title: Transforming growth factor-β1 may be a key mediator of the fibrogenic properties of neural cells in leprosy.
abstract: Fibrosis is the main cause of irreversible nerve damage in leprosy. Phenotypic changes in Mycobacterium leprae (ML)-infected Schwann cells (SCs) have been suggested to mediate this process. We found that SC line cultures stimulated with ML upregulated transforming growth factor-β1 (TGF-β1), and that TGF-β1 or ML induced increased numbers of α-smooth muscle actin (α-SMA)-positive cells with characteristic stress fibers. Mycobacterium leprae and TGF-β1 also induced increased type I collagen and fibronectin mRNA and secretion and augmented mRNA levels of SOX9 and ZEB1, which are involved in the epithelial-mesenchymal transition. These effects could be inhibited by the TGF-β1 type I receptor (ALK5) inhibitor, SB-431542. In nerve biopsies from leprosy-infected patients with varying grades of fibrosis (n = 11), type I and III collagen and fibronectin were found in the endoneurium and perineurium, α-SMA-positive cells filled the fibrotic perineurium but not the endoneurium, and CD34-positive fibroblasts predominated in the endoneurium. Results of transcriptional studies of 3 leprosy nerves and 5 controls were consistent with these data, but α-SMA and other mRNA levels were not different from those in the control samples. Our findings suggest that TGF-β1 may orchestrate events, including reprogramming of the SC phenotype, leading to transdifferentiation, connective tissue cell expansion, and fibrogenesis in the evolution of leprosy nerve lesions during some evolutionary stages.
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, Fluminense Federal University, Niterói (RTV), Rio de Janeiro, Brazil.
authors.forename: Rafael B
authors.initials: RB
authors.lastname: Petito
authors.forename: Thaís P
authors.initials: TP
authors.lastname: Amadeu
authors.forename: Bernardo M O
authors.initials: BM
authors.lastname: Pascarelli
authors.forename: Márcia R
authors.initials: MR
authors.lastname: Jardim
authors.forename: Robson T
authors.initials: RT
authors.lastname: Vital
authors.forename: Sérgio L
authors.initials: SL
authors.lastname: Antunes
authors.forename: Euzenir N
authors.initials: EN
authors.lastname: Sarno
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005355:Fibrosis; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007918:Leprosy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009166:Mycobacterium leprae; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000502:physiology* / Q000633:toxicity; D055815:Young Adult
chemical_list: D018836:Inflammation Mediators; D053773:Transforming Growth Factor beta1