Abstract
Pulmonary fibrosis is a result of an abnormal wound healing in lung tissue triggered by an excessive accumulation of extracellular matrix proteins, loss of tissue elasticity, and debit of ventilatory function. NKT cells are a major source of Th1 and Th2 cytokines and may be crucial in the polarization of M1/M2 macrophages in pulmonary fibrogenesis. Although there appears to be constant scientific progress in that field, pulmonary fibrosis still exhibits no current cure. From these facts, we hypothesized that NKT cells could influence the development of pulmonary fibrosis via modulation of macrophage activation. Wild type (WT) and NKT type I cell-deficient mice (Jα18−/−) were subjected to the protocol of bleomycin-induced pulmonary fibrosis with or without treatment with NKT cell agonists α-galactosylceramide and sulfatide. The participation of different cell populations, collagen deposition, and protein levels of different cytokines involved in inflammation and fibrosis was evaluated. The results indicate a benign role of NKT cells in Jα18−/− mice and in wild-type α-galactosylceramide–sulfatide-treated groups. These animals presented lower levels of collagen deposition, fibrogenic molecules such as TGF-β and vimentin and improved survival rates. In contrast, WT mice developed a Th2-driven response augmenting IL-4, 5, and 13 protein synthesis and increased collagen deposition. Furthermore, the arginase-1 metabolic pathway was downregulated in wild-type NKT-activated and knockout mice indicating lower activity of M2 macrophages in lung tissue. Hence, our data suggest that NKT cells play a protective role in this experimental model by down modulating the Th2 milieu, inhibiting M2 polarization and finally preventing fibrosis.
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Acknowledgements
We would like to thank all who contributed to the accomplishment of this work. We would like to thank Masaru Taniguchi at the RIKEN Research Center for Allergy and Immunology (Japan) for Jα18KO. In addition, the authors are grateful to Bernardo Paulo Albe for helping set up the histology slides and Andrea Glatt, Renata Ricardi, Claudia Silva Cunha, and Marcílio Tablas Neto for technical assistance. This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Complex Fluids INCT). The funders had no role in study design, data collection, and analysis; decision to publish; or preparation of the manuscript.
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Grabarz, F., Aguiar, C.F., Correa-Costa, M. et al. Protective role of NKT cells and macrophage M2-driven phenotype in bleomycin-induced pulmonary fibrosis. Inflammopharmacol 26, 491–504 (2018). https://doi.org/10.1007/s10787-017-0383-7
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DOI: https://doi.org/10.1007/s10787-017-0383-7