CD11chi Dendritic Cells Regulate Ly-6Chi Monocyte Differentiation to Preserve Immune-privileged CNS in Lethal Neuroinflammation

Abstract

Although the roles of dendritic cells (DCs) in adaptive defense have been defined well, the contribution of DCs to T cell-independent innate defense and subsequent neuroimmunopathology in immune-privileged CNS upon infection with neurotropic viruses has not been completely defined. Notably, DC roles in regulating innate CD11b+Ly-6Chi monocyte functions during neuroinflammation have not yet been addressed. Using selective ablation of CD11chiPDCA-1int/lo DCs without alteration in CD11cintPDCA-1hi plasmacytoid DC number, we found that CD11chi DCs are essential to control neuroinflammation caused by infection with neurotropic Japanese encephalitis virus, through early and increased infiltration of CD11b+Ly-6Chi monocytes and higher expression of CC chemokines. More interestingly, selective CD11chi DC ablation provided altered differentiation and function of infiltrated CD11b+Ly-6Chi monocytes in the CNS through Flt3-L and GM-CSF, which was closely associated with severely enhanced neuroinflammation. Furthermore, CD11b+Ly-6Chi monocytes generated in CD11chi DC-ablated environment had a deleterious rather than protective role during neuroinflammation, and were more quickly recruited into inflamed CNS, depending on CCR2, thereby exacerbating neuroinflammation via enhanced supply of virus from the periphery. Therefore, our data demonstrate that CD11chi DCs provide a critical and unexpected role to preserve the immune-privileged CNS in lethal neuroinflammation via regulating the differentiation, function, and trafficking of CD11b+Ly-6Chi monocytes.

Critical roles of conventional dendritic cells in promoting T cell-dependent hepatitis through regulating natural killer T cells

“…To investigate the role of cDCs in hepatitis, age‐ and sex‐matched B6 wt and CD11c–DTR Tg mice were used. As expected, based on prior studies , a single injection of DT depleted approximately 90% of hepatic cDCs in CD11c–DTR mice (Fig. a).…”

“…Liver tissues at 12 h post-ConA treatment were fixed and embedded in paraffin for haematoxylin and eosin staining and one representative tissue staining is shown. 3 expected, based on prior studies [14,18,19,29], a single injection of DT depleted approximately 90% of hepatic cDCs in CD11c-DTR mice (Fig. 1a).…”

CCL2, but not its receptor, is essential to restrict immune privileged central nervous system‐invasion of Japanese encephalitis virus via regulating accumulation of CD11b+ Ly‐6Chi monocytes

“…A JEV Beijing-1 strain was obtained from Green Cross Research Institute (Suwon, Korea) and propagated in the mosquito cell line (C6/36) using Dulbecco's modified Eagle's medium supplemented with 2% fetal bovine serum, penicillin (100 U/ml), and streptomycin (100 U/ml). 26 The C6/36 cultures were infected with JEV Beijing-1 at a multiplicity of infection of 0Á1, and were incubated in a humidified CO 2 incubator for 1 hr at 28°C. After absorption, the inoculum was removed, and 7 ml of a maintenance medium containing 2% fetal bovine serum was added.…”

Exacerbation of Japanese Encephalitis by CD11chi Dendritic Cell Ablation Is Associated with an Imbalance in Regulatory Foxp3+ and IL-17+CD4+ Th17 Cells and in Ly-6Chi and Ly-6Clo Monocytes

“…altered features of CD11b + ly-6C lo monocytes in CD11c hi DCablated mice CD11c hi DC ablation induces the abnormal differentiation of inflammatory CD11b + Ly-6C hi monocytes and thereby exacerbates JE progression (18). Thus, we examined the differentiation of CD11b + Ly-6C lo monocytes in CD11c hi DC-ablated mice during JE progression.…”

“…in exacerbated JE progression. However, theoretically, it is conceivable that enhanced infiltration of IL-17 + CD4 + Th17 and inflammatory CD11b + Ly-6C hi monocytes in the CNS facilitates JE progression (18,26 aCKNOwleDgemeNTs This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MISP) (2015R1D1A3A01019213). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.…”