Histone H2B induces retinal ganglion cell death through toll-like receptor 4 in the vitreous of acute primary angle closure patients

Acute 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.

• Publication year

  2020

• Venue

  Laboratory Investigation

• Publication date

  2020-04-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/s41374-020-0427-2PMID 32321985PMCID 7374083
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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