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Sadeghi M, Moghaddam A, Amiri AM, Charoghdoozi K, Mohammadi M, Dehnavi S, Orazizadeh M. Improving the Wound Healing Process: Pivotal role of Mesenchymal stromal/stem Cells and Immune Cells. Stem Cell Rev Rep 2025; 21:680-697. [PMID: 39921839 DOI: 10.1007/s12015-025-10849-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2025] [Indexed: 02/10/2025]
Abstract
Wound healing, a physiological process, involves several different types of cells, from immune cells to non-immune cells, including mesenchymal stromal/stem cells (MSC), and their interactions. Immune cells including macrophages, neutrophils, dendritic cells (DC), innate lymphoid cells (ILC), natural killer (NK) cells, and B and T lymphocytes participate in wound healing by secreting various mediators and interacting with other cells. MSCs, as self-renewing, fast proliferating, and multipotent stromal/stem cells, are found in a wide variety of tissues and critically involved in different phases of wound healing by secreting various molecules that help to improve tissue healing and regeneration. In this review, first, we described the four main phases of wound healing, second, we reviewed the function of MSCs, MSC secretome and immune cells in improving the progress of wound repair (mainly focusing on skin wound healing), third, we explained the immune cells/MSCs interactions in the process of wound healing and regeneration, and finally, we introduce clinical applications of MSCs to improve the process of wound healing.
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Affiliation(s)
- Mahvash Sadeghi
- Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Asma Moghaddam
- Cellular and Molecular Research Center, Medical Basic Sciences Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Amir Mohammad Amiri
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Kianush Charoghdoozi
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mojgan Mohammadi
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sajad Dehnavi
- Allergy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mahmoud Orazizadeh
- Cellular and Molecular Research Center, Medical Basic Sciences Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Department of Anatomical Sciences, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Papa V, Li Pomi F, Di Gioacchino M, Mangifesta R, Borgia F, Gangemi S. Mast Cells and Microbiome in Health and Disease. FRONT BIOSCI-LANDMRK 2025; 30:26283. [PMID: 40152378 DOI: 10.31083/fbl26283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/11/2024] [Accepted: 11/21/2024] [Indexed: 03/29/2025]
Abstract
Inter-kingdom communication between human microbiota and mast cells (MCs), as sentinels of innate immunity, is crucial in determining health and disease. This complex signaling hub involves micro-organisms and, more importantly, their metabolic products. Gut microbiota is the host's largest symbiotic ecosystem and, under physiological conditions, it plays a vital role in mediating MCs tolerogenic priming, thus ensuring immune homeostasis across organs. Conversely, intestinal dysbiosis of various etiologies promotes MC-oriented inflammation along major body axes, including gut-skin, gut-lung, gut-liver, and gut-brain. This review of international scientific literature provides a comprehensive overview of the cross-talk under investigation. This process is a key biological event involved in disease development across clinical fields, with significant prognostic and therapeutic implications for future research.
