Editorial

5 pages, 751 KiB

Open AccessEditorial

Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration

by Anne-Laure Favier and Krisztina Nikovics

Biomedicines 2023, 11(5), 1416; https://doi.org/10.3390/biomedicines11051416 - 10 May 2023

Cited by 1 | Viewed by 2608

Over the past 70 years, significant progress has been made in understanding the molecular and cellular mechanisms of inflammation and tissue regeneration [...] Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration)

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Research

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17 pages, 3471 KiB

Open AccessArticle

Influence of the Immune Microenvironment Provided by Implanted Biomaterials on the Biological Properties of Masquelet-Induced Membranes in Rats: Metakaolin as an Alternative Spacer

by Marjorie Durand, Myriam Oger, Krisztina Nikovics, Julien Venant, Anne-Cecile Guillope, Eugénie Jouve, Laure Barbier, Laurent Bégot, Florence Poirier, Catherine Rousseau, Olivier Pitois, Laurent Mathieu, Anne-Laure Favier, Didier Lutomski and Jean-Marc Collombet

Biomedicines 2022, 10(12), 3017; https://doi.org/10.3390/biomedicines10123017 - 23 Nov 2022

Cited by 1 | Viewed by 1556

Abstract

Macrophages play a key role in the inflammatory phase of wound repair and foreign body reactions—two important processes in the Masquelet-induced membrane technique for extremity reconstruction. The macrophage response depends largely on the nature of the biomaterials implanted. However, little is known about [...] Read more.

Macrophages play a key role in the inflammatory phase of wound repair and foreign body reactions—two important processes in the Masquelet-induced membrane technique for extremity reconstruction. The macrophage response depends largely on the nature of the biomaterials implanted. However, little is known about the influence of the macrophage microenvironment on the osteogenic properties of the induced membrane or subsequent bone regeneration. We used metakaolin, an immunogenic material, as an alternative spacer to standard polymethylmethacrylate (PMMA) in a Masquelet model in rats. Four weeks after implantation, the PMMA- and metakaolin-induced membranes were harvested, and their osteogenic properties and macrophage microenvironments were investigated by histology, immunohistochemistry, mass spectroscopy and gene expression analysis. The metakaolin spacer induced membranes with higher levels of two potent pro-osteogenic factors, transforming growth factor-β (TGF-β) and bone morphogenic protein-2 (BMP-2). These alternative membranes thus had greater osteogenic activity, which was accompanied by a significant expansion of the total macrophage population, including both the M1-like and M2-like subtypes. Microcomputed tomographic analysis showed that metakaolin-induced membranes supported bone regeneration more effectively than PMMA-induced membranes through better callus properties (+58%), although this difference was not significant. This study provides the first evidence of the influence of the immune microenvironment on the osteogenic properties of the induced membranes. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration)

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25 pages, 7220 KiB

Open AccessArticle

Tauroursodeoxycholic Acid Reduces Neuroinflammation but Does Not Support Long Term Functional Recovery of Rats with Spinal Cord Injury

by Siyu Wu, Concepción García-Rama, Lorenzo Romero-Ramírez, Johannes P. J. M. de Munter, Erik Ch. Wolters, Boris W. Kramer and Jörg Mey

Biomedicines 2022, 10(7), 1501; https://doi.org/10.3390/biomedicines10071501 - 25 Jun 2022

Cited by 6 | Viewed by 1702

Abstract

The bile acid tauroursodeoxycholic acid (TUDCA) reduces cell death under oxidative stress and inflammation. Implants of bone marrow-derived stromal cells (bmSC) are currently under investigation in clinical trials of spinal cord injury (SCI). Since cell death of injected bmSC limits the efficacy of [...] Read more.

The bile acid tauroursodeoxycholic acid (TUDCA) reduces cell death under oxidative stress and inflammation. Implants of bone marrow-derived stromal cells (bmSC) are currently under investigation in clinical trials of spinal cord injury (SCI). Since cell death of injected bmSC limits the efficacy of this treatment, the cytoprotective effect of TUDCA may enhance its benefit. We therefore studied the therapeutic effect of TUDCA and its use as a combinatorial treatment with human bmSC in a rat model of SCI. A spinal cord contusion injury was induced at thoracic level T9. Treatment consisted of i.p. injections of TUDCA alone or in combination with one injection of human bmSC into the cisterna magna. The recovery of motor functions was assessed during a surveillance period of six weeks. Biochemical and histological analysis of spinal cord tissue confirmed the anti-inflammatory activity of TUDCA. Treatment improved the recovery of autonomic bladder control and had a positive effect on motor functions in the subacute phase, however, benefits were only transient, such that no significant differences between vehicle and TUDCA-treated animals were observed 1–6 weeks after the lesion. Combinatorial treatment with TUDCA and bmSC failed to have an additional effect compared to treatment with bmSC only. Our data do not support the use of TUDCA as a treatment of SCI. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration)

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22 pages, 5803 KiB

Open AccessArticle

TIRAP/Mal Positively Regulates TLR8-Mediated Signaling via IRF5 in Human Cells

by Kaja Elisabeth Nilsen, Astrid Skjesol, June Frengen Kojen, Terje Espevik, Jørgen Stenvik and Maria Yurchenko

Biomedicines 2022, 10(7), 1476; https://doi.org/10.3390/biomedicines10071476 - 22 Jun 2022

Cited by 4 | Viewed by 2735

Abstract

Toll-like receptor 8 (TLR8) recognizes single-stranded RNA of viral and bacterial origin as well as mediates the secretion of pro-inflammatory cytokines and type I interferons by human monocytes and macrophages. TLR8, as other endosomal TLRs, utilizes the MyD88 adaptor protein for initiation of [...] Read more.

Toll-like receptor 8 (TLR8) recognizes single-stranded RNA of viral and bacterial origin as well as mediates the secretion of pro-inflammatory cytokines and type I interferons by human monocytes and macrophages. TLR8, as other endosomal TLRs, utilizes the MyD88 adaptor protein for initiation of signaling from endosomes. Here, we addressed the potential role of the Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP) in the regulation of TLR8 signaling in human primary monocyte-derived macrophages (MDMs). To accomplish this, we performed TIRAP gene silencing, followed by the stimulation of cells with synthetic ligands or live bacteria. Cytokine-gene expression and secretion were analyzed by quantitative PCR or Bioplex assays, respectively, while nuclear translocation of transcription factors was addressed by immunofluorescence and imaging, as well as by cell fractionation and immunoblotting. Immunoprecipitation and Akt inhibitors were also used to dissect the signaling mechanisms. Overall, we show that TIRAP is recruited to the TLR8 Myddosome signaling complex, where TIRAP contributes to Akt-kinase activation and the nuclear translocation of interferon regulatory factor 5 (IRF5). Recruitment of TIRAP to the TLR8 signaling complex promotes the expression and secretion of the IRF5-dependent cytokines IFNβ and IL-12p70 as well as, to a lesser degree, TNF. These findings reveal a new and unconventional role of TIRAP in innate immune defense. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration)

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21 pages, 3265 KiB

Open AccessArticle

Long-Term Anxiety-like Behavior and Microbiota Changes Induced in Mice by Sublethal Doses of Acute Sarin Surrogate Exposure

by Sabine François, Stanislas Mondot, Quentin Gerard, Rosalie Bel, Julie Knoertzer, Asma Berriche, Sophie Cavallero, Rachid Baati, Cyrille Orset, Gregory Dal Bo and Karine Thibault

Biomedicines 2022, 10(5), 1167; https://doi.org/10.3390/biomedicines10051167 - 18 May 2022

Cited by 1 | Viewed by 1949

Abstract

Anxiety disorder is one of the most reported complications following organophosphorus (OP) nerve agent (NA) exposure. The goal of this study was to characterize the long-term behavioral impact of a single low dose exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. We [...] Read more.

