TNF-α and IL-1β Do Not Induce Langerhans Cell Migration by Inhibiting TGFβ Activation

While skin is a site of active immune surveillance, primary melanomas often escape detection. Here, we have developed an in silico model to determine the local cross-talk between melanomas and Langerhans cells (LCs), the primary antigen-presenting cells at the site of melanoma development. The model predicts that melanomas fail to activate LC migration to lymph nodes until tumors reach a critical size, which is determined by a positive TNF-α feedback loop within melanomas, in line with our observations of murine tumors. In silico drug screening, supported by subsequent experimental testing, shows that treatment of primary tumors with MAPK pathway inhibitors may further prevent LC migration. In addition, our in silico model predicts treatment combinations that bypass LC dysfunction. In conclusion, our combined approach of in silico and in vivo studies suggests a molecular mechanism that explains how early melanomas develop under the radar of immune surveillance by LC.

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Loricrin at the Boundary between Inside and Outside

Ishitsuka

Roop

2022

Biomolecules

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Cornification is a specialized mode of the cell-death program, exclusively, and is allowed for terrestrial amniotes. Recent investigations suggest that loricrin (LOR) is an important cornification effector. As the connotation of its name (“lorica” meaning an armor in Latin) suggests, the keratin-associated protein LOR promotes the maturation of the epidermal structure through organizing covalent cross-linkages, endowing the epidermis with the protection against oxidative injuries. By reviewing cornification mechanisms, we seek to classify ichthyosiform dermatoses based on their function, rather than clinical manifestations. We also reviewed recent mechanistic insights into the Kelch-like erythroid cell-derived protein with the cap “n” collar homology-associated protein 1/nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in skin health and diseases, as LOR and NRF2 coordinate the epidermis-intrinsic xenobiotic metabolism. Finally, we refine the theoretical framework of cross-talking between keratinocytes and epidermal resident leukocytes, dissecting an LOR immunomodulatory function.

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TNF-α and IL-1β Do Not Induce Langerhans Cell Migration by Inhibiting TGFβ Activation

Cited by 3 publications

References 37 publications

TGFβ activating integrins β6 and β8 are dysregulated in inflammatory skin disease and cutaneous melanoma

TGFβ activating integrins β6 and β8 are dysregulated in inflammatory skin disease and cutaneous melanoma

Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling

Loricrin at the Boundary between Inside and Outside

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