# Epithelial cytokeratins control corneal inflammation through intrinsic mechanisms

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $491,334

## Abstract

PROJECT SUMMARY/ABSTRACT
Epithelial Cytokeratins Control Corneal Inflammation Through Intrinsic Mechanisms
Keratitis, both infectious and sterile, can cause serious tissue destruction to the cornea and jeopardize vision.
In clinical practice, the current standard of care for corneal inflammation is topical corticosteroids. Although
powerful, corticosteroids are associated with a number of serious side effects. Therefore, the search for new
and better therapeutic options to control inflammation is necessary to improve patient care and clinical
outcomes. Keratin 6a (K6a), a major intermediate filament protein, is ubiquitous and wound-induced in many
epithelial cell types. We have demonstrated that inflammatory bacterial components induce phosphorylation of
K6a that promotes its filament depolymerization and hence increases its cytosolic level. Preliminary data
showed that corneal K6a knockdown in vitro and in vivo augments inflammatory responses to injury and
bacterial components, as evidenced by the increased secretion of proinflammatory cytokines and chemokines.
K6a deficiency also leads to increased secretion of DKK-1, the inhibitory ligand of Wnt/β-catenin signaling
pathway. In animal models, K6a deficiency exacerbates LPS-induced sterile corneal inflammation and
Pseudomonas aeruginosa keratitis, as well as impairs corneal epithelial wound healing. By
immunoprecipitation-mass spectrometry, we have identified interaction partners of cytosolic K6a in corneal
epithelial cells, including major regulators of NF-κB signaling and selective degradative autophagy. This
proposal aims to characterize the immunoregulatory function of this abundant pool of cytosolic K6a through
investigating its physical and functional partnerships with key pathway regulators; as the knowledge will
facilitate development of anti-inflammatory drugs that are more tissue-specific with less systemic side-effects.
The central hypothesis is that K6a partners with major pathway regulators to control inflammatory responses
such that inflamed and/or barrier-disrupted corneas can return to homeostasis. Our specific aims will test the
hypotheses that (1) cytosolic K6a antagonizes NF-κB pathway by directly sequestering ELKS (IKK activator)
and hnRNPA1 (IκBα destabilizer); (2) cytosolic K6a activates Wnt/β-catenin pathway by facilitating miR-152-
mediated downregulation of DKK-1; (3) cytosolic K6a promotes TRIM- and/or HSPA8 chaperone-mediated
degradative autophagy to control inflammatory mediator production; and (4) topical delivery of K6a-loaded
nanoparticles controls the inflammatory milieu of the cornea during P. aeruginosa infection and epithelial
wound healing. Both cell culture and corneal epithelial specific K6a knockout mice will be used in the studies.
Results are expected to define the anti-inflammatory role of cytokeratins in epithelial immunobiology and may
lead to specific therapeutic strategies to restore homeostasis of the cornea and other sites during acute and
chronic ...

## Key facts

- **NIH application ID:** 10200071
- **Project number:** 5R01EY030577-03
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** K. P. Connie Tam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $491,334
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200071

## Citation

> US National Institutes of Health, RePORTER application 10200071, Epithelial cytokeratins control corneal inflammation through intrinsic mechanisms (5R01EY030577-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10200071. Licensed CC0.

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