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Novel Targets for Fibrosis Development: Macrophages as a Source of Ligands and Myofibroblast Transition

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 19056

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Special Issue Editor

Prof. Dr. Dolores Ortiz-Masiá

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Guest Editor

1. Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain
2. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), 46010 Valencia, Spain
Interests: macrophages; fibrosis; TGF; WNT; myofibroblasts; MMT; NOTCH; complications; succinate; autophagy; senescence; chronic inflammation
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Dear Colleagues,

Macrophages play an important role in the maintenance of tissue homeostasis; their reply to injury varies immensely depending on the nature and duration of the insult. Macrophages can promote tissue fibrosis, a major driver of progression to end-stage of a lot of diseases (e.g., renal, pulmonary, hepatic or intestinal), via paracrine effects or direct transition to myofibroblast-like cells. Macrophages contribute to fibrosis by dysregulated release of mediators (e.g., TGF-beta, PDGF, VEGF, IGF1, galactin3, WNT ligands) that, acting in a paracrine manner, modulate the function of surrounding cells, including fibroblasts, myofibroblasts and epithelial cells. In addition, recent studies demonstrate that macrophages can directly transform into myofibroblasts within the injured tissue. This process is termed macrophage-to-myofibroblast transition (MMT) and is driven by transforming growth factor-β1 (TGFβ1)-Smad3 signaling. In this regard, therapeutic strategies aimed at controlling macrophage activation, polarization and transition should be emphasized in the prevention of fibrosis.

Prof. Dr. Dolores Ortiz-Masiá
Guest Editor

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Keywords

Macrophages
fibrosis
TGF
WNT
myofibroblasts
MMT
NOTCH
complications
succinate
autophagy

Published Papers (5 papers)

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Research

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27 pages, 3540 KiB

Open AccessArticle

The Human Myofibroblast Marker Xylosyltransferase-I: A New Indicator for Macrophage Polarization

by Thanh-Diep Ly, Monika Wolny, Christopher Lindenkamp, Ingvild Birschmann, Doris Hendig, Cornelius Knabbe and Isabel Faust-Hinse

Biomedicines 2022, 10(11), 2869; https://doi.org/10.3390/biomedicines10112869 - 09 Nov 2022

Cited by 1 | Viewed by 1781

Abstract

Chronic inflammation and excessive synthesis of extracellular matrix components, such as proteoglycans (PG), by fibroblast- or macrophage-derived myofibroblasts are the hallmarks of fibrotic diseases, including systemic sclerosis (SSc). Human xylosyltransferase-I (XT-I), which is encoded by the gene XYLT1, is the key enzyme that is involved in PG biosynthesis. Increased cellular XYLT1 expression and serum XT-I activity were measured in SSc. Nothing is known so far about the regulation of XT-I in immune cells, and their contribution to the increase in measurable serum XT-I activity. We utilized an in vitro model, with primary human CD14⁺CD16⁺ monocyte-derived macrophages (MΦ), in order to investigate the role of macrophage polarization on XT-I regulation. The MΦ generated were polarized towards two macrophage phenotypes that were associated with SSc, which were classified as classical pro-inflammatory (M1-like), and alternative pro-fibrotic (M2-like) MΦ. The fully characterized M1- and M2-like MΦ cultures showed differential XT-I gene and protein expressions. The fibrotic M2-like MΦ cultures exhibited higher XT-I secretion, as well as increased expression of myofibroblast marker α-smooth muscle actin, indicating the onset of macrophage-to-myofibroblast transition (MMT). Thus, we identified XT-I as a novel macrophage polarization marker for in vitro generated M1- and M2-like MΦ subtypes, and broadened the view of XT-I as a myofibroblast marker in the process of MMT. Full article

(This article belongs to the Special Issue Novel Targets for Fibrosis Development: Macrophages as a Source of Ligands and Myofibroblast Transition)

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14 pages, 4183 KiB

Open AccessArticle

IFNγ-Treated Macrophages Induce EMT through the WNT Pathway: Relevance in Crohn’s Disease

by Dulce C. Macias-Ceja, Sandra Coll, Cristina Bauset, Marta Seco-Cervera, Laura Gisbert-Ferrándiz, Francisco Navarro, Jesus Cosin-Roger, Sara Calatayud, María D. Barrachina and Dolores Ortiz-Masia

Biomedicines 2022, 10(5), 1093; https://doi.org/10.3390/biomedicines10051093 - 08 May 2022

Cited by 8 | Viewed by 2004

Abstract

Background: Fibrosis is a common complication of Crohn’s disease (CD) in which macrophages play a central role. Epithelial-mesenchymal transition (EMT) and the WNT pathway have been associated with fibrosis. We aim to analyse the relevance of the tissue microenvironment in macrophage phenotype and the EMT process. Methods: Intestinal surgical resections are obtained from control and CD patients with stenotic or penetrating behaviour. Cytokine’s expression, macrophage phenotype, EMT markers and WNT signalling pathway are determined by WB, RT-PCR, ELISA or Cytometry. U937 cells are treated with IFNγ, TNFα, IL1β, IL4 or IL10 and co-cultured with HT29 cells and, in some cases, are treated with XAV939 or miFZD4. The expression of macrophage, EMT and WNT pathway markers in U937 or HT29 cells is analysed by WB or RT-PCR. Results: IFNγ, WNT6, CD16 and CD86 are increased in the intestinal tissue of CD patients. IFNγ-treated U937 activated the EMT process and WNT pathway in HT29 cells, and the EMT process is mediated by FZD4. Conclusions: An IFNγ-rich microenvironment polarises macrophages, which induces EMT through the WNT pathway. Full article