Anxiety disorder is one of the most reported complications following organophosphorus (OP) nerve agent (NA) exposure. The goal of this study was to characterize the long-term behavioral impact of a single low dose exposure to 4-nitrophenyl isopropyl methylphosphonate (NIMP), a sarin surrogate. We chose two different sublethal doses of NIMP, each corresponding to a fraction of the median lethal dose (one mild and one convulsive), and evaluated behavioral changes over a 6-month period following exposure. Mice exposed to both doses showed anxious behavior which persisted for six-months post-exposure. A longitudinal magnetic resonance imaging examination did not reveal any anatomical changes in the amygdala throughout the 6-month period. While no cholinesterase activity change or neuroinflammation could be observed at the latest timepoint in the amygdala of NIMP-exposed mice, important modifications in white blood cell counts were noted, reflecting a perturbation of the systemic immune system. Furthermore, intestinal inflammation and microbiota changes were observed at 6-months in NIMP-exposed animals regardless of the dose received. This is the first study to identify long-term behavioral impairment, systemic homeostasis disorganization and gut microbiota alterations following OP sublethal exposure. Our findings highlight the importance of long-term care for victims of NA exposure, even in asymptomatic cases. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration)

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Review

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18 pages, 2017 KiB

Open AccessReview

Critical Role of Inflammation and Specialized Pro-Resolving Mediators in the Pathogenesis of Atherosclerosis

by Subhapradha Rangarajan, Davit Orujyan, Patrida Rangchaikul and Mohamed M. Radwan

Biomedicines 2022, 10(11), 2829; https://doi.org/10.3390/biomedicines10112829 - 06 Nov 2022

Cited by 4 | Viewed by 2518

Abstract

Recent research on how the body resolves this inflammation is gaining traction and has shed light on new avenues for future management of cardiovascular diseases. In this narrative review, we discuss the pathophysiological mechanisms of atherosclerosis, the recent development in the understanding of [...] Read more.

Recent research on how the body resolves this inflammation is gaining traction and has shed light on new avenues for future management of cardiovascular diseases. In this narrative review, we discuss the pathophysiological mechanisms of atherosclerosis, the recent development in the understanding of a new class of molecules called Specialized Pro-resolving Mediators (SPMs), and the impact of such findings in the realm of cardiovascular treatment options. We searched the MEDLINE database restricting ourselves to original research articles as much as possible on the complex pathophysiology of atherosclerosis and the role of SPMs. We expect to see further research in translating these findings to bedside clinical trials in treating conditions with a pathophysiological basis of inflammation, such as coronary artery disease, asthma, and periodontal disease. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration)

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19 pages, 1459 KiB

Open AccessReview

Wound Healing versus Metastasis: Role of Oxidative Stress

by Tatiana Lopez, Maeva Wendremaire, Jimmy Lagarde, Oriane Duquet, Line Alibert, Brice Paquette, Carmen Garrido and Frédéric Lirussi

Biomedicines 2022, 10(11), 2784; https://doi.org/10.3390/biomedicines10112784 - 02 Nov 2022

Cited by 7 | Viewed by 2190

Abstract

Many signaling pathways, molecular and cellular actors which are critical for wound healing have been implicated in cancer metastasis. These two conditions are a complex succession of cellular biological events and accurate regulation of these events is essential. Apart from inflammation, macrophages-released ROS [...] Read more.

Many signaling pathways, molecular and cellular actors which are critical for wound healing have been implicated in cancer metastasis. These two conditions are a complex succession of cellular biological events and accurate regulation of these events is essential. Apart from inflammation, macrophages-released ROS arise as major regulators of these processes. But, whatever the pathology concerned, oxidative stress is a complicated phenomenon to control and requires a finely tuned balance over the different stages and responding cells. This review provides an overview of the pivotal role of oxidative stress in both wound healing and metastasis, encompassing the contribution of macrophages. Indeed, macrophages are major ROS producers but also appear as their targets since ROS interfere with their differentiation and function. Elucidating ROS functions in wound healing and metastatic spread may allow the development of innovative therapeutic strategies involving redox modulators. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration)

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16 pages, 323 KiB

Open AccessReview

Critical Review on Toxicological Mechanisms Triggered by Inhalation of Alumina Nanoparticles on to the Lungs

by Samir Dekali, Alexandra Bourgois and Sabine François

Biomedicines 2022, 10(10), 2664; https://doi.org/10.3390/biomedicines10102664 - 21 Oct 2022

Cited by 4 | Viewed by 1684

Abstract

Alumina nanoparticles (Al₂O₃ NPs) can be released in occupational environments in different contexts such as industry, defense, and aerospace. Workers can be exposed by inhalation to these NPs, for instance, through welding fumes or aerosolized propellant combustion residues. Several clinical [...] Read more.

