MiR-146a negatively regulates dectin-1-induced inflammatory responses.

Leilei Du,Caixia Liu,Rong Zeng,Qing Chen,Zhimin Duan,Min Li,Xu Chen

doi:10.18632/oncotarget.16958

Abstract

Dectin-1 is the critical sensor for β-glucan from Candida which is the most common human fungal pathogen and cause superficial and system infection. MicroRNAs (miRNAs) play crucial roles in regulating innate immunity. However, the functional role of miRNAs in inflammatory response dependent on the activation of dectin-1 pathway has not been defined. In the present study, we found insoluble β-glucan from the cell wall of Candida albicans (CaIG) was able to increase the production of of IL-6 and TNFα through Dectin-1-Syk-NF-κB and p38MAPK pathway. MiRNAs profiles combined with real-time PCR validation revealed that miR-146a, miR-30-5p, miR-210-3p expression level were increased in THP-1 cells treated with CaIG. The interaction between Dectin-1 and CaIG resulted in an long lasting increase of miR-146a expression dependent on Dectin-1-Syk-NF-κB, p38MAPK, contrasting with a rapid and transient increase of IL-6 and TNFα. Overexpression of miR-146a significantly suppressed the production of IL-6 and TNFα. MiR-146a mimics inhibited CaIG-induced activity of p-IκBα and translocation of NF-κB p65. Luciferase reporter assays showed miR-146a inhibited NF-κB promoter-binding activity. Together, our data suggest miR-146a may play the potent negative feedback regulator in inflammatory response following Dectin-1 stimulation.

Highlights

Candida species are most common cause of opportunistic fungal pathogens infections
Our previous report showed that CaIG, the highly branched polymers of D-glucose containing β-(1,3) and β-(1,6) linkage isolated from C. albicans cell wall, induced the production of cytokine and chemokine (TNF-α and IL-8) and H2O2 release [24]
We further demonstrated that CaIG as a dectin-1 ligand was able to trigger www.impactjournals.com/oncotarget activation of dectin-1 downstream signal molecules including spleen tyrosine kinase (Syk), NF-κB and p38MAPK, upregulate secretion of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) in the dectin-1-Syk-NF-κB and p38MAPK signaling pathway dependent manner

Summary

Introduction

Candida species are most common cause of opportunistic fungal pathogens infections. As a result of the growing number of immunosuppressive population over the recent decade, the incidence of life-threatening invasive Candida infections has dramatically increased. Innate immune system including neutrophils, monocytes, macrophages and dendritic cells constitute the first line of host defense against Candida infection. Candida cell walls are mainly composed of β-glucan, mannan and chitin. Recognition of these polysaccrides by pattern-recognition receptors (PRRs) leads to the activation of innate immune responses. Toll-like receptors (TLRs) TLR2 and 4, C-type lectin receptors (CLRs) including dectin-1, dectin-2, mannose receptor (MR), DC-SIGN, Galectin-3 and Mincle are sensors for Candida invasion [5,6,7,8,9,10,11,12,13,14]. The interaction between Dectin-1 and β-glucan can trigger two intracellular signaling transduction pathways, the spleen tyrosine kinase (Syk)-caspase recruitment domaincontaining protein 9 (CARD9) pathway and the RAF pathway [15,16,17,18]

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Results

Conclusion