A loss of inter-α-inhibitor Heavy Chain 5 (ITIH5) leads to corneal thinning and increased corneal inflammation following injury and early onset geriatric decline.

Abstract

BACKGROUND: Inter-alpha trypsin inhibitor (IαI) proteins contain heavy chains (ITIHs, traditionally HCs), and ITIH5 is the most highly expressed ITIH isoform in the cornea. In skin, ITIH5 is upregulated during inflammatory skin diseases, however little is known about the biological functions of ITIH5 in other tissues. The aim of this study was to characterize the role of ITIH5 in the cornea during homeostasis, in corneal wound healing and in aging using mice lacking ITIH5 (Itih5). METHODS: The ocular surface of Itih5mice were analyzed at 8 weeks (adult) and 1 year (aging) and following an alkali burn injury (AB) with white light, ring light and following fluorescein administration. Corneas were collected and processed for histological analysis and real time PCR. RESULTS: Upon injury, Itih5mice presented increased and sustained inflammation, with increased scar tissue deposition, angiogenesis and epithelial erosions present at 2 weeks and 1 month after injury. When analyzing aging mice, Itih5mice presented early-onset geriatric decline including corneal clouding, loss of corneal smoothness and corneal epithelial defects, and Itih5mice presented thinner corneas than age matched WT mice. CONCLUSIONS: Our data suggest that ITIH5 is necessary for maintaining corneal structure and homeostasis, and that it has a role in resolving inflammation following injury. Future studies should be dedicated to investigating whether alterations in ITIH5 expression could contribute towards age related corneal pathologies including corneal ectasias, and whether ITIH5 could be explored as a treatment for promoting wound healing and suppressing inflammation.