Koduri, M. A. | Search bioRxiv

bioRxiv2026

Extracellular matrix proteoglycans lumican and biglycan promote innate immune signals and viral clearance in HSV-1 infections of mouse corneas

The extracellular matrix (ECM) regulates innate immunity, but its role in HSV-1 keratitis is unclear. Here, we identify the ECM proteoglycans lumican (Lum) and biglycan (Bgn) as key regulators of early antiviral defense in the cornea. Lum-/- and BgnKO mice showed impaired viral clearance, increased corneal opacity, and worse keratitis than wild-type controls. These defects were associated with reduced early recruitment of neutrophils, monocytes, and plasmacytoid dendritic cells, and blunted induction of pro-inflammatory cytokines, chemokines, and type I interferons. In infected wild-type corneas, Lum and Bgn were upregulated, including in the basal epithelium, where Ccl2 emerged as an early epithelial response that was diminished in knockout mice. In human corneal epithelial cells, recombinant LUM or BGN enhanced HSV-1-induced CCL2 secretion, and human corneal organoids recapitulated epithelial viral tropism and CCL2 induction. Together, these findings identify Lum and Bgn as regulators of epithelial-innate immune crosstalk that promote early antiviral immunity during corneal HSV-1 infection.

immunology↗

bioRxiv2025

Oxidative-stress related increase in keratoconus tear MDA and GPX3 while NRF2-antioxidant functions decrease in stromal cells

Keratoconus (KC) is a common eye disease where the cornea undergoes degenerative thinning and steepening. The absence of biomarkers for early diagnosis prior to the onset of overt corneal phenotypes and the lack of curative treatments rooted in a fundamental understanding of KC biology remain significant challenges. To address these issues, we investigated the role of unresolved oxidative stress in KC pathogenesis. Malondialdehyde (MDA) a lipid peroxidation byproduct that accumulates during oxidative stress was significantly elevated in the tears of KC patients compared to unaffected controls and positively correlated with maximal keratometry (Kmax), a measure of KC severity. Similarly, the secreted antioxidant glutathione peroxidase 3 (GPX3), was significantly increased in patient tears, and strongly correlated with Kmax. In a cell culture model of oxidative stress, KC corneal stromal cells displayed increased apoptosis and suboptimal activation of NRF2, a transcription factor master regulator of antioxidant genes. Conversely, inhibition of NRF2 in donor stromal cells elicited KC-like cellular phenotype, whereas sulforaphane, an NRF2 booster restored antioxidant gene expression and the deposition of cornea-typical collagens. Our study identified cellular antioxidant signaling dysregulations in keratoconus where sulforaphane treatment may be restorative. Consistent increases in patient tear MDA and GPX3 present these as promising biomarkers for KC diagnosis and severity predictions.

cell biology↗