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Galectin-3, histone deacetylases, and Hedgehog signaling: Possible convergent targets in schistosomiasis-induced liver fibrosis.
PLoS Negl Trop Dis 2017; 11(2):e0005137PN

Abstract

Schistosomiasis affects approximately 240 million people in the world. Schistosoma mansoni eggs in the liver induce periportal fibrosis and hepatic failure driven by monocyte recruitment and macrophage activation, resulting in robust Th2 response. Here, we suggested a possible involvement of Galectin-3 (Gal-3), histone deacetylases (HDACs), and Hedgehog (Hh) signaling with macrophage activation during Th1/Th2 immune responses, fibrogranuloma reaction, and tissue repair during schistosomiasis. Gal-3 is highly expressed by liver macrophages (Kupffer cells) around Schistosoma eggs. HDACs and Hh regulate macrophage polarization and hepatic stellate cell activation during schistosomiasis-associated fibrogenesis. Previously, we demonstrated an abnormal extracellular matrix distribution in the liver that correlated with atypical monocyte-macrophage differentiation in S. mansoni-infected, Gal-3-deficient (Lgals3-/-) mice. New findings explored in this review focus on the chronic phase, when wild-type (Lgals3+/+) and Lgals3-/- mice were analyzed 90 days after cercariae infection. In Lgals3-/- infected mice, there was significant inflammatory infiltration with myeloid cells associated with egg destruction (hematoxylin and eosin staining), phagocytes (specifically Kupffer cells), numerically reduced and diffuse matrix extracellular deposition in fibrotic areas (Gomori trichrome staining), and severe disorganization of collagen fibers surrounding the S. mansoni eggs (reticulin staining). Granuloma-derived stromal cells (GR cells) of Lgals3-/- infected mice expressed lower levels of alpha smooth muscle actin (α-SMA) and eotaxin and higher levels of IL-4 than Lgals3+/+ mice (real-time PCR). The relevant participation of macrophages in these events led us to suggest distinct mechanisms of activation that culminate in defective fibrosis in the liver of Lgals3-/- infected mice. These aspects were discussed in this review, as well as the possible interference between Gal-3, HDACs, and Hh signaling during progressive liver fibrosis in S. mansoni-infected mice. Further studies focused on macrophage roles could elucidate these questions and clear the potential utility of these molecules as antifibrotic targets.

Authors+Show Affiliations

Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.Departmento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil.Section of Gastroenterology, Ralph H Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States of America. Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina, United States of America.MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Pub Type(s)

Journal Article
Review
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28231240

Citation

de Oliveira, Felipe Leite, et al. "Galectin-3, Histone Deacetylases, and Hedgehog Signaling: Possible Convergent Targets in Schistosomiasis-induced Liver Fibrosis." PLoS Neglected Tropical Diseases, vol. 11, no. 2, 2017, pp. e0005137.
de Oliveira FL, Carneiro K, Brito JM, et al. Galectin-3, histone deacetylases, and Hedgehog signaling: Possible convergent targets in schistosomiasis-induced liver fibrosis. PLoS Negl Trop Dis. 2017;11(2):e0005137.
de Oliveira, F. L., Carneiro, K., Brito, J. M., Cabanel, M., Pereira, J. X., Paiva, L. A., ... El-Cheikh, M. C. (2017). Galectin-3, histone deacetylases, and Hedgehog signaling: Possible convergent targets in schistosomiasis-induced liver fibrosis. PLoS Neglected Tropical Diseases, 11(2), pp. e0005137. doi:10.1371/journal.pntd.0005137.
de Oliveira FL, et al. Galectin-3, Histone Deacetylases, and Hedgehog Signaling: Possible Convergent Targets in Schistosomiasis-induced Liver Fibrosis. PLoS Negl Trop Dis. 2017;11(2):e0005137. PubMed PMID: 28231240.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Galectin-3, histone deacetylases, and Hedgehog signaling: Possible convergent targets in schistosomiasis-induced liver fibrosis. AU - de Oliveira,Felipe Leite, AU - Carneiro,Katia, AU - Brito,José Marques, AU - Cabanel,Mariana, AU - Pereira,Jonathas Xavier, AU - Paiva,Ligia de Almeida, AU - Syn,Wingkin, AU - Henderson,Neil C, AU - El-Cheikh,Marcia Cury, Y1 - 2017/02/23/ PY - 2017/2/24/entrez PY - 2017/2/24/pubmed PY - 2017/7/14/medline SP - e0005137 EP - e0005137 JF - PLoS neglected tropical diseases JO - PLoS Negl Trop Dis VL - 11 IS - 2 N2 - Schistosomiasis affects approximately 240 million people in the world. Schistosoma mansoni eggs in the liver induce periportal fibrosis and hepatic failure driven by monocyte recruitment and macrophage activation, resulting in robust Th2 response. Here, we suggested a possible involvement of Galectin-3 (Gal-3), histone deacetylases (HDACs), and Hedgehog (Hh) signaling with macrophage activation during Th1/Th2 immune responses, fibrogranuloma reaction, and tissue repair during schistosomiasis. Gal-3 is highly expressed by liver macrophages (Kupffer cells) around Schistosoma eggs. HDACs and Hh regulate macrophage polarization and hepatic stellate cell activation during schistosomiasis-associated fibrogenesis. Previously, we demonstrated an abnormal extracellular matrix distribution in the liver that correlated with atypical monocyte-macrophage differentiation in S. mansoni-infected, Gal-3-deficient (Lgals3-/-) mice. New findings explored in this review focus on the chronic phase, when wild-type (Lgals3+/+) and Lgals3-/- mice were analyzed 90 days after cercariae infection. In Lgals3-/- infected mice, there was significant inflammatory infiltration with myeloid cells associated with egg destruction (hematoxylin and eosin staining), phagocytes (specifically Kupffer cells), numerically reduced and diffuse matrix extracellular deposition in fibrotic areas (Gomori trichrome staining), and severe disorganization of collagen fibers surrounding the S. mansoni eggs (reticulin staining). Granuloma-derived stromal cells (GR cells) of Lgals3-/- infected mice expressed lower levels of alpha smooth muscle actin (α-SMA) and eotaxin and higher levels of IL-4 than Lgals3+/+ mice (real-time PCR). The relevant participation of macrophages in these events led us to suggest distinct mechanisms of activation that culminate in defective fibrosis in the liver of Lgals3-/- infected mice. These aspects were discussed in this review, as well as the possible interference between Gal-3, HDACs, and Hh signaling during progressive liver fibrosis in S. mansoni-infected mice. Further studies focused on macrophage roles could elucidate these questions and clear the potential utility of these molecules as antifibrotic targets. SN - 1935-2735 UR - https://www.unboundmedicine.com/medline/citation/28231240/Galectin_3_histone_deacetylases_and_Hedgehog_signaling:_Possible_convergent_targets_in_schistosomiasis_induced_liver_fibrosis_ L2 - http://dx.plos.org/10.1371/journal.pntd.0005137 DB - PRIME DP - Unbound Medicine ER -