(This article belongs to the Special Issue Novel Targets for Fibrosis Development: Macrophages as a Source of Ligands and Myofibroblast Transition)

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19 pages, 3813 KiB

Open AccessArticle

Macrophages Modulate Hepatic Injury Involving NLRP3 Inflammasome: The Example of Efavirenz

by Fernando Alegre, Alberto Martí-Rodrigo, Miriam Polo, Dolores Ortiz-Masiá, Celia Bañuls, Marcello Pinti, Ángeles Álvarez, Nadezda Apostolova, Juan V. Esplugues and Ana Blas-García

Biomedicines 2022, 10(1), 109; https://doi.org/10.3390/biomedicines10010109 - 05 Jan 2022

Cited by 4 | Viewed by 2036

Abstract

Drug-induced liver injury (DILI) constitutes a clinical challenge due to the incomplete characterization of the mechanisms involved and potential risk factors. Efavirenz, an anti-HIV drug, induces deleterious actions in hepatocytes that could underlie induction of the NLRP3 inflammasome, an important regulator of inflammatory responses during liver injury. We assessed the potential of efavirenz to modulate the inflammatory and fibrogenic responses of major liver cell types involved in DILI. The effects of efavirenz were evaluated both in vitro and in vivo. Efavirenz triggered inflammation in hepatocytes, in a process that involved NF-κB and the NLRP3 inflammasome, and activated hepatic stellate cells (HSCs), thereby enhancing expression of inflammatory and fibrogenic markers. The NLRP3 inflammasome was not altered in efavirenz-treated macrophages, but these cells polarized towards the anti-inflammatory M2 phenotype and displayed upregulated anti-inflammatory mediators. Conversely, no evidence of damage was observed in efavirenz-treated animals, except when macrophages were depleted, which resulted in the in vivo manifestation of the deleterious effects detected in hepatocytes and HSCs. Efavirenz elicits a cell-specific activation of the NLRP3 inflammasome in hepatocytes and HSCs, but macrophages appear to counteract efavirenz-induced liver injury. Our results highlight the dynamic nature of the interaction among liver cell populations and emphasize the potential of targeting macrophage polarization as a strategy to treat NLRP3 inflammasome-induced liver injury. Full article

(This article belongs to the Special Issue Novel Targets for Fibrosis Development: Macrophages as a Source of Ligands and Myofibroblast Transition)

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Review

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20 pages, 923 KiB

Open AccessReview

Lung Fibrosis and Fibrosis in the Lungs: Is It All about Myofibroblasts?

by Elena Ortiz-Zapater, Jaime Signes-Costa, Paula Montero and Inés Roger

Biomedicines 2022, 10(6), 1423; https://doi.org/10.3390/biomedicines10061423 - 15 Jun 2022

Cited by 28 | Viewed by 6261

Abstract

In the lungs, fibrosis is a growing clinical problem that results in shortness of breath and can end up in respiratory failure. Even though the main fibrotic disease affecting the lung is idiopathic pulmonary fibrosis (IPF), which affects the interstitial space, there are many fibrotic events that have high and dangerous consequences for the lungs. Asthma, chronic obstructive pulmonary disease (COPD), excessive allergies, clearance of infection or COVID-19, all are frequent diseases that show lung fibrosis. In this review, we describe the different kinds of fibrosis and analyse the main types of cells involved—myofibroblasts and other cells, like macrophages—and review the main fibrotic mechanisms. Finally, we analyse present treatments for fibrosis in the lungs and highlight potential targets for anti-fibrotic therapies. Full article

(This article belongs to the Special Issue Novel Targets for Fibrosis Development: Macrophages as a Source of Ligands and Myofibroblast Transition)

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30 pages, 6003 KiB

Open AccessReview

Is the Macrophage Phenotype Determinant for Fibrosis Development?

by Lluis Lis-López, Cristina Bauset, Marta Seco-Cervera and Jesús Cosín-Roger

Biomedicines 2021, 9(12), 1747; https://doi.org/10.3390/biomedicines9121747 - 23 Nov 2021

Cited by 33 | Viewed by 5888

Abstract

Fibrosis is a pathophysiological process of wound repair that leads to the deposit of connective tissue in the extracellular matrix. This complication is mainly associated with different pathologies affecting several organs such as lung, liver, heart, kidney, and intestine. In this fibrotic process, macrophages play an important role since they can modulate fibrosis due to their high plasticity, being able to adopt different phenotypes depending on the microenvironment in which they are found. In this review, we will try to discuss whether the macrophage phenotype exerts a pivotal role in the fibrosis development in the most important fibrotic scenarios. Full article

(This article belongs to the Special Issue Novel Targets for Fibrosis Development: Macrophages as a Source of Ligands and Myofibroblast Transition)

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