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Affiliation(s)
- Vincenzo Papa
- Department of Clinical and Experimental Medicine, School and Operative Unit of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy
| | - Federica Li Pomi
- Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), University of Palermo, 90127 Palermo, Italy
| | - Mario Di Gioacchino
- Center of Advanced Science and Technology (CAST), G. D'Annunzio University, 66100 Chieti, Italy
- Institute of Clinical Immunotherapy and Advanced Biological Treatments, 65121 Pescara, Italy
| | - Rocco Mangifesta
- Center of Advanced Science and Technology (CAST), G. D'Annunzio University, 66100 Chieti, Italy
| | - Francesco Borgia
- Department of Clinical and Experimental Medicine, Section of Dermatology, University of Messina, 98125 Messina, Italy
| | - Sebastiano Gangemi
- Department of Clinical and Experimental Medicine, School and Operative Unit of Allergy and Clinical Immunology, University of Messina, 98125 Messina, Italy
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Farid A, Mohsen A, Nasser B, Alaa H, Abdelaziz M, Mustafa M, Mansour M, Adel N, Magdy S, Mohsen S, Adel S, Ibrahim S, Abdel-Rahman S, Mohamed S, El-Karamany Y. Treatment of Staphylococcus aureus-infected diabetic wounds by melatonin loaded nanocarriers. AMB Express 2025; 15:46. [PMID: 40088373 PMCID: PMC11910460 DOI: 10.1186/s13568-025-01854-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Accepted: 02/20/2025] [Indexed: 03/17/2025] Open
Abstract
One of the complication of diabetes mellitus is chronic wounds. The healing of wounds in diabetic patients is retarded by the elevation in the pro-inflammatory cytokines secretion and free radicles accumulation. Wound management in diabetic patients requires preventing bacterial biofilm development. Due to the wound healing activity of chitosan (CS), lecithin (Le) and melatonin (M), the present study aimed to load melatonin on CS/Le NPs and examine their effect on diabetic wounds infected with Staphylococcus aureus. Melatonin loaded chitosan/lecithin nanoparticles (M-CS/Le NPs) were physically characterized and their antioxidant, anti-inflammatory and antimicrobial activities were examined in vitro. Male Sprague Dawley rats included two division (non-diabetic and diabetic) which were further divided in nine groups. Diabetes induction and follow up throughout the experimental period was confirmed by measuring the levels of fructosamine and blood glucose. Full-thickness wounds was induced in both non-diabetic and diabetic animals followed by infection with Staphylococcus aureus according to the experimental design. The wound healing effect of M-CS/Le NPs was evaluated through measurements of the oxidative stress, inflammatory cytokines and apoptotic proteins. Our results showed the anti-microbial, free radical scavenging and hemolysis inhibition effects of M-CS/Le NPs in vitro. Moreover, the preparation of M-CS/Le NPs decreased the dose of used melatonin (when compared to free melatonin). M-CS/Le NPs significantly decreased the wound area percent in treated infected wounds of both non-diabetic and diabetic rats more than free melatonin or unloaded CS/Le NPs. In conclusion, M-CS/Le NPs promoted the wound healing in Staphylococcus aureus-infected wounds in diabetic rats.
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Affiliation(s)
- Alyaa Farid
- Biotechnology Department, Faculty of Science, Cairo University, Giza, Egypt.
| | - Ayah Mohsen
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Bassant Nasser
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Habiba Alaa
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
| | - Mariam Abdelaziz
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
| | - Maryam Mustafa
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
| | - Mustafa Mansour
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
| | - Nourhan Adel
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Salma Magdy
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
| | - Salma Mohsen
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
| | - Samah Adel
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Sarah Ibrahim
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | | | - Sohaila Mohamed
- Biochemistry Department, Faculty of Science, Cairo University, Giza, Egypt
| | - Yomna El-Karamany
- Biotechnology/Biomolecular chemistry program, Faculty of Science, Cairo University, Giza, Egypt
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Nakamura H, Makiguchi T, Yamada Y, Tsunoda A, Tomaru N, Yokoo S. Evaluation of CONUT Score and Serum Zinc Levels in Patients with Diabetic Foot Ulcers. INT J LOW EXTR WOUND 2025:15347346251326247. [PMID: 40080868 DOI: 10.1177/15347346251326247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/15/2025]
Abstract
BackgroundDiabetic foot ulcer (DFU) is a severe complication of diabetes. Nutritional deficiencies, including poor nutritional status reflected by a high CONUT score and low serum zinc have been implicated in the severity and wound healing failure of DFU. However, the association between these factors and DFU remains unclear.MethodsA retrospective cohort study was performed in 319 patients categorized into three groups: healthy controls (HC, n = 213), patients with diabetes without foot ulcer (DM, n = 67), and patients with diabetes with foot ulcer (DFU, n = 39). Demographic, clinical, nutritional, and biochemical data were collected, including age, sex, body mass index, the presence of chronic limb-threatening ischemia (CLTI), the presence of maintenance dialysis, CONUT score, hemoglobin A1c, hemoglobin (Hb), total protein (TP), and zinc levels. The severity of DFU was assessed using the PEDIS score, while wound healing failure was defined based on specific clinical criteria. Statistical analyses were conducted to identify factors associated with DFU severity and wound healing failure.ResultsDFU cases had significantly lower Hb, TP, and zinc levels and higher CONUT score compared to the HC and DM cases. Within the DFU group, high PEDIS score (>8) was associated with significantly higher CONUT score, lower TP levels, and the presence of CLTI. Patients with wound healing failure had significantly lower zinc and Hb levels and a higher prevalence of CLTI. Multivariable logistic regression identified CONUT score and the prevalence of CLTI as independent factors associated with DFU severity, while serum zinc levels and the prevalence of CLTI were independently associated with wound healing failure.ConclusionsThis study highlighted the critical role of poor nutritional status, as indicated by high CONUT score, and zinc deficiency in the severity and poor healing outcomes of DFU. These findings underscore the critical role of nutritional management in comprehensive treatment of DFU.
