June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
SARM1 protects the cornea from sensory nerve degeneration and persistent severe inflammation in murine Herpes Stromal Keratitis (HSK)
Author Affiliations & Notes
  • Hongmin Yun
    Ophthalmology, Eye and Ear Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Kate L Carroll
    Ophthalmology, Eye and Ear Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Anthony St. Leger
    Ophthalmology, Eye and Ear Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Hongmin Yun None; Kate Carroll None; Anthony St. Leger None
  • Footnotes
    Support  NIH grants R01 EY026891 (AJS), P30 EY0898, the Eye & Ear Foundation of Pittsburgh and unrestricted grants from Research to Prevent Blindness Inc, New York, NY.
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 3831. doi:
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    • Get Citation

      Hongmin Yun, Kate L Carroll, Anthony St. Leger; SARM1 protects the cornea from sensory nerve degeneration and persistent severe inflammation in murine Herpes Stromal Keratitis (HSK). Invest. Ophthalmol. Vis. Sci. 2022;63(7):3831.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : HSK is a blinding corneal disease caused by herpes simplex virus type 1 (HSV-1) infection, which manifests in both humans and mice as corneal opacity, neovascularization, and hypoesthesia. The replacement of corneal sensory nerves with sympathetic nerves in murine HSK plays a central role in maintaining the severe and persistent inflammation in the cornea. Here, we identify sterile apha and TIR motif containing 1 (SARM1) as a host factor that is critical for maintaining corneal nerve homeostasis after HSV-1 infection. Conventionally, SARM1 is expressed in neurons and is responsible for axonal degradation after insult or injury. In this study, we provide evidence that SARM1 acts intrinsically on immune and neuronal cells to prevent HSK.

Methods : SARM1-/- and litter mate wild-type (WT) mice were infected with HSV-1 KOS strain and were monitored for corneal opacity, neovascularization, and blink reflex. SARM1 gene expression in various tissues was assessed by qPCR. At 7dpi and 14 dpi, immune cell infiltration of the cornea was measured by flow cytometry. To assess the intrinsic effect of SARM1 on monocytes, BM derived myeloid cells were infected with HSV-1 KOS and were assayed for inflammatory factors using flow cytometry and metabolic activity using a Seahorse XFP. Differences in nerve architecture were measured using corneal whole mounts and immunohistochemistry.

Results : SARM1-/- mice developed more severe corneal pathology, lost corneal sensitivity, and showed more disrupted corneal nerves compared to WT controls. After HSV-1 infection, SARM1-/- BM derived monocytes were more metabolically active and expressed more vascular endothelial growth factor (VEGF-A) and iNOS compared to WT BM monocytes. Similarly, monocytes from SARM1-/- corneas expressed more VEGF after HSV-1 infection compared to WT corneas. Finally, superior cervical ganglia, the source of sympathetic nerves, were larger in size in SARM1-/- compared to WT mice.

Conclusions : Together, our data reveal that SARM1 is a host factor responsible for suppressing HSK. Specifically, SARM1 appears to act on immune cells by regulating inflammatory mediators in myeloid cells after HSV-1 infection. Additionally, SARM1 also appears to restrict the growth of sympathetic nerves after infection. Therefore, we conclude that due SARM1 may be key factor in determining susceptibility pathology associated with HSK.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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