targeted-knockdown-of-genes-in-the-choroid-plexus

Targeted Knockdown of Genes in the Choroid Plexus

The choroid plexus (ChP) serves as a critical gateway for immune cell infiltration into the central nervous system (CNS) under both physiological and ...

Wenzhou Medical University

The choroid plexus (CP) is one of the key gateways regulating the entry of peripheral immune cells into the CNS. However, the neuromodulatory mechanisms of maintaining its gateway activity are not fully understood. Here, we identified adenosine A receptor (AR) activity as a regulatory signal for the activity of CP gateway under physiological conditions. In association with a tightly closed CP gateway, we found that AR was present at low density in the CP. The RNA-seq analysis revealed that the AR antagonist KW6002 affected the expression of the cell adhesion molecules' (CAMs) pathway and cell response to IFN-γ in the CP. Furthermore, blocking or activating AR signaling in the CP resulted in a decreased and an increased, respectively, expression of lymphocyte trafficking determinants and disruption of the tight junctions (TJs). Furthermore, AR signaling regulates the CP permeability. Thus, AR activity in the CP may serve as a therapeutic target for remodeling the immune homeostasis in the CNS with implications for the treatment of neuroimmunological disorders.

Adenosine A receptor controls the gateway of the choroid plexus.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory infiltration and demyelination in the central nervous system (CNS). IFN-gamma (IFN-γ), a critically important immunomodulator, has been widely studied in MS pathology. The confusing and complex effects of IFN-γ in MS patients and rodent models, however, cause us to look more closely at its exact role in MS. In this study, we identified the role of the IFN-γ signaling in the choroid plexus (CP) in the experimental autoimmune encephalomyelitis (EAE) model. We found that the IFN-γ signal was rapidly amplified when CNS immune cell infiltration occurred in the CP during the progressive stage. Furthermore, using two CP-specific knockdown strategies, we demonstrated that blocking the IFN-γ signal via knockdown of IFN-γR1 in the CP could protect mice against EAE pathology, as evidenced by improvements in clinical scores and infiltration. Notably, knocking down IFN-γR1 in the CP reduced the local expression of adhesion molecules and chemokines. This finding suggests that IFN-γ signaling in the CP may participate in the pathological process of EAE by preventing pathological T helper (Th) 17 cells from infiltrating into the CNS. Finally, we showed that the unbalanced state of IFN-γ signaling between peripheral lymphocytes and the choroid plexus may determine whether IFN-γ has a protective or aggravating effect on EAE pathology. Above all, we discovered that IFN-γR1-mediated IFN-γ signaling in the CP was a vital pathway in the pathological process of EAE.

Yuwen Yang

State Key Laboratory of Ophthalmology,
Optometry and Visual Science,
Eye Hospital,
State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital

Wenzhou Medical University

Targeted Knockdown of Genes in the Choroid Plexus

Yuwen Yang

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}State Key Laboratory of Ophthalmology,Optometry and Visual Science,Eye Hospital,State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital

Wenzhou Medical University

Targeted Knockdown of Genes in the Choroid Plexus

State Key Laboratory of Ophthalmology,
Optometry and Visual Science,
Eye Hospital,
State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital