Hedgehog receptors exert immune-surveillance roles in the epidermis across species

Hedgehog signaling plays pivotal roles in the development and homeostasis of epithelial barrier tissues. However, whether and how Hedgehog signaling directly regulates innate immunity in epithelial cells remains unknown. By utilizing C. elegans epidermis as the model, we found that several Hedgehog receptors are involved in cell-autonomous regulation of the innate immune response in the epidermis. Particularly, loss of the Patched family receptor induces aberrant up-regulation of epidermal antimicrobial peptides in a STAT-dependent manner. External or internal insult to the epidermis triggers rapid rearrangement of Patched distribution along the plasma membrane, indicating that the Hedgehog (Hh) receptor is likely involved in recognition and defense against epidermal damage. Loss of PTCH1 function in primary human keratinocytes and intact mouse skin also results in STAT-dependent immune activation. These findings reveal an evolutionally conserved immune-surveillance function of Hedgehog receptors and an insult-sensing and response strategy of epithelial tissues.