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Wound Repair and Regeneration: Mechanisms, Signaling

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 53101

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Special Issue Editor

Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 9601247, Japan
Interests: wound healing; inflammation; scarring; extracellular matrix; regeneration; biomaterials; chronic wounds; remodeling; stem cells; growth factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Wound healing plays an integral part in cellular and molecular events. This process is implicated in regeneration. Regeneration is also a process of restoring defects and disfigurement towards the original or more ideal states by cells, molecules and environmental factors. Cellular and molecular events are orchestrated both spatially and temporally. When targeting each disease, understanding wound healing and the process of regeneration, as well as the findings of pathophysiology will deliver a new insights into realistic novel therapeutic options.

This Special Issue calls for original articles, reviews, and perspectives that address the current knowledge and progress in the field of wound healing and regeneration by conventional approaches as well as highly technologically advanced approaches. These include, but are not limited to, the fields that are mentioned in the keywords.

Prof. Dr. Sadanori Akita
Guest Editor

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Keywords

  • wound healing
  • regeneration
  • disease
  • pathophsyiogy
  • therapy
  • temporal
  • spatial

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Published Papers (11 papers)

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Editorial

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2 pages, 168 KiB  
Editorial
Wound Repair and Regeneration: Mechanisms, Signaling
by Sadanori Akita
Int. J. Mol. Sci. 2019, 20(24), 6328; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246328 - 15 Dec 2019
Cited by 37 | Viewed by 3951
Abstract
Wound healing plays an integral part of cellular and molecular events [...] Full article
(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)

