| First Author | Nüesch U | Year | 2019 |
| Journal | J Allergy Clin Immunol | Volume | 143 |
| Issue | 1 | Pages | 292-304.e8 |
| PubMed ID | 29775636 | Mgi Jnum | J:329677 |
| Mgi Id | MGI:6780993 | Doi | 10.1016/j.jaci.2018.02.057 |
| Citation | Nuesch U, et al. (2019) Epithelial proliferation in inflammatory skin disease is regulated by tetratricopeptide repeat domain 7 (Ttc7) in fibroblasts and lymphocytes. J Allergy Clin Immunol 143(1):292-304.e8 |
| abstractText | BACKGROUND: Mutations in tetratricopeptide repeat domain 7A (TTC7A) and its mouse orthologue, Ttc7, result in a multisystemic disease, mostly affecting the epithelial barriers and immune system. Despite successful hematopoietic stem cell transplantation, ongoing progression of gastrointestinal manifestations can be life-threatening in TTC7A-deficient patients. OBJECTIVE: We sought to identify whether TTC7A mutations dysregulate epithelial cells only or whether a cell-intrinsic defect in lymphocytes or other cells contributes to disease manifestations. METHODS: Ttc7-mutated (Ttc7(fsn/fsn)) mice were crossed to generate double-mutant (Rag2(-/-)Ttc7(fsn/fsn)) and triple-mutant (Rag2(-/-)IL2rg(-/-)Ttc7(fsn/fsn)) mice. These models, together with bone marrow chimeras, were used to explore the role of adaptive and innate lymphocytes in the flaky skin phenotype. The effect of the Ttc7(fsn/fsn) mutation on stromal cells was tested in a xenograft model in conjunction with transcriptomic analysis of Ttc7(fsn/fsn) fibroblasts. RESULTS: We observed that the severity of epithelial hyperproliferation was accentuated by lymphocytes, whereas the phenotype was not induced by transfer of Ttc7-mutated hematopoietic cells. Furthermore, mice completely lacking the lymphocytic compartment were not protected from epithelial hyperproliferation. Ttc7-mutated mouse fibroblasts expressed increased transcript levels of insulin-like growth factor 1 (Igf1) and the antimicrobial protein regenerating islet-derived protein 3gamma (Reg3gamma). In a xenograft model Ttc7-mutated fibroblasts markedly increased epithelial proliferation of keratinocytes. Thus Ttc7-mutated fibroblasts were identified as potent instigators of epithelial hyperproliferation. CONCLUSION: Our results reveal a previously unsuspected fundamental cell-extrinsic role of Ttc7. We have identified potential candidates for molecularly targeted treatment strategies that will need to be evaluated in future preclinical studies. |
