MicroRNA-mediated inflammatory responses induced by Cryptococcus neoformans are dependent on the NF-κB pathway in human monocytes

Cryptococcosis is a significant invasive fungal infection with noteworthy morbidity and mortality that is usually caused by either Cryptococcus neoformans (C. neoformans) or Cryptococcus gattii (C. gattii). Epidemiological studies have indicated that C. neoformans are more often reported in immunocompromised and immunocompetent patients. It has been well established that the cytokine profile of the host markedly affects the outcome of cryptococcal disease, and the negative regulators of microRNAs(miRs or miRNAs) are critically important for immunomodulation. However, the role of miRNAs and the molecular basis of the inflammatory response induced by C. neoformans in monocytes remain unknown. In this study, we identified 7 differentially expressed miRNAs in THP-1 cells exposed to C. neoformans by Illumina sequencing, and confirmed our findings by RT-qPCR. Furthermore, miR-146a was selected for further analysis to identify the regulatory mechanisms of inflammation induced by C. neoformans. An examination of the function of miR-146a in monocytes was performed by overexpressing and inhibiting miR-146a. In addition, we identified a pattern of induction in response to a variety of microbial components and pro-inflammatory cytokines. Our data suggested that the nuclear factor-kappa B (NF-kappa B) pathway was required for the induction of miR-146a, whereas miR-146a negatively regulated NF-kappa B activation by targeting interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor associated factor 6 (TRAF6), then inhibiting NF-kappa B activation and the release of inflammatory cytokines in monocytes induced by C. neoformans.