A corneo-retinal hypercitrullination axis underlies ocular injury to nitrogen mustard

• Published in: Experimental eye research Vol. 231; p. 109485
• Main Authors: Umejiego, Ezigbobiara, Paramo, Ricky, Zafiris, Alexander, Mullane, Elias, Bargagna-Mohan, Paola, Mohan, Royce
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2023
• Subjects: Animals; Apoptosis; Citrullination; Cornea - metabolism; Corneal and retinal response; Eye Injuries - chemically induced; Eye Injuries - metabolism; Gliosis - chemically induced; Gliosis - metabolism; Irritants - adverse effects; Irritants - metabolism; Mechlorethamine - toxicity; Mice; Mustard Gas - toxicity; Nitrogen mustard; Reactive gliosis; Retina; Retinal Diseases - chemically induced; Retinal Diseases - metabolism; Citrullination; Reactive gliosis; Corneal and retinal response; Nitrogen mustard; Apoptosis
• ISSN: 0014-4835; 1096-0007
• DOI: 10.1016/j.exer.2023.109485

The vesicant sulfur mustard (SM) is a chemical warfare agent that causes acute and chronic injury to the cornea and proximal anterior segment structures. Despite clinical evidence of SM-exposure causing unexplained retinal deficits, there have been no animal studies conducted to examine the retinal toxicity of this vesciant. The cardinal hallmark of retinal response to stressors or injury is the activation of reactive gliosis, a cellular process largely governed by Müller glia. Previously we showed that corneal exposure to sodium hydroxide elicits rapid induction of reactive gliosis and results in retinal degeneration in a dose-related manner. Based on this evidence, we hypothesized that the vesicant nitrogen mustard (NM), an analog of SM, may also elicit reactive gliosis. To test this idea, we developed a mouse model of NM ocular injury and investigated corneal and retinal effects focusing on citrullination, a posttranslational modification (PTM) of proteins. This PTM was recently linked to alkali injury and has also been shown to occur in retinal degenerative conditions. Here, we demonstrate that corneal exposure to 1% NM causes a synchronous activation of citrullination in both the cornea and retina with hypercitrullination becoming apparent temporally and manifesting with altered cellular expression characteristics. A key finding is that ocular citrullination occurs acutely as early as 1-h post-injury in both the cornea and retina, which underscores a need for expeditious interception of this acute corneal and retinal response. Moreover, exploiting dose response and temporal studies, we uncoupled NM-induced retinal citrullination from its induction of retinal gliosis. Our findings demonstrate that hypercitrullination is a common corneo-retinal mechanism that sensitizes the eye to NM injury and suggests that counteracting hypercitrullination may provide a suitable countermeasure to vesicant injury. [Display omitted] •We have developed a mouse model of nitrogen mustard to study ocular injury.•Corneal and retinal apoptosis is induced by nitrogen mustard.•Citrullination occurs acutely in both cornea and retina.•Retinal citrullination and gliosis are differentiated in a temporal and dose-dependent manner.•Chronic hypercitrullination remains elicited in cornea and retina.