Exacerbation of japanese encephalitis by CD11c^hi dendritic cell ablation is associated with an imbalance in regulatory foxp3⁺ and IL-17⁺CD4⁺ Th17 cells and in Ly-6C^hi and Ly-6C^lo monocytes

Japanese encephalitis (JE) is neuroinflammation characterized by uncontrolled infiltration of peripheral leukocytes into the central nervous system (CNS). We previously demonstrated exacerbation of JE following CD11c^hi dendritic cell (DC) ablation in CD11c-DTR transgenic mice. Moreover, CD11c^hi DC ablation led to abnormal differentiation of CD11b⁺Ly-6C^hi monocytes and enhanced permeability of the blood-brain barrier (BBB), resulting in promoting the progression of JE. Here, we examined changes in lymphoid and myeloid-derived leukocyte subpopulations associated with pro- and anti-inflammation during JE progression. The analyses of this study focused on regulatory CD4⁺Foxp3⁺ regulatory T cells (Tregs), IL-17⁺CD4⁺ Th17 cells, and CD11b⁺Ly-6C^hi and Ly-6C^lo monocytes. CD11c^hi DC ablation resulted in the accumulation of IL-17⁺CD4⁺ Th17 cells in the CNS, thereby leading to lower ratio of Tregs to Th17 cells. This result was corroborated by the higher expression levels of IL-17 and RORgT in CD4⁺ T cells from the brains of CD11c^hi DC-ablated mice. In addition, CD11c^hi DC-ablated mice showed higher frequency and total number of inflammatory CD11b⁺Ly-6C^hi monocytes, whereas CD11b⁺Ly-6C^lo monocytes were detected with lower frequency and total number in CD11c^hi DC-ablated mice. Furthermore, CD11c^hi DC ablation altered the phenotype and function of CD11b⁺Ly-6C^lo monocytes, resulting in lower levels of activation marker and anti-inflammatory cytokine (IL-10 and TGF-b) expression. Collectively, these results indicate that CD11c^hi DC ablation caused an imbalance in CD4⁺ Th17/Treg cells and CD11b⁺Ly-6C^hi/Ly-6C^lo monocytes in the lymphoid tissue and CNS during JE progression. This imbalanced orchestration of pro- and anti-inflammatory leukocytes following CD11c^hi DC ablation may contribute to the exacerbation of JE.