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Affiliation(s)
- Hideharu Nakamura
- Department of Plastic and Reconstructive Surgery, National Hospital Organization (NHO) Takasaki General Medical Center, Takasaki, Japan
| | - Takaya Makiguchi
- Department of Oral and Maxillofacial Surgery, and Plastic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Yumi Yamada
- Department of Plastic and Reconstructive Surgery, National Hospital Organization (NHO) Takasaki General Medical Center, Takasaki, Japan
| | - Aya Tsunoda
- Department of Oral and Maxillofacial Surgery, and Plastic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Nana Tomaru
- Department of Oral and Maxillofacial Surgery, and Plastic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Satoshi Yokoo
- Department of Oral and Maxillofacial Surgery, and Plastic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
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Fukuishi N, Takahama K, Kurosaki H, Ono S, Asai H. The Role of Endogenous Specialized Proresolving Mediators in Mast Cells and Their Involvement in Inflammation and Resolution. Int J Mol Sci 2025; 26:1491. [PMID: 40003957 PMCID: PMC11855587 DOI: 10.3390/ijms26041491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 02/05/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
Many polyunsaturated fatty acids within cells exhibit diverse physiological functions. Particularly, arachidonic acid is the precursor of highly bioactive prostaglandins and leukotrienes, which are pro-inflammatory mediators. However, polyunsaturated fatty acids, such as arachidonic, docosahexaenoic, and eicosapentaenoic acids, can be metabolized into specialized proresolving mediators (SPMs), which have anti-inflammatory properties. Given that pro-inflammatory mediators and SPMs are produced via similar enzymatic pathways, SPMs can play a crucial role in mitigating excessive tissue damage induced by inflammation. Mast cells are immune cells that are widely distributed and strategically positioned at interfaces with the external environment, such as the skin and mucosa. As immune system sentinels, they respond to harmful pathogens and foreign substances. Upon activation, mast cells release various pro-inflammatory mediators, initiating an inflammatory response. Furthermore, these cells secrete factors that promote tissue repair and inhibit inflammation. This dual function positions mast cells as central regulators, balancing between the body's defense mechanisms and the need to minimize tissue injury. This review investigates the production of SPMs by mast cells and their subsequent effects on these cells. By elucidating the intricate relationship between mast cells and SPMs, this review aims to provide a comprehensive understanding of the mechanism by which these cells regulate the delicate balance between tissue damage and repair at inflammatory sites, ultimately contributing to the resolution of inflammatory responses.
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Affiliation(s)
- Nobuyuki Fukuishi
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kinjo Gakuin University, Nagoya 463-8521, Japan; (H.K.); (S.O.); (H.A.)
| | - Kentaro Takahama
- Technology Center, Tokai National Higher Education and Research System, Nagoya 464-8601, Japan;
| | - Hiromasa Kurosaki
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kinjo Gakuin University, Nagoya 463-8521, Japan; (H.K.); (S.O.); (H.A.)
| | - Sayaka Ono
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kinjo Gakuin University, Nagoya 463-8521, Japan; (H.K.); (S.O.); (H.A.)
| | - Haruka Asai
- Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kinjo Gakuin University, Nagoya 463-8521, Japan; (H.K.); (S.O.); (H.A.)
