Autocrine IL-1α controls corneal keratocyte transition to the repair fibroblast phenotype

Keratocyte transition to the repair fibroblast phenotype is characterized by the activation of genes for cytokines, extracellular matrix (ECM) receptors, ECM components, and proteolytic enzymes. Not only must these genes be induced to enable repair tissue deposition, but their expression must be precisely modulated over the prolonged period of repair tissue remodelling. An epithelial-stromal cell interaction may control many of these gene inductions and modulations. However, interaction of repair fibroblasts with their surrounding ECM also appears to play an important regulatory function, especially during the remodelling phase of corneal repair. Work in our lab over the past several years has elucidated a novel control mechanism for communication between a repair fibroblast and its ECM. We have found that changes in cell shape, via alterations in the actin cytoskeleton, stimulate synthesis and release of a cytokine intermediate, IL-1α. It is IL-1α which then stimulates expression of many of the genes which determine the repair fibroblast phenotype. We have also found that IL-1α acts as a common signalling intermediate between several other controlling agents which can either up-regulate or down-regulate repair gene expression. This routing of signals from diverse regulators to a common node (IL-1α) located outside of the cell offers features which might be conveniently exploited for therapeutic intervention to control the wound healing response. Importantly, quiescent keratocytes resident in the uninjured cornea are not competent to express IL-1α, but must become activated by wounding. Our lab is currently investigating molecular mechanisms determining competency, by focusing on transcription factors regulating expression of the IL-1α gene.