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The Role of Fibroblasts in Acute and Chronic Inflammatory Processes
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The Role of Fibroblasts in Acute and Chronic Inflammatory Processes

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (15 April 2023) | Viewed by 12760

Special Issue Editor

Dr. Scott Levick

E-Mail Website
Guest Editor
Robert C. Byrd Health Sciences Center, 64 Medical Center Drive, West Virginia University, Morgantown, WV, USA
Interests: fibrosis; inflammation; neuropeptides
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Fibrosis, the excess accumulation of extracellular matrix (ECM), is an aberrant process whereby normal wound healing and repair processes fail to resolve. The consequence of fibrosis is organ dysfunction. While fibroblasts represent the end effector cells responsible for the secretion of excess ECM, inflammatory cells also form a critical part of the fibrotic process by establishing a pro-inflammatory environment that influences fibroblast phenotype and function. Furthermore, a critical but generally understudied element is the reciprocal relationship, whereby fibroblasts regulate inflammatory cell function. Under proper wound healing conditions, fibroblasts are important in resolving inflammation at the appropriate time; however, in fibrosis, fibroblasts can perpetuate an inflammatory environment via the release pro-inflammatory cytokines. 

In this Special Issue of Cells, we invite you to contribute original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “The Role of Fibroblasts in Acute and Chronic Inflammatory Processes”. Expert articles describing genetic, mechanistic, functional, cellular, or biochemical aspects of fibroblast regulation of inflammation are highly welcome. 

Dr. Scott Levick
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (6 papers)