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Al Mamun A, Shao C, Geng P, Wang S, Xiao J. Recent advances in the role of neuroregulation in skin wound healing. BURNS & TRAUMA 2025; 13:tkae072. [PMID: 39872039 PMCID: PMC11770601 DOI: 10.1093/burnst/tkae072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 10/24/2024] [Accepted: 11/01/2024] [Indexed: 01/29/2025]
Abstract
Neuroregulation during skin wound healing involves complex interactions between the nervous system and intricate tissue repair processes. The skin, the largest organ, depends on a complex system of nerves to manage responses to injury. Recent research has emphasized the crucial role of neuroregulation in maximizing wound healing outcomes. Recently, researchers have also explained the interactive contact between the peripheral nervous system and skin cells during the different phases of wound healing. Neurotransmitters and neuropeptides, once observed as simple signalling molecules, have since been recognized as effective regulators of inflammation, angiogenesis, and cell proliferation. The significance of skin innervation and neuromodulators is underscored by the delayed wound healing observed in patients with diabetes and the regenerative capabilities of foetal skin. Foetal skin regeneration is influenced by the neuroregulatory environment, immature immune system, abundant growth factors, and increased pluripotency of cells. Foetal skin cells exhibit greater flexibility and specialized cell types, and the extracellular matrix composition promotes regeneration. The extracellular matrix composition of foetal skin promotes regeneration, making it more capable than adult skin because neuroregulatory signals affect skin regeneration. The understanding of these systems can facilitate the development of therapeutic strategies to alter the nerve supply to the skin to enhance the process of wound healing. Neuroregulation is being explored as a potential therapeutic strategy for enhancing skin wound repair. Bioelectronic strategies and neuromodulation techniques can manipulate neural signalling, optimize the neuroimmune axis, and modulate inflammation. This review describes the function of skin innervation in wound healing, emphasizing the importance of neuropeptides released by sensory and autonomic nerve fibres. This article discusses significant discoveries related to neuroregulation and its impact on skin wound healing.
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Affiliation(s)
- Abdullah Al Mamun
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chuxiao Shao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Peiwu Geng
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Shuanghu Wang
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
| | - Jian Xiao
- Central Laboratory of The Lishui Hospital of Wenzhou Medical University, The First Affiliated Hospital of Lishui University, Lishui People's Hospital, Lishui, Zhejiang 323000, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
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Bawazir M, Roy S, Ali H. The development of murine bone marrow-derived mast cells expressing functional human MRGPRX2 for ex vivo and in vivo studies. Front Immunol 2024; 15:1523393. [PMID: 39749337 PMCID: PMC11693745 DOI: 10.3389/fimmu.2024.1523393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 11/29/2024] [Indexed: 01/04/2025] Open
Abstract
Introduction A subtype of human mast cells (MCs) found in the skin and to a lesser extent in the lung and gut express a novel G protein-coupled receptor (GPCR) known as Mas-related GPCR-X2 (MRGPRX2, mouse counterpart MrgprB2). In addition to drug-induced pseudoallergy and cutaneous disorders, MrgprB2 contributes to ulcerative colitis, IgE-mediated lung inflammation and systemic anaphylaxis. Interestingly, most agonists activate MRGPRX2 with higher potency than MrgprB2. In this study, we sought to replace mouse MrgprB2 with human MRGPRX2 and to study receptor function ex vivo and in vivo. Methods MrgprB2-/- bone marrow (BM) cells were transduced with retrovirus encoding MRGPRX2 and differentiated into BMMCs (MRGRPX2-BMMCs) ex vivo. Cell surface MRGPRX2 expression was determined by flow cytometry. Effects of substance P (SP) and LL-37 on Ca2+ mobilization, degranulation and TNF-α generation were determined. MRGPRX2-BMMCs were engrafted intraperitoneally into MC-deficient Wsh/Wsh mice. After 6-8 weeks, immunofluorescence staining was performed on peritoneal lavage cells (PLCs), and sections of small intestine and colon with anti c-Kit and anti-MRGPRX2 antibodies. SP-induced degranulation in PLCs obtained from engrafted mice was determined. Results MRGPRX2-BMMCs expressed cell surface MRGPRX2 and responded to both SP and LL-37 for Ca2+ mobilization, degranulation and TNF-α generation. Furthermore, Wsh/Wsh mice engrafted with MRGPRX2-BMMCs expressed the receptor in peritoneal, intestinal and colonic MCs. In addition, PLCs from engrafted mice responded to SP for degranulation. Conclusion Replacing mouse MrgprB2 with functional human MRGPRX2 in primary BMMCs and their engraftment in MC-deficient mice demonstrated the expression of this receptor in different tissues, which provides unique opportunities to study receptor signaling ex vivo and disease phenotype in vivo.
