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Published on: May 22, 2014
MicroRNA-mediated inflammatory responses induced by Cryptococcus neoformans are dependent on the NF-κB pathway in
Hong Chen1, Yi Jin1, Huan Chen2
1Department of Dermatology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China.
Abstract:
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-κB (NF-κB) pathway was required for the induction of miR‑146a, whereas miR‑146a negatively regulated NF-κB activation by targeting interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor associated factor 6 (TRAF6), then inhibiting NF-κB activation and the release of inflammatory cytokines in monocytes induced by C. neoformans.
Insights
MicroRNAs regulate inflammation in Cryptococcus neoformans infections. This study found miR-146a inhibits the NF-κB pathway, reducing inflammatory cytokine release in monocytes during cryptococcosis.
Area of Science:
- Mycology
- Immunology
- Molecular Biology
Background:
- Cryptococcosis, caused by Cryptococcus neoformans (C. neoformans) and Cryptococcus gattii (C. gattii), is a serious fungal infection with high morbidity and mortality.
- Host cytokine profiles significantly influence cryptococcal disease outcomes, with microRNAs (miRNAs) playing a key role in immunomodulation.
- The specific roles of miRNAs and the molecular basis of C. neoformans-induced inflammation in monocytes are not well understood.
Purpose of the Study:
- To investigate the role of differentially expressed miRNAs in monocytes upon exposure to C. neoformans.
- To elucidate the molecular mechanisms underlying C. neoformans-induced inflammatory responses in monocytes, focusing on miR-146a.
- To identify the regulatory pathway involving miR-146a in the context of C. neoformans infection.
Main Methods:
- Illumina sequencing to identify differentially expressed miRNAs in THP-1 cells exposed to C. neoformans.
- RT-qPCR validation of miRNA expression.
- Functional analysis of miR-146a by overexpression and inhibition in monocytes.
- Investigation of the nuclear factor-κB (NF-κB) pathway and its interaction with miR-146a.
Main Results:
- Seven differentially expressed miRNAs were identified in THP-1 cells after C. neoformans exposure.
- miR-146a was found to be induced by C. neoformans and regulated by the NF-κB pathway.
- miR-146a negatively regulated NF-κB activation by targeting IRAK1 and TRAF6.
- Overexpression of miR-146a inhibited NF-κB activation and subsequent inflammatory cytokine release.
Conclusions:
- miR-146a plays a crucial role in modulating the inflammatory response to C. neoformans in monocytes.
- The NF-κB pathway is essential for miR-146a induction, and miR-146a, in turn, acts as a negative feedback regulator of this pathway.
- Targeting the miR-146a/NF-κB axis presents a potential therapeutic strategy for managing cryptococcal infections.
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