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Research

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10 pages, 1273 KiB  
Communication
Bromodomain Protein Inhibitors Reorganize the Chromatin of Synovial Fibroblasts
by Monika Krošel, Larissa Moser, Miranda Houtman, Jasna Friščić, Matija Tomšič, Oliver Distler, Markus H. Hoffmann, Caroline Ospelt and Kerstin Klein
Cells 2023, 12(8), 1149; https://doi.org/10.3390/cells12081149 - 13 Apr 2023
Cited by 3 | Viewed by 1270
Abstract
Bromodomain- and extra-terminal domain (BET) proteins are epigenetic reader proteins that regulate transcription of their target genes by binding to acetylated histone side chains. Small molecule inhibitors, such as I-BET151, have anti-inflammatory properties in fibroblast-like synoviocytes (FLS) and in animal models of arthritis. [...] Read more.
Bromodomain- and extra-terminal domain (BET) proteins are epigenetic reader proteins that regulate transcription of their target genes by binding to acetylated histone side chains. Small molecule inhibitors, such as I-BET151, have anti-inflammatory properties in fibroblast-like synoviocytes (FLS) and in animal models of arthritis. Here, we investigated whether BET inhibition can also affect the levels of histone modifications, a novel mechanism underlying BET protein inhibition. On the one hand, FLSs were treated with I-BET151 (1 µM) for 24 h in absence and presence of TNF. On the other hand, FLSs were washed with PBS after 48 h of I-BET151 treatment, and the effects were measured 5 days after I-BET151 treatment or after an additional 24 h stimulation with TNF (5 d + 24 h). Mass spectrometry analysis indicated that I-BET151 induced profound changes in histone modifications, with a global reduction in acetylation on different histone side chains 5 days after treatment. We confirmed changes on acetylated histone side chains in independent samples by Western blotting. I-BET151 treatment reduced mean TNF-induced levels of total acetylated histone 3 (acH3), H3K18ac, and H3K27ac. In line with these changes, the TNF-induced expression of BET protein target genes was suppressed 5 d after I-BET151 treatment. Our data indicate that BET inhibitors not only prevent the reading of acetylated histones but directly influence overall chromatin organization, in particular after stimulation with TNF. Full article
(This article belongs to the Special Issue The Role of Fibroblasts in Acute and Chronic Inflammatory Processes)
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16 pages, 5407 KiB  
Article
Complete Freund’s Adjuvant Induces a Fibroblast-like Synoviocytes (FLS) Metabolic and Migratory Phenotype in Resident Fibroblasts of the Inoculated Footpad at the Earliest Stage of Adjuvant-Induced Arthritis
by Susana Aideé González-Chávez, Eduardo Chaparro-Barrera, María Fernanda Alvarado-Jáquez, Rubén Cuevas-Martínez, Rosa Elena Ochoa-Albíztegui and César Pacheco-Tena
Cells 2023, 12(6), 842; https://doi.org/10.3390/cells12060842 - 8 Mar 2023
Viewed by 1990
Abstract
The fibroblast-like synoviocytes (FLS) have a crucial role in the pathogenesis of Rheumatoid Arthritis (RA); however, its precise mechanisms remain partially unknown. The involvement of the fibroblast in activating adjuvant-induced arthritis (AA) has not been previously reported. The objective was to describe the [...] Read more.
The fibroblast-like synoviocytes (FLS) have a crucial role in the pathogenesis of Rheumatoid Arthritis (RA); however, its precise mechanisms remain partially unknown. The involvement of the fibroblast in activating adjuvant-induced arthritis (AA) has not been previously reported. The objective was to describe the participation of footpads’ fibroblasts in the critical initial process that drives the AA onset. Wistar rats were injected with Complete Freund’s Adjuvant (CFA) or saline solution in the hind paws’ footpads and euthanized at 24 or 48 h for genetic and histological analyses. Microarrays revealed the differentially expressed genes between the groups. The CFA dysregulated RA-linked biological processes at both times. Genes of MAPK, Jak-STAT, HIF, PI3K-Akt, TLR, TNF, and NF-κB signaling pathways were altered 24 h before the arrival of immune cells (CD4, CD8, and CD68). Key markers TNF-α, IL-1β, IL-6, NFκB, MEK-1, JAK3, Enolase, and VEGF were immunodetected in fibroblast in CFA-injected footpads at 24 h but not in the control group. Moreover, fibroblasts in the CFA inoculation site overexpressed cadherin-11, which is linked to the migration and invasion ability of RA-FLS. Our study shows that CFA induced a pathological phenotype in the fibroblast of the inoculation site at very early AA stages from 24 h, suggesting a prominent role in arthritis activation processes. Full article
(This article belongs to the Special Issue The Role of Fibroblasts in Acute and Chronic Inflammatory Processes)
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14 pages, 2433 KiB  
Article
Lower Metabolic Potential and Impaired Metabolic Flexibility in Human Lymph Node Stromal Cells from Patients with Rheumatoid Arthritis
by Tineke A. de Jong, Johanna F. Semmelink, Simone W. Denis, Janne W. Bolt, Mario Maas, Marleen G. H. van de Sande, Riekelt H. L. Houtkooper and Lisa G. M. van Baarsen
Cells 2023, 12(1), 1; https://doi.org/10.3390/cells12010001 - 20 Dec 2022
Cited by 4 | Viewed by 1382
Abstract
Cellular metabolism is important for determining cell function and shaping immune responses. Studies have shown a crucial role for stromal cells in steering proper immune responses in the lymph node microenvironment. These lymph node stromal cells (LNSCs) tightly regulate immune tolerance. We hypothesize [...] Read more.
Cellular metabolism is important for determining cell function and shaping immune responses. Studies have shown a crucial role for stromal cells in steering proper immune responses in the lymph node microenvironment. These lymph node stromal cells (LNSCs) tightly regulate immune tolerance. We hypothesize that malfunctioning LNSCs create a microenvironment in which normal immune responses are not properly controlled, possibly leading to the development of autoimmune diseases such as rheumatoid arthritis (RA). Therefore, we set out to determine their metabolic profile during health and systemic autoimmunity. We included autoantibody positive individuals at risk of developing RA (RA-risk individuals), RA patients and healthy volunteers. All study subjects underwent lymph node biopsy sampling. Mitochondrial function in cultured LNSCs was assessed by quantitative PCR, flow cytometry, Seahorse and oleate oxidation assays. Overall, mitochondrial respiration was lower in RA(-risk) LNSCs compared with healthy LNSCs, while metabolic potential was only lower in RA LNSCs. To maintain basal mitochondrial respiration, all LNSCs were mostly dependent on fatty acid oxidation. However, RA(-risk) LNSCs were also dependent on glutamine oxidation. Finally, we showed that RA LNSCs have impaired metabolic flexibility. Our results show that the metabolic landscape of LNSCs is not only altered during established disease, but partly already in individuals at risk of developing RA. Future studies are needed to investigate the impact of restoring metabolic capacity in LNSC-mediated immunomodulation and disease progression. Full article
(This article belongs to the Special Issue The Role of Fibroblasts in Acute and Chronic Inflammatory Processes)
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15 pages, 12975 KiB  
Article
[68Ga]Ga-Pentixafor and Sodium [18F]Fluoride PET Can Non-Invasively Identify and Monitor the Dynamics of Orthodontic Tooth Movement in Mouse Model
by Rogerio B. Craveiro, Alexandru Florea, Christian Niederau, Sihem Brenji, Fabian Kiessling, Sabri E. M. Sahnoun, Agnieszka Morgenroth, Felix M. Mottaghy and Michael Wolf
Cells 2022, 11(19), 2949; https://doi.org/10.3390/cells11192949 - 21 Sep 2022
Cited by 3 | Viewed by 1797
Abstract
The cellular and molecular mechanisms of orthodontic tooth movement (OTM) are not yet fully understood, partly due to the lack of dynamical datasets within the same subject. Inflammation and calcification are two main processes during OTM. Given the high sensitivity and specificity of [...] Read more.
The cellular and molecular mechanisms of orthodontic tooth movement (OTM) are not yet fully understood, partly due to the lack of dynamical datasets within the same subject. Inflammation and calcification are two main processes during OTM. Given the high sensitivity and specificity of [68Ga]Ga-Pentixafor and Sodium [18F]Fluoride (Na[18F]F) for inflammation and calcification, respectively, the aim of this study is to assess their ability to identify and monitor the dynamics of OTM in an established mouse model. To monitor the processes during OTM in real time, animals were scanned using a small animal PET/CT during week 1, 3, and 5 post-implantation, with [68Ga]Ga-Pentixafor and Na[18F]F. Both tracers showed an increased uptake in the region of interest compared to the control. For [68Ga]Ga-Pentixafor, an increased uptake was observed within the 5-week trial, suggesting the continuous presence of inflammatory markers. Na[18F]F showed an increased uptake during the trial, indicating an intensification of bone remodelling. Interim and end-of-experiment histological assessments visualised increased amounts of chemokine receptor CXCR4 and TRAP-positive cells in the periodontal ligament on the compression side. This approach establishes the first in vivo model for periodontal remodelling during OTM, which efficiently detects and monitors the intricate dynamics of periodontal ligament. Full article
(This article belongs to the Special Issue The Role of Fibroblasts in Acute and Chronic Inflammatory Processes)
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18 pages, 3545 KiB  
Article
Cell-Type-Specific Effects of the Ovarian Cancer G-Protein Coupled Receptor (OGR1) on Inflammation and Fibrosis; Potential Implications for Idiopathic Pulmonary Fibrosis
by David J. Nagel, Ashley R. Rackow, Wei-Yao Ku, Tyler J. Bell, Patricia J. Sime and Robert Matthew Kottmann
Cells 2022, 11(16), 2540; https://doi.org/10.3390/cells11162540 - 16 Aug 2022
Cited by 3 | Viewed by 2081
Abstract
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by irreversible lung scarring. The pathophysiology is not fully understood, but the working hypothesis postulates that a combination of epithelial injury and myofibroblast differentiation drives progressive pulmonary fibrosis. We previously demonstrated that a reduction in [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by irreversible lung scarring. The pathophysiology is not fully understood, but the working hypothesis postulates that a combination of epithelial injury and myofibroblast differentiation drives progressive pulmonary fibrosis. We previously demonstrated that a reduction in extracellular pH activates latent TGF-β1, and that TGF-β1 then drives its own activation, creating a feed-forward mechanism that propagates myofibroblast differentiation. Given the important roles of extracellular pH in the progression of pulmonary fibrosis, we sought to identify whether pH mediates other cellular phenotypes independent of TGF-β1. Proton-sensing G-protein coupled receptors are activated by acidic environments, but their role in fibrosis has not been studied. Here, we report that the Ovarian Cancer G-Protein Coupled Receptor1 (OGR1 or GPR68) has dual roles in both promoting and mitigating pulmonary fibrosis. We demonstrate that OGR1 protein expression is significantly reduced in lung tissue from patients with IPF and that TGF-β1 decreases OGR1 expression. In fibroblasts, OGR1 inhibits myofibroblast differentiation and does not contribute to inflammation. However, in epithelial cells, OGR1 promotes epithelial to mesenchymal transition (EMT) and inflammation. We then demonstrate that sub-cellular localization and alternative signaling pathways may be responsible for the differential effect of OGR1 in each cell type. Our results suggest that strategies to selectively target OGR1 expression may represent a novel therapeutic strategy for pulmonary fibrosis. Full article
(This article belongs to the Special Issue The Role of Fibroblasts in Acute and Chronic Inflammatory Processes)
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Review