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Affiliation(s)
- Maram Bawazir
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Oral Diagnostic Sciences, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Saptarshi Roy
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Hydar Ali
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
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Guth C, Limjunyawong N, Pundir P. The evolving role of mast cells in wound healing: insights from recent research and diverse models. Immunol Cell Biol 2024; 102:878-890. [PMID: 39377394 DOI: 10.1111/imcb.12824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 09/16/2024] [Accepted: 09/18/2024] [Indexed: 10/09/2024]
Abstract
Chronic wounds significantly burden health care systems worldwide, requiring novel strategies to ease their impact. Many physiological processes underlying wound healing are well studied but the role of mast cells remains controversial. Mast cells are innate immune cells and play an essential role in barrier function by inducing inflammation to defend the host against chemical irritants and infections, among others. Many mast cell-derived mediators have proposed roles in wound healing; however, in vivo evidence using mouse models has produced conflicting results. Recently, studies involving more complex wound models such as infected wounds, diabetic wounds and wounds healing under psychological stress suggest that mast cells play critical roles in these processes. This review briefly summarizes the existing literature regarding mast cells in normal wounds and the potential reasons for the contradictory results. Focus will be placed on examining more recent work emerging in the last 5 years that explores mast cells in more complex systems of wound healing, including infection, psychological stress and diabetes, with a discussion of how these discoveries may inspire future work in the field.
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Affiliation(s)
- Colin Guth
- Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, ON, Canada
| | - Nathachit Limjunyawong
- Research Department, Center of Research Excellence in Allergy and Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Priyanka Pundir
- Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, ON, Canada
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Peña OA, Martin P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol 2024; 25:599-616. [PMID: 38528155 DOI: 10.1038/s41580-024-00715-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2024] [Indexed: 03/27/2024]
Abstract
Wound healing is a complex process that involves the coordinated actions of many different tissues and cell lineages. It requires tight orchestration of cell migration, proliferation, matrix deposition and remodelling, alongside inflammation and angiogenesis. Whereas small skin wounds heal in days, larger injuries resulting from trauma, acute illness or major surgery can take several weeks to heal, generally leaving behind a fibrotic scar that can impact tissue function. Development of therapeutics to prevent scarring and successfully repair chronic wounds requires a fuller knowledge of the cellular and molecular mechanisms driving wound healing. In this Review, we discuss the current understanding of the different phases of wound healing, from clot formation through re-epithelialization, angiogenesis and subsequent scar deposition. We highlight the contribution of different cell types to skin repair, with emphasis on how both innate and adaptive immune cells in the wound inflammatory response influence classically studied wound cell lineages, including keratinocytes, fibroblasts and endothelial cells, but also some of the less-studied cell lineages such as adipocytes, melanocytes and cutaneous nerves. Finally, we discuss newer approaches and research directions that have the potential to further our understanding of the mechanisms underpinning tissue repair.
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Affiliation(s)
- Oscar A Peña
- School of Biochemistry, University of Bristol, Bristol, UK.
| | - Paul Martin
- School of Biochemistry, University of Bristol, Bristol, UK.