Research

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13 pages, 1657 KiB  
Article
Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation
by Emi Kanno, Hiromasa Tanno, Airi Masaki, Ayako Sasaki, Noriko Sato, Maiko Goto, Mayu Shisai, Kenji Yamaguchi, Naoyuki Takagi, Miki Shoji, Yuki Kitai, Ko Sato, Jun Kasamatsu, Keiko Ishii, Tomomitsu Miyasaka, Kaori Kawakami, Yoshimichi Imai, Yoichiro Iwakura, Ryoko Maruyama, Masahiro Tachi and Kazuyoshi Kawakamiadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2019, 20(22), 5657; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225657 - 12 Nov 2019
Cited by 31 | Viewed by 3763
Abstract
Interferon (IFN)-γ is mainly secreted by CD4+ T helper 1 (Th1), natural killer (NK) and NKT cells after skin injury. Although IFN-γ is well known regarding its inhibitory effects on collagen synthesis by fibroblasts in vitro, information is limited regarding its role in [...] Read more.
Interferon (IFN)-γ is mainly secreted by CD4+ T helper 1 (Th1), natural killer (NK) and NKT cells after skin injury. Although IFN-γ is well known regarding its inhibitory effects on collagen synthesis by fibroblasts in vitro, information is limited regarding its role in wound healing in vivo. In the present study, we analyzed how the defect of IFN-γ affects wound healing. Full-thickness wounds were created on the backs of wild type (WT) C57BL/6 and IFN-γ-deficient (KO) mice. We analyzed the percent wound closure, wound breaking strength, accumulation of leukocytes, and expression levels of COL1A1, COL3A1, and matrix metalloproteinases (MMPs). IFN-γKO mice exhibited significant attenuation in wound closure on Day 10 and wound breaking strength on Day 14 after wound creation, characteristics that are associated with prolonged neutrophil accumulation. Expression levels of COL1A1 and COL3A1 mRNA were lower in IFN-γKO than in WT mice, whereas expression levels of MMP-2 (gelatinase) mRNA were significantly greater in IFN-γKO than in WT mice. Moreover, under neutropenic conditions created with anti-Gr-1 monoclonal antibodies, wound closure in IFN-γKO mice was recovered through low MMP-2 expression levels. These results suggest that IFN-γ may be involved in the proliferation and maturation stages of wound healing through the regulation of neutrophilic inflammatory responses. Full article
(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)
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12 pages, 3007 KiB  
Article
Biological Features Implies Potential Use of Autologous Adipose-Derived Stem/Progenitor Cells in Wound Repair and Regenerations for the Patients with Lipodystrophy
by Keiji Suzuki, Sadanori Akita, Hiroshi Yoshimoto, Akira Ohtsuru, Akiyoshi Hirano and Shunichi Yamashita
Int. J. Mol. Sci. 2019, 20(21), 5505; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215505 - 05 Nov 2019
Cited by 8 | Viewed by 2706
Abstract
A paradigm shift in plastic and reconstructive surgery is brought about the usage of cell-based therapies for wound healing and regeneration. Considering the imitations in the reconstructive surgeries in restoring tissue loss and deficiency, stem cell-based therapy, in particular, has been expected to [...] Read more.
A paradigm shift in plastic and reconstructive surgery is brought about the usage of cell-based therapies for wound healing and regeneration. Considering the imitations in the reconstructive surgeries in restoring tissue loss and deficiency, stem cell-based therapy, in particular, has been expected to pave the way for a new solution to the regenerative approaches. Limitations in the reconstructive surgeries in restoring tissue loss and deficiency have paved the way for new regenerative approaches. Among them, adipose-derived stem/progenitor cells (ADSCs)-based therapy could be the most promising clue, since ADSCs have pluripotent differentiation capabilities not only in adipocytes but also in a variety of cell types. Accumulating evidences have indicated that the unfavorable development of adipose-tissue damage, namely, lipodystrophy, is a systemic complication, which is closely related to metabolic abnormality. Considering ADSC-based regenerative medicine should be applied for the treatment of lipodystrophy, it is inevitable to ascertain whether the ADSCs obtained from the patients with lipodystrophy are capable of being used. It will be very promising and realistic if this concept is applied to lipoatrophy; one form of lipodystrophies that deteriorates the patients’ quality of life because of excessive loss of soft tissue in the exposed areas such as face and extremities. Since lipodystrophy is frequently observed in the human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART), the present study aims to examine the biological potentials of ADSCs isolated from the HIV-infected patients with lipodystrophy associated with the HAART treatment. Growth properties, adipogenic differentiation, and mitochondrial reactive oxygen species (ROS) production were examined in ADSCs from HIV-infected and HIV-uninfected patients. Our results clearly demonstrated that ADSCs from both patients showed indistinguishable growth properties and potentials for adipocyte differentiation in vitro. Thus, although the number of cases were limited, ADSCs isolated from the patients with lipodystrophy retain sufficient physiological and biological activity for the reconstitution of adipose-tissue, suggesting that ADSCs from the patients with lipodystrophy could be used for autologous ADSC-based regenerative therapy. Full article
(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)
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15 pages, 3643 KiB  
Article
B-Cell Activating Factor Enhances Hepatocyte-Driven Angiogenesis via B-Cell CLL/Lymphoma 10/Nuclear Factor-KappaB Signaling during Liver Regeneration
by Chia-Hung Chou, Cheng-Maw Ho, Shou-Lun Lai, Chiung-Nien Chen, Yao-Ming Wu, Chia-Tung Shun, Wen-Fen Wen and Hong-Shiee Lai