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11 pages, 498 KiB  
Review
Biological Roles of Fibroblasts in Periodontal Diseases
by Koji Naruishi
Cells 2022, 11(21), 3345; https://doi.org/10.3390/cells11213345 - 24 Oct 2022
Cited by 18 | Viewed by 2919
Abstract
Periodontal diseases include periodontitis and gingival overgrowth. Periodontitis is a bacterial infectious disease, and its pathological cascade is regulated by many inflammatory cytokines secreted by immune or tissue cells, such as interleukin-6. In contrast, gingival overgrowth develops as a side effect of specific [...] Read more.
Periodontal diseases include periodontitis and gingival overgrowth. Periodontitis is a bacterial infectious disease, and its pathological cascade is regulated by many inflammatory cytokines secreted by immune or tissue cells, such as interleukin-6. In contrast, gingival overgrowth develops as a side effect of specific drugs, such as immunosuppressants, anticonvulsants, and calcium channel blockers. Human gingival fibroblasts (HGFs) are the most abundant cells in gingival connective tissue, and human periodontal ligament fibroblasts (HPLFs) are located between the teeth and alveolar bone. HGFs and HPLFs are both crucial for the remodeling and homeostasis of periodontal tissue, and their roles in the pathogenesis of periodontal diseases have been examined for 25 years. Various responses by HGFs or HPLFs contribute to the progression of periodontal diseases. This review summarizes the biological effects of HGFs and HPLFs on the pathogenesis of periodontal diseases. Full article
(This article belongs to the Special Issue The Role of Fibroblasts in Acute and Chronic Inflammatory Processes)
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