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10
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Barone V, Scirocco L, Surico PL, Micera A, Cutrupi F, Coassin M, Di Zazzo A. Mast cells and ocular surface: An update review. Exp Eye Res 2024; 245:109982. [PMID: 38942134 DOI: 10.1016/j.exer.2024.109982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 06/10/2024] [Accepted: 06/25/2024] [Indexed: 06/30/2024]
Abstract
Mast cells (MCs), traditionally viewed as key players in IgE-mediated allergic responses, are increasingly recognized for their versatile roles. Situated at critical barrier sites such as the ocular surface, these sentinel cells participate in a broad array of physiological and pathological processes. This review presents a comprehensive update on the immune pathophysiology of MCs, with a particular focus on the mechanisms underlying innate immunity. It highlights their roles at the ocular surface, emphasizing their participation in allergic reactions, maintenance of corneal homeostasis, neovascularization, wound healing, and immune responses in corneal grafts. The review also explores the potential of MCs as therapeutic targets, given their significant contributions to disease pathogenesis and their capacity to modulate immunity. Through a thorough examination of current literature, we aim to elucidate the immune pathophysiology and multifaceted roles of MCs in ocular surface health and disease, suggesting directions for future research and therapeutic innovation.
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Affiliation(s)
- Vincenzo Barone
- Ophthalmology Campus Bio-Medico University, Rome, Italy; Ophthalmology Operative Complex Unit, Campus Bio-Medico University Hospital Foundation, Rome, Italy
| | - Laura Scirocco
- Ophthalmology Campus Bio-Medico University, Rome, Italy; Ophthalmology Operative Complex Unit, Campus Bio-Medico University Hospital Foundation, Rome, Italy
| | - Pier Luigi Surico
- Ophthalmology Campus Bio-Medico University, Rome, Italy; Ophthalmology Operative Complex Unit, Campus Bio-Medico University Hospital Foundation, Rome, Italy; Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Alessandra Micera
- Research and Development Laboratory for Biochemical, Molecular and Cellular Applications in Ophthalmological Science, IRCCS - Fondazione Bietti, Rome, Italy
| | - Francesco Cutrupi
- Ophthalmology Campus Bio-Medico University, Rome, Italy; Ophthalmology Operative Complex Unit, Campus Bio-Medico University Hospital Foundation, Rome, Italy
| | - Marco Coassin
- Ophthalmology Campus Bio-Medico University, Rome, Italy; Ophthalmology Operative Complex Unit, Campus Bio-Medico University Hospital Foundation, Rome, Italy
| | - Antonio Di Zazzo
- Ophthalmology Campus Bio-Medico University, Rome, Italy; Ophthalmology Operative Complex Unit, Campus Bio-Medico University Hospital Foundation, Rome, Italy; Rare Corneal Diseases Center, Campus Bio-Medico University Hospital Foundation, Rome, Italy.
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11
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Norrby K. On Connective Tissue Mast Cells as Protectors of Life, Reproduction, and Progeny. Int J Mol Sci 2024; 25:4499. [PMID: 38674083 PMCID: PMC11050338 DOI: 10.3390/ijms25084499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/10/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
The connective tissue mast cell (MC), a sentinel tissue-residing secretory immune cell, has been preserved in all vertebrate classes since approximately 500 million years. No physiological role of the MC has yet been established. Considering the power of natural selection of cells during evolution, it is likely that the MCs exert essential yet unidentified life-promoting actions. All vertebrates feature a circulatory system, and the MCs interact readily with the vasculature. It is notable that embryonic MC progenitors are generated from endothelial cells. The MC hosts many surface receptors, enabling its activation via a vast variety of potentially harmful exogenous and endogenous molecules and via reproductive hormones in the female sex organs. Activated MCs release a unique composition of preformed and newly synthesized bioactive molecules, like heparin, histamine, serotonin, proteolytic enzymes, cytokines, chemokines, and growth factors. MCs play important roles in immune responses, tissue remodeling, cell proliferation, angiogenesis, inflammation, wound healing, tissue homeostasis, health, and reproduction. As recently suggested, MCs enable perpetuation of the vertebrates because of key effects-spanning generations-in ovulation and pregnancy, as in life-preserving activities in inflammation and wound healing from birth till reproductive age, thus creating a permanent life-sustaining loop. Here, we present recent advances that further indicate that the MC is a specific life-supporting and progeny-safeguarding cell.
