Topical phenylbutyrate antagonizes NF-κB signaling and resolves corneal inflammation

Raghuram Koganti; Tejabhiram Yadavalli; Yogesh Sutar; Sudipta Mallick; Abhijit Date; Deepak Shukla

doi:10.1016/j.isci.2022.105682

Topical phenylbutyrate antagonizes NF-κB signaling and resolves corneal inflammation

iScience. 2022 Nov 26;25(12):105682. doi: 10.1016/j.isci.2022.105682. eCollection 2022 Dec 22.

Authors

Raghuram Koganti¹, Tejabhiram Yadavalli¹, Yogesh Sutar^{2

3}, Sudipta Mallick², Abhijit Date^{2

3}, Deepak Shukla^{1

4}

Affiliations

¹ Department of Ophthalmology and Visual Sciences, University of Illinois Medical Center, 1855 W. Taylor Street, MC 648, Chicago, IL 60612, USA.
² Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawaii Hilo, Hilo, HI 96720, USA.
³ R. Ken Coit College of Pharmacy, The University of Arizona, Tuscon, AZ 85721, USA.
⁴ Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA.

Abstract

Chronic inflammation of the immune privileged cornea originating from viral or nonviral conditions results in significant vision loss. Topical corticosteroids are the common treatments for corneal inflammation, but the drugs cause serious and potentially blinding side effects in the long term. Therefore, new standalone and/or synergistic anti-inflammatory therapies with lower side effects are desperately needed. Here, we show that the aromatic fatty acid phenylbutyrate (PBA) acts as a potent inhibitor of inflammation in preclinical ocular-inflammation models. PBA prevents the transcription as well as translation of pro-inflammatory cytokines by LPS and poly(I:C) via persistent inhibition of NF-κB signaling. PBA quickens the resolution of ocular inflammation in mice by decreasing corneal thickness and immune cell infiltration. More importantly, PBA can synergize with the dexamethasone to antagonize NF-κB signaling at lower drug concentrations. Our results demonstrate that PBA therapy exerts previously unreported anti-inflammatory effects in the eye and facilitates corneal healing during persistent inflammation.

Keywords: Immune response; Molecular medicine; Ophthalmology.

Grants and funding

R24 EY033598/EY/NEI NIH HHS/United States