Elevated inflammatory
cytokines contribute to the pathogenesis of various
retinal diseases such as
diabetic retinopathy,
retinal vasculitis and
retinitis. However, the underlying mechanism of
retinal inflammation remains largely unknown. Recent studies demonstrated that
acetylcholinesterase (ACHE) is an inflammatory
indicator in central neural system. This study was aimed to dissect the role of ACHE in
retinal inflammation, and its mechanism of action.
Retinal inflammation was induced by
intravitreal injection of
tumor necrosis factor-α (TNF-α) in heterozygous ACHE knockdown mice (ACHE+/-) and wild type mice (ACHE+/+).
Donepezil, a well-known ACHE inhibitor, was administrated by daily gavage. Expression of ACHE and intercellular adherent molecule-1 (ICAM-1), infiltration of CD11b+ inflammatory cells,
retinal leukostasis and vascular leakage was determined in both ACHE+/- and ACHE+/+ mice. ARPE-19 cells, a human
retinal pigment epithelial cell line, were cultured for in vitro assay. Knockdown of ACHE was achieved by
lipofectamine-mediated
siRNA transfection and
pharmaceutical suppression of ACHE was manipulated by
donepezil. Cellular expression and distribution of ACHE,
ICAM-1, and phosphorylation of NF-κB, IκB and IKKα/β were detected by western-blot analysis or immunocytochemistry.
Retinal expression of ACHE was dramatically upregulated, in parallel with increased
ICAM-1 expression, enhanced
leukostasis and augmented CD11b+ inflammatory cell infiltration as well as vascular hyperpermeability in ACHE+/+ mice injected with TNF-α. However, TNF-α-injected ACHE+/- mice showed lower level of
ICAM-1, less
leukostasis and fewer infiltrated CD11b+ cells. Moreover, TNF-α-induced
retinal vascular leakage was significantly reduced in ACHE+/- mice. Similarly, TNF-α-induced
retinal inflammatory response were also attenuated by
donepezil intervention. In addition, TNF-α treatment resulted in significant induction of ACHE, upregulation of
ICAM-1 and nuclear translocation of NF-κB, phosphorylation of IκB and IKKα/β in ARPE-19 cells. However, inhibition of ACHE reduced TNF-α-induced phosphorylation of NF-κB, IκB and IKKα/β in ARPE-19 cells. The present study reveals a pivotal role of ACHE in
retinal inflammation. Inhibition of ACHE attenuates
retinal inflammation and
retinal leakage likely through suppressing NF-κB signaling activation.