Inflammatory chronic pathologies are complex processes characterized by an imbalance between the resolution of the inflammatory phase and the establishment of tissue repair. The main players in these inflammatory pathologies are bone marrow derived monocytes (BMDMs). However, how monocyte differentiation is modulated to give rise to specific macrophage subpopulations (M1 or M2) that may either maintain the chronic inflammatory process or lead to wound healing is still unclear. Considering that inhibitors of Histone Deacetylase (HDAC) have an anti-inflammatory activity, we asked whether this enzyme would play a role on monocyte differentiation into M1 or M2 phenotype and in the cell shape transition that follows. We then induced murine bone marrow progenitors into monocyte/macrophage differentiation pathway using media containing GM-CSF and the HDAC blocker, Trichostatin A (TSA). We found that the pharmacological inhibition of HDAC activity led to a shape transition from the typical macrophage pancake-like shape into an elongated morphology, which was correlated to a mixed M1/M2 profile of cytokine and chemokine secretion. Our results present, for the first time, that HDAC activity acts as a regulator of macrophage differentiation in the absence of lymphocyte stimuli. We propose that HDAC activity down regulates macrophage plasticity favoring the pro-inflammatory phenotype.

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.

Background The molecular pathways that drive bone marrow myeloid progenitors (BMMP) development are very well understood and include a tight controlled multi-stage gene hierarch. Monocytes are versatile cells that display remarkable plasticity and may give rise to specific subsets of macrophages to proper promote tissue homesostasis upon an injury. However, the epigenetic mechanisms that underlie monocyte differentiation into the pro-inflammatory Ly6C high or the repairing Ly6C low subsets are yet to be elucidated. We have previously shown that Epigenetic mechanisms Histone Deacetylase (HDAC) dependent are crucial for monocyte behavior and plasticity and in this work, we propose that this same mechanism underlies BMMP plasticity upon an inflammatory challenge in vivo. Methods BMMP were culture in the presence of GM-CSF alone or in combination with HDAC inhibitor (iHDAC) and phenotyped by flow cytometry, immune staining or western blot. iHDAC was topically added to skin wounds for 7 consecutive days and wound healing was monitored by flow cytometry and histopathological analysis. Results When BMMP were cultured in the presence of iHDAC, we showed that the CD11b low /Ly6C low subset was the specific target of iHDAC that underwent chromatin hyperacetylation in vitro. Upon 13 days in the presence of iHDAC, BMMP gave rise to very elongated macrophages, that in turn, displayed a remarkable plasticity in a HDAC activity dependent fashion. HDAC-dependent cell shape was tight related to macrophage behavior and phenotype through the control of iNOS protein levels, showing that chromatin remodeling is a key component of macrophage plasticity and function. We then hypothesized that iHDAC would modulate the inflammatory response and favor tissue repair in vivo. To test this hypothesis, we topically added iHDAC to skin wounds during 7 consecutive days and followed tissue repair dynamics. In fact, iHDAC treated skin wounds presented an increase in wound closure at day 5 that was correlated to an enrichment in the CD11b low /Ly6C low subset and in very elongated F4/80 positives macrophages in vivo, fully recapitulating the behavior previously observed in vitro. Conclusion Our work provides the biological basis that connects chromatin remodeling to phenotypic plasticity, which in turn, may become a tractable therapeutic strategy in further translational studies. Electronic supplementary material The online version of this article (10.1186/s12967-019-1998-9) contains supplementary material, which is available to authorized users.

Galectin-3 is a β-galactoside-binding protein with an inhibitory role in B cell differentiation into plasma cells in distinct lymphoid tissues. We use a model of chronic schistosomiasis, a well-characterized experimental disease hallmarked by polyclonal B cell activation, in order to investigate the role of galectin-3 in controlling IgA production through peritoneal B1 cells. Chronically infected, galectin-3-deficient mice (Lgals3 −/− ) display peritoneal fluid hypercellularity, increased numbers of atypical peritoneal IgM + /IgA + B1a and B1b lymphocytes and histological disturbances in plasma cell niches when compared with Lgals3 + / + mice. Similar to our infection model, peritoneal B1 cells from uninfected Lgals3 −/− mice show enhanced switching to IgA after in vitro treatment with interleukin-5 plus transforming growth factor-β (IL-5 + TGF-β1). A higher number of IgA + B1a lymphocytes was found in the peritoneal cavity of Lgals3 −/− -uninfected mice at 1 week after i.p. injection of IL-5 + TGF-β1; this correlates with the increased levels of secreted IgA detected in the peritoneal fluid of these mice after cytokine treatment. Interestingly, a higher number of degranulated mast cells is present in the peritoneal cavity of uninfected and Schistosoma mansoni-infected Lgals3 −/− mice, indicating that, at least in part, mast cells account for the enhanced differentiation of B1 into IgAproducing B cells found in the absence of galectin-3. Thus, a novel role is revealed for galectin-3 in controlling the expression of surface IgA by peritoneal B1 lymphocytes; this might have important implications for manipulating the mucosal immune response.

Galectin-3 (Gal-3) is a multifunctional β-galactoside-binding lectin that once synthesized is expressed in the nucleus, cytoplasm, cell surface, and extracellular environment. Gal-3 plays an important role in breast cancer tumors due to its ability to promote interactions between cell-cell and cell-extracellular matrix (ECM) elements, increasing tumor survival and metastatic dissemination. Still, the mechanism by which Gal-3 interferes with tumor cell migration and metastasis formation is complex and not fully understood. Here, we showed that Gal-3 knockdown increased the migration ability of 4T1 murine breast cancer cells in vitro. Using the 4T1 orthotopic breast cancer spontaneous metastasis mouse model, we demonstrated that 4T1-derived tumors were significantly larger in the presence of Gal-3 (scramble) in comparison with Gal-3 knockdown 4T1-derived tumors. Nevertheless, Gal-3 knockdown 4T1 cells were outnumbered in the bone marrow in comparison with scramble 4T1 cells. Finally, we reported here a decrease in the content of cell-surface syndecan-1 and an increase in the levels of chondroitin sulfate proteoglycans such as versican in Gal-3 knockdown 4T1 cells both in vitro and in vivo. Overall, our findings establish that Gal-3 downregulation during breast cancer progression regulates cell-associated and tumor microenvironment glycosaminoglycans (GAGs)/proteoglycans (PG), thus enhancing the metastatic potential of tumor cells.