Int. J. Mol. Sci. 2019, 20(20), 5022; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205022 - 10 Oct 2019
Cited by 5 | Viewed by 3839
Abstract
B-cell activating factor (BAFF) is found to be associated with the histological severity of nonalcoholic steatohepatitis (NASH). BAFF was also found to have a protective role in hepatic steatosis via down regulating the expression of steatogenesis genes and enhancing steatosis in hepatocytes through [...] Read more.
B-cell activating factor (BAFF) is found to be associated with the histological severity of nonalcoholic steatohepatitis (NASH). BAFF was also found to have a protective role in hepatic steatosis via down regulating the expression of steatogenesis genes and enhancing steatosis in hepatocytes through BAFF-R. However, the roles of BAFF during liver regeneration are not well defined. In this study, C57/B6 mice with 70% partial hepatectomy were used as a liver regeneration model. BAFF expression was determined by enzyme immunoassay, and anti-BAFF-neutralizing antibodies were administered to confirm the effects of BAFF on liver regeneration. Western blotting, immunohistochemistry, and florescence staining determined the expression of B-cell CCL/lymphoma 10 (BCL10). The angiogenesis promoting capability was evaluated after the transfection of cells with siRNA targeting BCL10 expression, and the role of NF-κB was assessed. The results revealed that the BAFF and BCL10 levels were upregulated after partial hepatectomy. Treatment with anti-BAFF-neutralizing antibodies caused death in mice that were subjected to 70% partial hepatectomy within 72 h. In vitro, recombinant BAFF protein did not enhance hepatocyte proliferation; however, transfection with BCL10 siRNA arrested hepatocytes at the G2/M phase. Interestingly, conditioned medium from BAFF-treated hepatocytes enhanced angiogenesis and endothelial cell proliferation. Moreover, Matrix metalloproteinase-9 (MMP-9), Fibroblast growth factor 4 (FGF4), and Interleukin-8 (IL-8) proteins were upregulated by BAFF through BCL10/NF-κB signaling. In mice that were treated with anti-BAFF-neutralizing antibodies, the microvessel density (MVD) of the remaining liver tissues and liver regeneration were both reduced. Taken together, our study demonstrated that an increased expression of BAFF and activation of BCL10/NF-κB signaling were involved in hepatocyte-driven angiogenesis and survival during liver regeneration. Full article
(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)
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17 pages, 7871 KiB  
Article
Cloning, Expression and Effects of P. americana Thymosin on Wound Healing
by Jie Jing, Xiaohong Sun, Chuang Zhou, Yifan Zhang, Yongmei Shen, Xiaomao Zeng, Bisong Yue and Xiuyue Zhang
Int. J. Mol. Sci. 2019, 20(19), 4932; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194932 - 05 Oct 2019
Cited by 14 | Viewed by 3412
Abstract
The American cockroach (Periplaneta americana) is a medicinal insect. Its extract is used clinically to promote wound healing and tissue regeneration, but the effective medicinal components and mechanisms are not yet clear. It has been reported that human thymosin beta 4 [...] Read more.
The American cockroach (Periplaneta americana) is a medicinal insect. Its extract is used clinically to promote wound healing and tissue regeneration, but the effective medicinal components and mechanisms are not yet clear. It has been reported that human thymosin beta 4 (Tβ4) may accelerate skin wound healing, however, the role of P. americana thymosin (Pa-THYs) is still poorly understood. In the present study, we identify and analyze the DNA sequences of Pa-THYs by bioinformatics analysis. Then we clone, express, and purify the Pa-THYs proteins and evaluate the activity of recombinant Pa-THYs proteins by cell migration and proliferation assays in NIH/3T3 cells. To elucidate the role of Pa-THYs in wound healing, a mouse model is established, and we evaluate wound contraction, histopathological parameters, and the expressions of several key growth factors after Pa-THYs treatment. Our results showed that three THY variants were formed by skipping splicing of exons. Pa-THYs could promote fibroblast migration, but have no effect on fibroblast proliferation. In wound repair, Pa-THYs proteins could effectively promote wound healing through stimulating dermal tissue regeneration, angiogenesis, and collagen deposition. On the molecular mechanism, Pa-THYs also stimulated the expression of several key growth factors to promote wound healing. The data suggest that Pa-THYs could be a potential drug for promoting wound repair. Full article
(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)
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15 pages, 3942 KiB  
Article
Local Growth Hormone Therapy for Pressure Ulcer Healing on a Human Skin Mouse Model
by Lara Cristóbal, Nerea de los Reyes, Miguel A. Ortega, Melchor Álvarez-Mon, Natalio García-Honduvilla, Julia Buján and Andrés A. Maldonado
Int. J. Mol. Sci. 2019, 20(17), 4157; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20174157 - 26 Aug 2019
Cited by 16 | Viewed by 5818
Abstract
The growth hormone is involved in skin homeostasis and wound healing. We hypothesize whether it is possible to improve pressure ulcer (PU) healing by locally applying the recombinant human growth hormone (rhGH) in a human skin mouse model. Non-obese diabetic/severe combined immunodeficient mice [...] Read more.
