IMMUNOMODULATORS OF TISSUE REGENERATION AND MORPHOGENESIS

The mechanisms that regulate wound healing and tissue regeneration require further elucidation. Unlike amphibians, mammals lack the ability to completely form limbs after amputation due to incompetent blastema formation. However, a rare mammalian regenerative phenomenon, known as Wound Induced Hair Neogenesis (WIHN), results in de novo hair follicle growth after tissue damage. Because hair follicles represent miniature organs, WIHN allows us to study tissue regeneration in mammals. After skin injury, non-coding dsRNA is released, which stimulates the activation of the pattern recognition receptor toll-like receptor 3 (TLR3) and downstream morphogenesis cascades including the Wnt/β-catenin and sonic hedgehog (SHH) pathways. However, it is unclear why mammals are still prone to fibrotic scarring and have limited regenerative capacities. Using WIHN, we uncover various regeneration repressors that basally inhibit epimorphic processes. Through trans-species transcriptomic analyses, we find that the endoribonuclease RNase L restricts de novo hair morphogenesis. Realizing that de novo hair follicles have a topographical affinity to form in the center of scars, we are able to use proteomics to uncover interleukin-36 alpha (IL-36α) as a pro-regenerative cytokine. Additional in vivo and in vitro experiments allowed us to understand that IL-36α is natively inhibited by RNase L. Functional in vivo experiments allowed us to define caspase signaling as the intermediate between RNase L and IL-36 signaling. By using a small-molecule irreversible caspase inhibitor, we are not only able to induce regeneration of the skin, but intestinal tissue as well. Altogether, we are able to mechanistically highlight novel repressors that restrain IL-36 signaling, which is required for regeneration. Furthermore, this signaling axis can be therapeutically targeted for future clinical purposes