Mice Plasmacytoid Dendritic Cells Were Activated by Lipopolysaccharides Through Toll-Like Receptor 4/Myeloid Differentiation Factor 2.

Wei Zhang,Juyoung Hwang,Eun-Koung An,Jun-O Jin

doi:10.3389/fimmu.2021.727161

Abstract

Plasmacytoid dendritic cells (pDCs) are known to respond to viral infections. However, the activation of pDCs by bacterial components such as lipopolysaccharides (LPS) has not been well studied. Here, we found that pDCs, conventional dendritic cells (cDCs), and B cells express high levels of toll-like receptor 4 (TLR4), a receptor for LPS. Moreover, LPS could effectively bind to not only cDCs but also pDCs and B cells. Intraperitoneal administration of LPS promoted activation of splenic pDCs and cDCs. LPS treatment led to upregulation of interferon regulatory factor 7 (IRF7) and induced production of interferon-alpha (IFN-α) in splenic pDCs. Furthermore, LPS-dependent upregulation of co-stimulatory molecules in pDCs did not require the assistance of other immune cells, such as cDCs. However, the production levels of IFN-α were decreased in cDC-depleted splenocytes, indicating that cDCs may contribute to the enhancement of IFN-α production in pDCs. Finally, we showed that activation of pDCs by LPS requires the TLR4 and myeloid differentiation factor 2 (MD2) signaling pathways. Thus, these results demonstrate that the gram-negative component LPS can directly stimulate pDCs via TLR4/MD2 stimulation in mice.

Highlights

Lipopolysaccharides (LPS) are lipid polysaccharides present in the outer membrane of gram-negative bacteria and are known to stimulate the immune system [1, 2]
We observed that FITC-conjugated LPS could efficiently bind to plasmacytoid dendritic cell (pDC), conventional dendritic cell (cDC), and B cells (Figure 1C)
Our data indicate that pDCs express considerable levels of toll-like receptor 4 (TLR4) on their surface, and that LPS can bind to pDCs in mouse splenocytes

Summary

Introduction

Lipopolysaccharides (LPS) are lipid polysaccharides present in the outer membrane of gram-negative bacteria and are known to stimulate the immune system [1, 2]. The first signaling pathway depends on myeloid differentiation primary response 88 (MyD88) and induces to the secretion of inflammatory cytokines by activating nuclear transcription factor kB (NF-kB) in innate immune cells, whereas the second pathway is independent of MyD88 and mediates interferon regulatory factor 3 (IRF3) activation to induce type-I interferon (IFN) responses [8, 9]. TLR4 is the crucial receptor of the mammalian innate immune system and can be expressed by various types of immune cells [10]. It is highly expressed by antigenpresenting cells (APCs) such as macrophages, dendritic cells (DCs), and B cells [11]. After sensing LPS via TLR4, DCs undergo maturation and migration and show improved regulation of the adaptive immune responses [16, 17]

Methods

Results

Conclusion