The Role of Hedgehog Receptors in Regulating the Epidermal Immune Response

National Healthy Skin Month emphasizes the importance of maintaining healthy skin as a key aspect of overall health and well-being. The skin barrier, specifically the epidermis, protects the body against environmental threats, such as pathogens and chemicals, while also helping to maintain internal homeostasis and preventing water loss from the body. Improving our understanding of the factors that maintain and strengthen the skin barrier, as well as the mechanisms behind its dysfunction, is critical for developing strategies to prevent and treat skin conditions, including skin cancer.

Primary Skin Cells for Research

Scientists rely on primary skin cells to study skin health and disease in vitro because they retain the unique characteristics of their tissue of origin, allowing researchers to study cellular responses, signaling pathways, and immune functions in a biologically relevant context. Lifeline® Cell Technology offers a wide range of high-quality primary skin cells with the consistency and reliability needed for precise experimentation. Our skin cell product portfolio includes:

• Human Dermal Fibroblasts – Neonatal, Primary
• Epidermal Keratinocytes — Neonatal, Primary
• Epidermal Melanocytes — Neonatal
• Normal Human Dermal Fibroblasts — Adult, Primary
• Epidermal Keratinocytes — Adult, Primary
• Epidermal Melanocytes — Adult
• Human Dermal Fibroblasts – Neonatal, Xeno-Free, Primary
• Dermal Microvascular Endothelial Cells — Neonatal
• Human Epidermal Keratinocytes, 10-Donor Pool
• Epidermal Melanocytes — Neonatal, Highly Pigmented
• Epidermal Melanocytes — Adult, Highly Pigmented

Investigating the Hedgehog Pathway in Epidermal Immunity

Epithelial tissues forming the epidermis serve as the first line of defense for the innate immune system. The Hedgehog (Hh) signaling pathway is known to be crucial for maintaining epithelial homeostasis and regeneration. However, the role of Hh signaling in the innate immune defense function of the epidermis remains unclear. To address this, Wang et al used the Caenorhabditis elegans (C. elegans) model system and human keratinocytes to investigate the role of Hh receptors in regulating epidermal innate immunity.

Findings in C. elegans

Using RNA interference to inactivate Hh signaling, the authors found that a specific subgroup of Hedgehog components plays a direct role in regulating the innate immune response of epidermal cells. Notably, the loss of the Patched (PTCH) family receptor resulted in the aberrant up-regulation of epidermal antimicrobial peptides in a STAT-dependent manner. Additionally, upon physical injury to the epidermis, induced through a needle-wounding technique, a rapid rearrangement of Patched receptor PTC-3 distribution along the plasma membrane was observed. These findings suggest that Hh receptors are integral to immune surveillance within the epidermis and play a critical role in defending against epidermal damage.

Findings in Human Keratinocytes

To determine whether similar mechanisms are present in mammalian epidermal tissues, Wang and colleagues utilized Lifeline®’s primary adult human epidermal keratinocyte (HEKa) to study the involvement of two major Hh receptors that are highly expressed in the epidermis: the inhibitory receptor Patched (PTCH) and the activating receptor Smoothened (SMO), in innate immune regulation. Consistent with findings from the C. elegans epidermis model, inactivation of the inhibitory receptor PTCH1 led to STAT activation, triggering up-regulation of pro-inflammatory molecules β-defensin hBD2 and cytokine IL-6. Conversely, inactivation of the SMO receptor resulted in significant down-regulation of hBD2 and IL-6. These experimental results suggest that the Hh receptors can regulate the innate immune response in the human keratinocytes.

Study Conclusions

The authors conclude that this study highlights a previously unappreciated, evolutionarily conserved immune-surveillance function of Hedgehog receptors and their role in sensing and responding to tissue insults. These findings emphasize the critical importance of the Hedgehog (Hh) signaling pathway in maintaining skin health and homeostasis. Moreover, PTCH1’s role in initiating the innate immune response suggests that its dysfunction could contribute to the development of basal cell carcinoma (BCC) by allowing uncontrolled activation of Hedgehog (Hh) signaling. A better understanding of these mechanisms could have significant implications for skin cancer prevention and treatment.

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