evidenced by results of IRAK1 and TRAF6 inhibition after TLR4 knockdown and TRAF6 inhibition after IRAK1 knockdown, concurring with other studies [31,32].…”

Decreased serum levels of the inflammaging marker miR-146a are associated with clinical non-response to tocilizumab in COVID-19 patients

“…MiR-146a-5p is of particular interest, given its ability to induce a negative feedback loop that restrains the activation of the NF-κB pathway by targeting TNF receptor associated factor 6 (TRAF6) and Interleukin-1 receptor-associated kinase 1 (IRAK1). The pivotal role of miR-146a-5p has been reported in a number of cell types that orchestrate the inflammatory response, including endothelial cells ( Mensà et al, 2019 ; Olivieri et al, 2013a ), microglial cells ( Liu et al, 2020b ), monocytes and macrophages, ( Li et al, 2015 ; Zhou et al, 2019 ), and adipocytes ( Roos et al, 2016 ). Recently, a reduced expression of miR-146a-5p was observed in a subgroup of patients affected by acute myeloid leukemia with inflammaging and poor outcome ( Grants et al, 2020 ).…”

Decreased serum levels of inflammaging marker miR-146a are associated with clinical response to tocilizumab in COVID-19 patients

“…MiR-146a-5p is of particular interest, given its ability to induce a negative feedback loop that restrains the activation of the NF-κB pathway by targeting TNF receptor associated factor 6 (TRAF6) and Interleukin-1 receptor-associated kinase 1 (IRAK1). The pivotal role of miR-146a-5p has been reported in a number of cell types that orchestrate the inflammatory response, including endothelial cells (Mensà et al, 2019; Olivieri et al, 2013a), microglial cells (Liu et al, 2020b), monocytes and macrophages, (Li et al, 2015; Zhou et al, 2019), and adipocytes (Roos et al, 2016). Recently, a reduced expression of miR-146a-5p was observed in a subgroup of patients affected by acute myeloid leukemia with inflammaging and poor outcome (Grants et al, 2020).…”