The growth hormone is involved in skin homeostasis and wound healing. We hypothesize whether it is possible to improve pressure ulcer (PU) healing by locally applying the recombinant human growth hormone (rhGH) in a human skin mouse model. Non-obese diabetic/severe combined immunodeficient mice (n = 10) were engrafted with a full-thickness human skin graft. After 60 days with stable grafts, human skin underwent three cycles of ischemia-reperfusion with a compression device to create a PU. Mice were classified into two groups: rhGH treatment group (n = 5) and control group (n = 5). In the rhGH group for local intradermal injections, each had 0.15 mg (0.5IU) applied to the PU edges, once per week for four weeks. Evaluation of the wound healing was conducted with photographic and visual assessments, and histological analysis was performed after complete wound healing. The results showed a healing rate twice as fast in the rhGH group compared to the control group (1.25 ± 0.33 mm2/day versus 0.61 ± 0.27 mm2/day; p-value < 0.05), with a faster healing rate during the first 30 days. The rhGH group showed thicker skin (1953 ± 457 µm versus 1060 ± 208 µm; p-value < 0.05) in the repaired area, with a significant decrease in collagen type I/III ratio at wound closure (62 days, range 60–70). Local administration of the rhGH accelerates PU healing in our model. The rhGH may have a clinical use in pressure ulcer treatment. Full article
(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)
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28 pages, 8032 KiB  
Article
Matrisome Properties of Scaffolds Direct Fibroblasts in Idiopathic Pulmonary Fibrosis
by Linda Elowsson Rendin, Anna Löfdahl, Emma Åhrman, Catharina Müller, Thomas Notermans, Barbora Michaliková, Oskar Rosmark, Xiao-Hong Zhou, Göran Dellgren, Martin Silverborn, Leif Bjermer, Anders Malmström, Anna-Karin Larsson-Callerfelt, Hanna Isaksson, Johan Malmström and Gunilla Westergren-Thorsson
Int. J. Mol. Sci. 2019, 20(16), 4013; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20164013 - 17 Aug 2019
Cited by 34 | Viewed by 5163
Abstract
In idiopathic pulmonary fibrosis (IPF) structural properties of the extracellular matrix (ECM) are altered and influence cellular responses through cell-matrix interactions. Scaffolds (decellularized tissue) derived from subpleural healthy and IPF lungs were examined regarding biomechanical properties and ECM composition of proteins (the matrisome). [...] Read more.
In idiopathic pulmonary fibrosis (IPF) structural properties of the extracellular matrix (ECM) are altered and influence cellular responses through cell-matrix interactions. Scaffolds (decellularized tissue) derived from subpleural healthy and IPF lungs were examined regarding biomechanical properties and ECM composition of proteins (the matrisome). Scaffolds were repopulated with healthy fibroblasts cultured under static stretch with heavy isotope amino acids (SILAC), to examine newly synthesized proteins over time. IPF scaffolds were characterized by increased tissue density, stiffness, ultimate force, and differential expressions of matrisome proteins compared to healthy scaffolds. Collagens, proteoglycans, and ECM glycoproteins were increased in IPF scaffolds, however while specific basement membrane (BM) proteins such as laminins and collagen IV were decreased, nidogen-2 was also increased. Findings were confirmed with histology, clearly showing a disorganized BM. Fibroblasts produced scaffold-specific proteins mimicking preexisting scaffold composition, where 11 out of 20 BM proteins were differentially expressed, along with increased periostin and proteoglycans production. We demonstrate how matrisome changes affect fibroblast activity using novel approaches to study temporal differences, where IPF scaffolds support a disorganized BM and upregulation of disease-associated proteins. These matrix-directed cellular responses emphasize the IPF matrisome and specifically the BM components as important factors for disease progression. Full article
(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)
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16 pages, 4389 KiB  
Article
Sphingosine-1-Phosphate Facilitates Skin Wound Healing by Increasing Angiogenesis and Inflammatory Cell Recruitment with Less Scar Formation
by Masayo Aoki, Hiroaki Aoki, Partha Mukhopadhyay, Takuya Tsuge, Hirofumi Yamamoto, Noriko M. Matsumoto, Eri Toyohara, Yuri Okubo, Rei Ogawa and Kazuaki Takabe
Int. J. Mol. Sci. 2019, 20(14), 3381; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143381 - 10 Jul 2019
Cited by 32 | Viewed by 5336
Abstract
Wound healing starts with the recruitment of inflammatory cells that secrete wound-related factors. This step is followed by fibroblast activation and tissue construction. Sphingosine-1-phosphate (S1P) is a lipid mediator that promotes angiogenesis, cell proliferation, and attracts immune cells. We investigated the roles of [...] Read more.
Wound healing starts with the recruitment of inflammatory cells that secrete wound-related factors. This step is followed by fibroblast activation and tissue construction. Sphingosine-1-phosphate (S1P) is a lipid mediator that promotes angiogenesis, cell proliferation, and attracts immune cells. We investigated the roles of S1P in skin wound healing by altering the expression of its biogenic enzyme, sphingosine kinase-1 (SphK1). The murine excisional wound splinting model was used. Sphingosine kinase-1 (SphK1) was highly expressed in murine wounds and that SphK1−/− mice exhibit delayed wound closure along with less angiogenesis and inflammatory cell recruitment. Nanoparticle-mediated topical SphK1 overexpression accelerated wound closure, which associated with increased angiogenesis, inflammatory cell recruitment, and various wound-related factors. The SphK1 overexpression also led to less scarring, and the interaction between transforming growth factor (TGF)-β1 and S1P receptor-2 (S1PR2) signaling is likely to play a key role. In summary, SphK1 play important roles to strengthen immunity, and contributes early wound healing with suppressed scarring. S1P can be a novel therapeutic molecule with anti-scarring effect in surgical, trauma, and chronic wound management. Full article
(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)
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Review

