Abstract
Limbal stem cell (LSC) deficiency is a frequent and severe complication after chemical injury to the eye. Previous studies have assumed that this is mediated directly by the injury. Here we show that LSC loss occurs through immune cell mediators, even without direct injury to LSCs. In particular, elevation of anterior chamber (AC) pH causes acute uveal stress, release of inflammatory cytokines at the basal limbal tissue, and subsequent LSC death. Peripheral CCR2+ CX3CR1- monocytes are key mediators through the upregulation of tumor necrosis factor alpha (TNF-α) at the limbus, which in turn causing LSC death. In contrast to peripherally-derived monocytes, CX3CR1+ CCR2- tissue-resident macrophages have a protective role and their pharmacological depletion prior to injury exacerbates LSC loss and increases LSC vulnerability to apoptosis following exposure to TNF-α. This, despite the reduced number of CCR2+ cell infiltration into the tissue. Consistently, repopulation of the cornea by new tissue-resident macrophages after depletion restores their M2-like polarization upon exposure to rTNF-α and suppresses LSC inflammatory cell death. This findings may have clinical implication in patient with chemical burns.
Significance Limbal stem cell (LSC) loss after chemical burn is a significant clinical problem that has long been thought to be the result of direct chemical injury. This study demonstrates the existence of competing inflammatory mechanism responsible for LSC death, mediated by infiltrating peripheral monocytes that antagonize and overcome the protective role of tissue-resident macrophages. Thus, enhancing the role of tissue-resident macrophages while suppressing that of infiltrating monocytes could be a novel therapeutic strategy for LSC survival.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
To expand on findings of tissue-resident macrophage repopulation after CSF1R cessation and ability to express M2-like markers upon exposure to rTNF-α