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TRANSFORMING GROWTH FACTOR-A1 MAY BE A KEY MEDIATOR OF THE FIBROGENIC PROPERTIES OF NEURAL CELLS IN LEPROSY
Fibrosis
Leprosy
Mycobacterium leprae
Peripheral neuropathy
Schwann cell
Transforming growth factor-A1
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil / Universidade Federal Fluminense. Departamento de Neurologia. Niterói, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil / Universidade Federal Fluminense. Departamento de Neurologia. Niterói, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Hanseníase. Rio de Janeiro, RJ, Brasil.
Abstract
Fibrosis is the main cause of irreversible nerve damage in leprosy.
Phenotypic changes inMycobacterium leprae (ML)Yinfected Schwann
cells (SCs) have been suggested to mediate this process. We found that
SC line cultures stimulated with ML upregulated transforming growth
factor-A1 (TGF-A1), and that TGF-A1 or ML induced increased
numbers of >-smooth muscle actin (>-SMA)Ypositive cells with
characteristic stress fibers. Mycobacterium leprae and TGF-A1 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-A1 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, >-SMAYpositive 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 >-SMA and other mRNA levels were not different from
those in the control samples. Our findings suggest that TGF-A1 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.
Keywords
Smooth muscle actinFibrosis
Leprosy
Mycobacterium leprae
Peripheral neuropathy
Schwann cell
Transforming growth factor-A1
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