Dendritic cell-derived nitric oxide inhibits the differentiation of effector dendritic cells.

Chuanping Si,Yuan Hu,Feihong Xu,Tianshu Wu,Kang Chen,Geming Lu,Ruihua Zhang,Garabet Yeretssian,Huabao Xiong,Hui Zhang,Peter Wei,Hua Tang

doi:10.18632/oncotarget.11361

Abstract

Dendritic cells (DCs) play a pivotal role in the development of effective immune defense while avoiding detrimental inflammation and autoimmunity by regulating the balance of adaptive immunity and immune tolerance. However, the mechanisms that govern the effector and regulatory functions of DCs are incompletely understood. Here, we show that DC-derived nitric oxide (NO) controls the balance of effector and regulatory DC differentiation. Mice deficient in the NO-producing enzyme inducible nitric oxide synthase (iNOS) harbored increased effector DCs that produced interleukin-12, tumor necrosis factor (TNF) and IL-6 but normal numbers of regulatory DCs that expressed IL-10 and programmed cell death-1 (PD-1). Furthermore, an iNOS-specific inhibitor selectively enhanced effector DC differentiation, mimicking the effect of iNOS deficiency in mice. Conversely, an NO donor significantly suppressed effector DC development. Furthermore, iNOS−/− DCs supported enhanced T cell activation and proliferation. Finally iNOS−/− mice infected with the enteric pathogen Citrobacter rodentium suffered more severe intestinal inflammation with concomitant expansion of effector DCs in colon and spleen. Collectively, our results demonstrate that DC-derived iNOS restrains effector DC development, and offer the basis of therapeutic targeting of iNOS in DCs to treat autoimmune and inflammatory diseases.

Highlights

The delicate immunological equilibrium between inflammation and tolerance is essential for the host to mount effective and controlled immune defense against noxious pathogens without causing destructive immunity against innocuous self-tissues or commensal microbes [1, 2]
Our result showed that inducible nitric oxide synthase (iNOS) expression on bone marrow-derived DCs (BMDCs) of WT mice with LPS/IFN-γ stimulation was significantly increased by intracellular staining of CD11b+CD11c+ BMDCs (Figure 1C)
We found that iNOS deficient mice showed normal development in T cells population and Dendritic cells (DCs) percentages compared with that in WT mice (Supplementary Figure S1B) and plasmacytoid dendritic cells maturation was affected treatment with nitric oxide (NO) in 7 days pDC culture in vitro (Supplementary Figure S3 and Supplementary Figure S4)

Summary

Introduction

The delicate immunological equilibrium between inflammation and tolerance is essential for the host to mount effective and controlled immune defense against noxious pathogens without causing destructive immunity against innocuous self-tissues or commensal microbes [1, 2]. Among the various immune cells, dendritic cells (DCs) are critical in processing and integrating various immunological cues to instruct the development of adaptive immunity. Effector DCs that secrete interleukin-12 (IL-12), tumor necrosis factor (TNF), IL-6 and interferon-γ (IFN-γ) can promote T helper (Th) cell differentiation into Th1, Th2 or Th17 effector subsets respectively, thereby tailoring adaptive immunity to effectively control and eradicate infections. Regulatory DCs that express IL-10, programmed cell death-1 (PD1), transforming growth factor-β (TGF-β) and argininase suppress effector T cell activation and promote regulatory T cell (Treg) differentiation to enforce immune tolerance to self and commensal antigens. Despite the knowledge of many DC-extrinsic signals that influence effector and regulatory DC differentiation, DC-intrinsic mechanisms that underlie the differentiation of effector and regulatory DC cells are poorly understood

Methods

Results

Conclusion