Abstract
AbstractAcute primary angle closure (APAC) is a disease of ophthalmic urgency; lack of treatment can lead to blindness. Even after adequate treatment for APAC, subsequent elevated acute intraocular pressure induces severe neuronal damage which can result in secondary glaucomatous optic neuropathy (GON). Damage-associated molecular patterns (DAMPs) are released from damaged and dead neuronal cells, which induce secondary inflammatory changes and further tissue damage. Our hypothesis is that histone H2B (H2B), which is one of the DAMPs, is released from damaged cells in the development of GON after APAC treatment. Intravitreal injection of H2B induces neuronal cell death through toll-like receptor 4 (TLR4) expression, following the upregulation of inflammatory cytokine mRNAs and phosphorylation of mitogen activated protein kinases (MAPKs). Knockdown of TLR4 caused a reduction of H2B neurotoxicity in damaged cells through TLR4 signaling. Significantly increased H2B was observed in the vitreous cells of APAC patients. In addition, enhanced H2B protein correlated with decreased ganglion cell analysis and retinal ganglion cell (RGC) layer thinning, which indicates the effect of H2B on RGCs. Our data from clinical and animal studies show the involvement of H2B-TLR4 pathways in the development of GON after APAC treatment providing new insight for the mechanism of RGC degeneration.Increased levels of histone H2B (H2B), a damage-associated protein, are found in the vitreous of patients with acute primary angle closure. Elevated H2B causes severe inflammation and subsequent retinal ganglion cell death through toll-like receptor 4 (TLR4) signaling. These results provide new insight for the mechanism of retinal ganglia degeneration.
Highlights
Toll-like receptors (TLRs) are type I transmembrane proteins containing extracellular leucine-rich repeats (LRR) and cytoplasmic toll/intracellular interleukin (IL)-1 receptor (TIR) domains similar to that of the IL-1 receptor [1, 2]
Acute primary angle closure (APAC) induces relatively acute retinal ganglion cell (RGC) death, showing that the optical coherence tomography (OCT) finding confirms that RGC axonal damage in acute primary angle closure (APAC) patients is due to nerve fiber layer thinning at a relatively early period after APAC treatment [14]
This result implies that the effect of H2B predominantly occurred in the inner retina (Fig. 1a). These results were confirmed by immunoblot, showing that increased toll-like receptor 4 (TLR4) was observed in the retina after intravitreal injection of H2B (Fig. 1b)
Summary
Toll-like receptors (TLRs) are type I transmembrane proteins containing extracellular leucine-rich repeats (LRR) and cytoplasmic toll/intracellular interleukin (IL)-1 receptor (TIR) domains similar to that of the IL-1 receptor [1, 2]. Homo- or heterodimers of these components stimulate the production of several adapter molecules, including myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapter-inducing interferon-β (TRIF), and the TRIF-related adapter molecule (TRAM). Activation of TLRs. The pattern of RGC degeneration in glaucomatous optic neuropathy (GON) is varied. Chronic RGC degeneration is observed in most patient cases of open angle glaucoma (OAG) and normal tension glaucoma (NTG) [12]. Acute primary angle closure (APAC) induces relatively acute RGC death, showing that the optical coherence tomography (OCT) finding confirms that RGC axonal damage in APAC patients is due to nerve fiber layer thinning at a relatively early period after APAC treatment [14]. Several studies have established the mechanism of chronic RGC death in OAG and NTG, the mechanism for acute RGC death in APAC has not been completely resolved.
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