Alumina nanoparticles (Al₂O₃ NPs) can be released in occupational environments in different contexts such as industry, defense, and aerospace. Workers can be exposed by inhalation to these NPs, for instance, through welding fumes or aerosolized propellant combustion residues. Several clinical and epidemiological studies have reported that inhalation of Al₂O₃ NPs could trigger aluminosis, inflammation in the lung parenchyma, respiratory symptoms such as cough or shortness of breath, and probably long-term pulmonary fibrosis. The present review is a critical update of the current knowledge on underlying toxicological, molecular, and cellular mechanisms induced by exposure to Al₂O₃ NPs in the lungs. A major part of animal studies also points out inflammatory cells and secreted biomarkers in broncho-alveolar lavage fluid (BALF) and blood serum, while in vitro studies on lung cells indicate contradictory results regarding the toxicity of these NPs. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration)

17 pages, 1575 KiB

Open AccessReview

Exogenous Antioxidants in Remyelination and Skeletal Muscle Recovery

by Ricardo Julián Cabezas Perez, Marco Fidel Ávila Rodríguez and Doris Haydee Rosero Salazar

Biomedicines 2022, 10(10), 2557; https://doi.org/10.3390/biomedicines10102557 - 13 Oct 2022

Cited by 5 | Viewed by 1749

Abstract

Inflammatory, oxidative, and autoimmune responses cause severe damage to the nervous system inducing loss of myelin layers or demyelination. Even though demyelination is not considered a direct cause of skeletal muscle disease there is extensive damage in skeletal muscles following demyelination and impaired [...] Read more.

Inflammatory, oxidative, and autoimmune responses cause severe damage to the nervous system inducing loss of myelin layers or demyelination. Even though demyelination is not considered a direct cause of skeletal muscle disease there is extensive damage in skeletal muscles following demyelination and impaired innervation. In vitro and in vivo evidence using exogenous antioxidants in models of demyelination is showing improvements in myelin formation alongside skeletal muscle recovery. For instance, exogenous antioxidants such as EGCG stimulate nerve structure maintenance, activation of glial cells, and reduction of oxidative stress. Consequently, this evidence is also showing structural and functional recovery of impaired skeletal muscles due to demyelination. Exogenous antioxidants mostly target inflammatory pathways and stimulate remyelinating mechanisms that seem to induce skeletal muscle regeneration. Therefore, the aim of this review is to describe recent evidence related to the molecular mechanisms in nerve and skeletal muscle regeneration induced by exogenous antioxidants. This will be relevant to identifying further targets to improve treatments of neuromuscular demyelinating diseases. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration)

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21 pages, 749 KiB

Open AccessReview

Creating an Optimal In Vivo Environment to Enhance Outcomes Using Cell Therapy to Repair/Regenerate Injured Tissues of the Musculoskeletal System

by David A. Hart and Norimasa Nakamura

Biomedicines 2022, 10(7), 1570; https://doi.org/10.3390/biomedicines10071570 - 01 Jul 2022

Cited by 5 | Viewed by 2283

Abstract

Following most injuries to a musculoskeletal tissue which function in unique mechanical environments, an inflammatory response occurs to facilitate endogenous repair. This is a process that usually yields functionally inferior scar tissue. In the case of such injuries occurring in adults, the injury [...] Read more.