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23 pages, 1038 KiB  
Review
Restoration of Neurological Function Following Peripheral Nerve Trauma
by Damien P. Kuffler and Christian Foy
Int. J. Mol. Sci. 2020, 21(5), 1808; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051808 - 06 Mar 2020
Cited by 27 | Viewed by 4461
Abstract
Following peripheral nerve trauma that damages a length of the nerve, recovery of function is generally limited. This is because no material tested for bridging nerve gaps promotes good axon regeneration across the gap under conditions associated with common nerve traumas. While many [...] Read more.
Following peripheral nerve trauma that damages a length of the nerve, recovery of function is generally limited. This is because no material tested for bridging nerve gaps promotes good axon regeneration across the gap under conditions associated with common nerve traumas. While many materials have been tested, sensory nerve grafts remain the clinical “gold standard” technique. This is despite the significant limitations in the conditions under which they restore function. Thus, they induce reliable and good recovery only for patients < 25 years old, when gaps are <2 cm in length, and when repairs are performed <2–3 months post trauma. Repairs performed when these values are larger result in a precipitous decrease in neurological recovery. Further, when patients have more than one parameter larger than these values, there is normally no functional recovery. Clinically, there has been little progress in developing new techniques that increase the level of functional recovery following peripheral nerve injury. This paper examines the efficacies and limitations of sensory nerve grafts and various other techniques used to induce functional neurological recovery, and how these might be improved to induce more extensive functional recovery. It also discusses preliminary data from the clinical application of a novel technique that restores neurological function across long nerve gaps, when repairs are performed at long times post-trauma, and in older patients, even under all three of these conditions. Thus, it appears that function can be restored under conditions where sensory nerve grafts are not effective. Full article
(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)
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19 pages, 2254 KiB  
Review
The Role of Immune Cells and Cytokines in Intestinal Wound Healing
by Xiang Xue and Daniel M. Falcon
Int. J. Mol. Sci. 2019, 20(23), 6097; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20236097 - 03 Dec 2019
Cited by 48 | Viewed by 8577
Abstract
Intestinal wound healing is a complicated process that not only involves epithelial cells but also immune cells. In this brief review, we will focus on discussing the contribution and regulation of four major immune cell types (neutrophils, macrophages, regulatory T cells, and innate [...] Read more.
Intestinal wound healing is a complicated process that not only involves epithelial cells but also immune cells. In this brief review, we will focus on discussing the contribution and regulation of four major immune cell types (neutrophils, macrophages, regulatory T cells, and innate lymphoid cells) and four cytokines (interleukin-10, tumor necrosis factor alpha, interleukin-6, and interleukin-22) to the wound repair process in the gut. Better understanding of these immune factors will be important for developing novel targeted therapy. Full article
(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)
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16 pages, 2101 KiB  
Review
The Role of Maresins in Inflammatory Pain: Function of Macrophages in Wound Regeneration
by Sung-Min Hwang, Gehoon Chung, Yong Ho Kim and Chul-Kyu Park
Int. J. Mol. Sci. 2019, 20(23), 5849; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235849 - 21 Nov 2019
Cited by 31 | Viewed by 5144
Abstract
Although acute inflammatory responses are host-protective and generally self-limited, unresolved and delayed resolution of acute inflammation can lead to further tissue damage and chronic inflammation. The mechanism of pain induction under inflammatory conditions has been studied extensively; however, the mechanism of pain resolution [...] Read more.
Although acute inflammatory responses are host-protective and generally self-limited, unresolved and delayed resolution of acute inflammation can lead to further tissue damage and chronic inflammation. The mechanism of pain induction under inflammatory conditions has been studied extensively; however, the mechanism of pain resolution is not fully understood. The resolution of inflammation is a biosynthetically active process, involving specialized pro-resolving mediators (SPMs). In particular, maresins (MaRs) are synthesized from docosahexaenoic acid (DHA) by macrophages and have anti-inflammatory and pro-resolving capacities as well as tissue regenerating and pain-relieving properties. A new class of macrophage-derived molecules—MaR conjugates in tissue regeneration (MCTRs)—has been reported to regulate phagocytosis and the repair and regeneration of damaged tissue. Macrophages not only participate in the biosynthesis of SPMs, but also play an important role in phagocytosis. They exhibit different phenotypes categorized as proinflammatory M1-like phenotypes and anti-inflammatory M2 phenotypes that mediate both harmful and protective functions, respectively. However, the signaling mechanisms underlying macrophage functions and phenotypic changes have not yet been fully established. Recent studies report that MaRs help resolve inflammatory pain by enhancing macrophage phagocytosis and shifting cytokine release to the anti-inflammatory M2 phenotypes. Consequently, this review elucidated the characteristics of MaRs and macrophages, focusing on the potent action of MaRs to enhance the M2 macrophage phenotype profiles that possess the ability to alleviate inflammatory pain. Full article
(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)
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