Stat6-Dependent Inhibition of Mincle Expression in Mouse and Human Antigen-Presenting Cells by the Th2 Cytokine IL-4.

Thomas Hupfer,Jenny Ostrop,Katrin Jozefowski,Judith Schick,David Voehringer,Roland Lang

doi:10.3389/fimmu.2016.00423

Abstract

The C-type lectin receptors (CLRs) Mincle, Mcl, and Dectin-2 bind mycobacterial and fungal cell wall glycolipids and carbohydrates. Recently, we described that expression of these CLR is downregulated during differentiation of human monocytes to dendritic cells (DC) in the presence of GM-CSF and IL-4. Here, we demonstrate that the Th2 cytokine IL-4 specifically inhibits expression of Mincle, Mcl, and Dectin-2 in human antigen-presenting cells (APC). This inhibitory effect of IL-4 was observed across species, as murine macrophages and DC treated with IL-4 also downregulated these receptors. IL-4 blocked upregulation of Mincle and Mcl mRNA expression and cell surface protein by murine macrophages in response to the Mincle ligand Trehalose-6,6-dibehenate (TDB), whereas the TLR4 ligand LPS overcame inhibition by IL-4. Functionally, downregulation of Mincle expression by IL-4 was accompanied by reduced cytokine production upon stimulation with TDB. These inhibitory effects of IL-4 were dependent on the transcription factor Stat6. Together, our results show that the key Th2 cytokine IL-4 exerts a negative effect on the expression of Mincle and other Dectin-2 cluster CLR in mouse and human macrophages and DC, which may render these sentinel cells less vigilant for sensing mycobacterial and fungal ligands.

Highlights

Following the identification of Dectin-1 as a Syk-coupled activating receptor for bacterial and fungal beta-glucans 15 years ago [1], C-type lectin receptors (CLRs) have received increasing attention as pattern recognition receptors of the innate immune system
In our recent characterization of CLR expression on primary human antigen-presenting cells, we observed higher expression of MINCLE mRNA in macrophages generated with M-CSF or GM-CSF compared to dendritic cells (DC) differentiated in the presence of GM-CSF plus IL-4 [28]
Quantitative RT-PCR analysis of mRNA expression for a range of CLR showed that the reduced expression in DC compared to GM-CSF-derived macrophages was selectively observed for MINCLE, MCL, DECTIN2, and CLEC12A whereas expression levels of the other tested CLR were not significantly different (Figure 1B)

Summary

Introduction

Following the identification of Dectin-1 as a Syk-coupled activating receptor for bacterial and fungal beta-glucans 15 years ago [1], C-type lectin receptors (CLRs) have received increasing attention as pattern recognition receptors of the innate immune system. The CLR Dectin-2, Mincle, and Mcl belong to the so-called Dectin-2 family with their genes adjacent to each other in the NK cell receptor gene cluster, localized on human chromosome 12 and mouse chromosome 6 [2]. These three receptors recognize mycobacterial and/or fungal ligands, are expressed constitutively or inducibly on innate immune cells, and have an emerging role in innate immunity to these infections. Dectin-2 (gene symbol Clec4n in mice, CLEC6A in humans) has a classical C-type lectin domain that binds structures with high mannose content from numerous pathogens, most notably Candida albicans [15, 16], and mycobacterial manLAM [17] and schistosomal egg antigen [18]

Methods

Results

Conclusion