Following most injuries to a musculoskeletal tissue which function in unique mechanical environments, an inflammatory response occurs to facilitate endogenous repair. This is a process that usually yields functionally inferior scar tissue. In the case of such injuries occurring in adults, the injury environment no longer expresses the anabolic processes that contributed to growth and maturation. An injury can also contribute to the development of a degenerative process, such as osteoarthritis. Over the past several years, researchers have attempted to use cellular therapies to enhance the repair and regeneration of injured tissues, including Platelet-rich Plasma and mesenchymal stem/medicinal signaling cells (MSC) from a variety of tissue sources, either as free MSC or incorporated into tissue engineered constructs, to facilitate regeneration of such damaged tissues. The use of free MSC can sometimes affect pain symptoms associated with conditions such as OA, but regeneration of damaged tissues has been challenging, particularly as some of these tissues have very complex structures. Therefore, implanting MSC or engineered constructs into an inflammatory environment in an adult may compromise the potential of the cells to facilitate regeneration, and neutralizing the inflammatory environment and enhancing the anabolic environment may be required for MSC-based interventions to fulfill their potential. Thus, success may depend on first eliminating negative influences (e.g., inflammation) in an environment, and secondly, implanting optimally cultured MSC or tissue engineered constructs into an anabolic environment to achieve the best outcomes. Furthermore, such interventions should be considered early rather than later on in a disease process, at a time when sufficient endogenous cells remain to serve as a template for repair and regeneration. This review discusses how the interface between inflammation and cell-based regeneration of damaged tissues may be at odds, and outlines approaches to improve outcomes. In addition, other variables that could contribute to the success of cell therapies are discussed. Thus, there may be a need to adopt a Precision Medicine approach to optimize tissue repair and regeneration following injury to these important tissues. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration)

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20 pages, 8139 KiB

Open AccessTechnical Note

Macrophages Characterization in an Injured Bone Tissue

by Krisztina Nikovics, Marjorie Durand, Cédric Castellarin, Julien Burger, Emma Sicherre, Jean-Marc Collombet, Myriam Oger, Xavier Holy and Anne-Laure Favier

Biomedicines 2022, 10(6), 1385; https://doi.org/10.3390/biomedicines10061385 - 11 Jun 2022

Cited by 6 | Viewed by 1921

Abstract

Biomaterial use is a promising approach to facilitate wound healing of the bone tissue. Biomaterials induce the formation of membrane capsules and the recruitment of different types of macrophages. Macrophages are immune cells that produce diverse combinations of cytokines playing an important role [...] Read more.

Biomaterial use is a promising approach to facilitate wound healing of the bone tissue. Biomaterials induce the formation of membrane capsules and the recruitment of different types of macrophages. Macrophages are immune cells that produce diverse combinations of cytokines playing an important role in bone healing and regeneration, but the exact mechanism remains to be studied. Our work aimed to identify in vivo macrophages in the Masquelet induced membrane in a rat model. Most of the macrophages in the damaged area were M2-like, with smaller numbers of M1-like macrophages. In addition, high expression of IL-1β and IL-6 cytokines were detected in the membrane region by RT-qPCR. Using an innovative combination of two hybridization techniques (in situ hybridization and in situ hybridization chain reaction (in situ HCR)), M2b-like macrophages were identified for the first time in cryosections of non-decalcified bone. Our work has also demonstrated that microspectroscopical analysis is essential for macrophage characterization, as it allows the discrimination of fluorescence and autofluorescence. Finally, this work has revealed the limitations of immunolabelling and the potential of in situ HCR to provide valuable information for in vivo characterization of macrophages. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration)

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14 pages, 4423 KiB

Open AccessTechnical Note

In Situ Gene Expression in Native Cryofixed Bone Tissue

by Krisztina Nikovics, Cédric Castellarin, Xavier Holy, Marjorie Durand, Halima Morin, Abdelhafid Bendahmane and Anne-Laure Favier

Biomedicines 2022, 10(2), 484; https://doi.org/10.3390/biomedicines10020484 - 18 Feb 2022

Cited by 2 | Viewed by 2250

Abstract

Bone is a very complex tissue that is constantly changing throughout the lifespan. The precise mechanism of bone regeneration remains poorly understood. Large bone defects can be caused by gunshot injury, trauma, accidents, congenital anomalies and tissue resection due to cancer. Therefore, understanding [...] Read more.

Bone is a very complex tissue that is constantly changing throughout the lifespan. The precise mechanism of bone regeneration remains poorly understood. Large bone defects can be caused by gunshot injury, trauma, accidents, congenital anomalies and tissue resection due to cancer. Therefore, understanding bone homeostasis and regeneration has considerable clinical and scientific importance in the development of bone therapy. Macrophages are well known innate immune cells secreting different combinations of cytokines and their role in bone regeneration during bone healing is essential. Here, we present a method to identify mRNA transcripts in cryosections of non-decalcified rat bone using in situ hybridization and hybridization chain reaction to explore gene expression in situ for better understanding the gene expression of the bone tissues. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Inflammation and Tissue Regeneration)

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