miR-181a-5p Regulates TNF-α and miR-21a-5p Influences Gualynate-Binding Protein 5 and IL-10 Expression in Macrophages Affecting Host Control of Brucella abortus Infection

Abstract

Brucella abortus is a Gram-negative intracellular bacterium that causes a worldwide zoonosis termed brucellosis, which is characterized as a debilitating infection with serious clinical manifestations leading to severe complications. In spite of great advances in studies involving host–B. abortus interactions, there are many gaps related to B. abortus modulation of the host immune response through regulatory mechanisms. Here, we deep sequenced small RNAs from bone marrow-derived macrophages infected with B. abortus, identifying 69 microRNAs (miRNAs) that were differentially expressed during infection. We further validated the expression of four upregulated and five downregulated miRNAs during infection in vitro that displayed the same profile in spleens from infected mice at 1, 3, or 6 days post-infection. Among these miRNAs, mmu-miR-181a-5p (upregulated) or mmu-miR-21a-5p (downregulated) were selected for further analysis. First, we determined that changes in the expression of both miRNAs induced by infection were dependent on the adaptor molecule MyD88. Furthermore, evaluating putative targets of mmu-miR-181a-5p, we demonstrated this miRNA negatively regulates TNF-α expression following Brucella infection. By contrast, miR-21a-5p targets included a negative regulator of IL-10, programmed cell death protein 4, and several guanylate-binding proteins (GBPs). As a result, during infection, miR-21a-5p led to upregulation of IL-10 expression and downregulation of GBP5 in macrophages infected with Brucella. Since GBP5 and IL-10 are important molecules involved in host control of Brucella infection, we decided to investigate the role of mmu-miR-21a-5p in bacterial replication in macrophages. We observed that treating macrophages with a mmu-miR-21a-5p mimic enhanced bacterial growth, whereas transfection of its inhibitor reduced Brucella load in macrophages. Taken together, the results indicate that downregulation of mmu-miR-21a-5p induced by infection increases GBP5 levels and decreases IL-10 expression thus contributing to bacterial control in host cells.

Neonatal Diet Impacts Circulatory miRNA Profile in a Porcine Model

“…miR-181 also plays a role in inflammation. It has been shown to downregulate production of TNF-α in Brucella abortus infections (39). These data, along with ours, suggest that breastmilk miRs are likely involved in protecting infants in modulating the immune system (i.e., to reduce inflammation by infection and to impact T-cell maturation).…”

Guanylate-binding protein 5 licenses caspase-11 for Gasdermin-D mediated host resistance to Brucella abortus infection

“…These findings suggest that GBP5 is the molecule responsible for the phenotype observed in GBP chr3 KO mice related to caspase-11 recognition of Brucella LPS. More recently, our research group identified that miR-21a-5p led to downregulation of GBP5 expression in macrophages infected with Brucella and increased bacterial counts in macrophages [67]. This study highlights the importance of GBP5 regulation by a miRNA in macrophage susceptibility to Brucella infection.…”

Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition

“…Experimental periodontitis using systemic microbial challenge (Porphyromonas gingivalis gavage) led to distinct patterns of inflammatory and epigenetic features [128]. miR-181a-5p and miR-21a-5p influenced the expression of inflammatory mediators in macrophages infected with Brucella abortus, thus contributing to bacterial control in host cells [129]. In addition, bacterial vaginosis predicted the length of gestation through miRNA-related epigenetic programming of the inflammatory response [130].…”