Immunoregulatory mechanisms of microRNAs during Clostridium difficile infection

Viladomiu Pujol, M., R. Hontecillas, K. Michalak, C. Philipson, E. Schiff, A. Carbo, P. Michalak, and J. Bassaganya-Riera, (2014) Immunoregulatory mechanisms of microRNAs during Clostridium difficile infection. Abstract Immunology 2014 (AAI) conference, Pittsburgh, Pennsylvania. J.Immunol.

MicroRNAs are small non-coding RNA molecules that play pivotal roles in the development and functionality of innate and adaptive immune cells, making them essential during the regulation of bacterial, viral and other immune infections. The role of miRNAs during host-pathogen interactions has recently been highlighted. However, the mechanisms by which miRNAs exert immunoregulatory actions are poorly understood. Our aim is to investigate the impact of Clostidium difficile infection (CDI) on host regulatory and effector pathways by focusing on the disruption of mucosal homeostasis by miRNAs. Sequencing studies on colonic samples and mucosal CD4+ T cells revealed a consistent upregulation of miR146b during CDI in mice, which correlated with worsened disease severity and upregulated MCP-1, IL-1b, IL-6 and IL-17. Moreover, upregulation of miR146b correlated with increased levels of Th17 cells in the spleen, MLN and colonic lamina propria of CDI mice, while abrogating anti-inflammatory responses characterized by IL-10 production. In vivo miR146b inhibition by using locked nucleic acid resulted in accelerated recovery as well as a significant induction of IL-10 production by CD4+, CD8+ and NK T cells and reduced expression of IL-17 by CD4+RORgt+ T cells. C. difficile infection induces upregulation of miR146b at the gut mucosa that contributes to pathogenic Th17 responses and impared immunoregulation.