The Roles and Perspectives of Toll-Like Receptors and CD4 + Helper T Cell Subsets in Acute Viral Encephalitis

Choi

et al. 2015

Sci Rep

Self Cite

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.

Section: Resultsmentioning

confidence: 99%

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

Choi

et al. 2015

Sci Rep

Self Cite

“…Pathologically, JE is a severe neuroinflammation in the central nervous system (CNS) closely associated with the disruption of the blood–brain barrier (BBB) [ 7 ]. Although little is known about the pathogenesis of JEV, considerable progress has been made in murine models [ 8 , 9 ]. While JEV infects and kills neurons directly in the CNS, CNS invasion of JEV causes the stimulation of microglia/glia and infiltrated leukocytes, leading to indirect neuronal killing via over-secreting pro-inflammatory cytokines (such as IL-6 and TNF-α) and soluble mediators that can induce neuronal death [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

CCR5 ameliorates Japanese encephalitis via dictating the equilibrium of regulatory CD4+Foxp3+ T and IL-17+CD4+ Th17 cells

Patil

Choi

et al. 2016

J Neuroinflammation

Self Cite

BackgroundCCR5 is a CC chemokine receptor involved in the migration of effector leukocytes including macrophages, NK, and T cells into inflamed tissues. Also, the role of CCR5 in CD4+Foxp3+ regulatory T cell (Treg) homing has recently begun to grab attention. Japanese encephalitis (JE) is defined as severe neuroinflammation of the central nervous system (CNS) following infection with mosquito-borne flavivirus JE virus. However, the potential contribution of CCR5 to JE progression via mediating CD4+Foxp3+ Treg homing has not been investigated.MethodsInfected wild-type (Ccr5+/+) and CCR5-deficient (Ccr5−/−) mice were examined daily for mortality and clinical signs, and neuroinflammation in the CNS was evaluated by infiltration of inflammatory leukocytes and cytokine expression. In addition, viral burden, NK- and JEV-specific T cell responses were analyzed. Adoptive transfer of CCR5+CD4+Foxp3+ Tregs was used to evaluate the role of Tregs in JE progression.ResultsCCR5 ablation exacerbated JE without altering viral burden in the extraneural and CNS tissues, as manifested by increased CNS infiltration of Ly-6Chi monocytes and Ly-6Ghi granulocytes. Compared to Ccr5+/+ mice, Ccr5−/− mice unexpectedly showed increased responses of IFN-γ+NK and CD8+ T cells in the spleen, but not CD4+ T cells. More interestingly, CCR5-ablation resulted in a skewed response to IL-17+CD4+ Th17 cells and correspondingly reduced CD4+Foxp3+ Tregs in the spleen and brain, which was closely associated with exacerbated JE. Our results also revealed that adoptive transfer of sorted CCR5+CD4+Foxp3+ Tregs into Ccr5−/− mice could ameliorate JE progression without apparently altering the viral burden and CNS infiltration of IL-17+CD4+ Th17 cells, myeloid-derived Ly-6Chi monocytes and Ly-6Ghi granulocytes. Instead, adoptive transfer of CCR5+CD4+Foxp3+ Tregs into Ccr5−/− mice resulted in increased expression of anti-inflammatory cytokines (IL-10 and TGF-β) in the spleen and brain, and transferred CCR5+ Tregs were found to produce IL-10.ConclusionsCCR5 regulates JE progression via governing timely and appropriate CNS infiltration of CD4+Foxp3+ Tregs, thereby facilitating host survival. Therefore, this critical and extended role of CCR5 in JE raises possible safety concerns regarding the use of CCR5 antagonists in human immunodeficiency virus (HIV)-infected individuals who inhabit regions in which both HIV and flaviviruses, such as JEV and West Nile virus, are endemic.

Trends in Infectious Diseases

“…JE is caused due to infection with the JE virus (JEV), a mosquito borne flavivrus. The main JEV transmission cycle involves Culex tritaeniorhynchus mosquitoes and similar species that lay eggs in rice paddies and other open water resources, with pigs and aquatic birds as principal vertebrate amplifying hosts [Han et al, 2012]. Humans are generally considered as dead-end JEV hosts i.e.…”

Section: Introductionmentioning

confidence: 99%

Japanese Encephalitis: A Neglected Viral Disease and Its Impact on Global Health

Saxena¹,

Agrawal²,

Nair³

2014