Abstract
Inflammation is a double-edged sword that can be induced by various PAMPs, resulting in the control of infection by invading pathogens or injuries. The inflammatory response requires strict and precise control and regulation. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression via translational inhibition or mRNA degradation. However, the role of miRNAs in inflammation induced by flagellin (ligand of TLR5) has yet to be fully determined. In this study, we identified differentially expressed miRNAs in murine bone marrow-derived dendritic cells (BMDCs) between flagellin treatment and medium alone using miRNA microarray. We found that flagellin stimulation downregulated miR-5112 expression in BMDCs and spleen DCs in vitro and in vivo. The overexpression of miR-5112 decreased inflammatory cytokine production, accompanied by a reduction of IKKγ in flagellin-stimulated BMDCs. We demonstrated that miR-5112 could directly target IKKγ to inhibit inflammatory cytokine production. Furthermore, miR-5112 inhibited the inflammatory response induced by flagellin or Salmonella infection in vivo. Interestingly, miR-5112 could also dampen the inflammatory response and alleviate dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice. These results suggest that miR-5112 could be a novel therapeutic target for both bacterial infection and DSS-induced colitis model.
Highlights
Inflammation plays an important role in the control of pathogens, and it can be triggered by the recognition of pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs)
The mean fluorescence intensity (MFI) associated with CD40 significantly increased in proportion to the percentage of positive cells in bone marrow-derived dendritic cells (BMDCs) treated with flagellin (P < 0.05) (Figure S2B)
We further validated the expression of the four miRNAs using Quantitative real-time PCR (qRT-PCR), and the results showed that the expression of miR-5112 and miR-193-5p was significantly downregulated in the flagellin-treated BMDCs (3.23- and 1.99fold change, respectively) compared to the medium control (Figure 1B), which was consistent with the array data
Summary
Inflammation plays an important role in the control of pathogens, and it can be triggered by the recognition of pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs). A family of Toll-like receptor (TLR) members of PRRs act as primary sensors that detect a wide variety of microbial components and elicit inflammatory responses [1]. TLR5, expressed on miR-5112 Regulates Inflammatory Response various immune cells, including macrophages, dendritic cells (DCs), can recognize flagellin, which is the major structural protein of bacterial flagella. TLR5 triggers the MyD88-dependent signaling pathway and activates nuclear factor kB (NF-kB), leading to the production of proinflammatory cytokines or chemokines to defend against invading bacteria [2, 3]. Inflammation can defend against invading bacteria, it is a double-edged sword. There is a need for inflammation induced by TLR signaling pathways to be tightly regulated and precisely controlled
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