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Affiliation(s)
- Klas Norrby
- Department of Pathology, Institute of Medical Biology, Sahlgren Academy, University of Gothenburg, 7 Ostindiefararen, SE-417 65 Gothenburg, Sweden
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12
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Gao M, Guo H, Dong X, Wang Z, Yang Z, Shang Q, Wang Q. Regulation of inflammation during wound healing: the function of mesenchymal stem cells and strategies for therapeutic enhancement. Front Pharmacol 2024; 15:1345779. [PMID: 38425646 PMCID: PMC10901993 DOI: 10.3389/fphar.2024.1345779] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/05/2024] [Indexed: 03/02/2024] Open
Abstract
A wound takes a long time to heal and involves several steps. Following tissue injury, inflammation is the primary cause of tissue regeneration and repair processes. As a result, the pathophysiological processes involving skin damage, healing, and remodeling depend critically on the control of inflammation. The fact that it is a feasible target for improving the prognosis of wound healing has lately become clear. Mesenchymal stem cells (MSCs) are an innovative and effective therapeutic option for wound healing due to their immunomodulatory and paracrine properties. By controlling the inflammatory milieu of wounds through immunomodulation, transplanted MSCs have been shown to speed up the healing process. In addition to other immunomodulatory mechanisms, including handling neutrophil activity and modifying macrophage polarization, there may be modifications to the activation of T cells, natural killer (NK) cells, and dendritic cells (DCs). Furthermore, several studies have shown that pretreating MSCs improves their ability to modulate immunity. In this review, we summarize the existing knowledge about how MSCs influence local inflammation in wounds by influencing immunity to facilitate the healing process. We also provide an overview of MSCs optimizing techniques when used to treat wounds.
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Affiliation(s)
| | | | | | | | | | | | - Qiying Wang
- Department of Plastic Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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13
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Bosveld CJ, Guth C, Limjunyawong N, Pundir P. Emerging Role of the Mast Cell-Microbiota Crosstalk in Cutaneous Homeostasis and Immunity. Cells 2023; 12:2624. [PMID: 37998359 PMCID: PMC10670560 DOI: 10.3390/cells12222624] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 11/07/2023] [Accepted: 11/09/2023] [Indexed: 11/25/2023] Open
Abstract
The skin presents a multifaceted microbiome, a balanced coexistence of bacteria, fungi, and viruses. These resident microorganisms are fundamental in upholding skin health by both countering detrimental pathogens and working in tandem with the skin's immunity. Disruptions in this balance, known as dysbiosis, can lead to disorders like psoriasis and atopic dermatitis. Central to the skin's defense system are mast cells. These are strategically positioned within the skin layers, primed for rapid response to any potential foreign threats. Recent investigations have started to unravel the complex interplay between these mast cells and the diverse entities within the skin's microbiome. This relationship, especially during times of both balance and imbalance, is proving to be more integral to skin health than previously recognized. In this review, we illuminate the latest findings on the ties between mast cells and commensal skin microorganisms, shedding light on their combined effects on skin health and maladies.
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Affiliation(s)
- Cameron Jackson Bosveld
- Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, ON N1G 2W1, Canada; (C.J.B.); (C.G.)
| | - Colin Guth
- Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, ON N1G 2W1, Canada; (C.J.B.); (C.G.)
| | - Nathachit Limjunyawong
- Center of Research Excellence in Allergy and Immunology, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Priyanka Pundir
- Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, ON N1G 2W1, Canada; (C.J.B.); (C.G.)
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14
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Allemailem KS, Alsahli MA, Almatroudi A, Alrumaihi F, Al Abdulmonem W, Moawad AA, Alwanian WM, Almansour NM, Rahmani AH, Khan AA. Innovative Strategies of Reprogramming Immune System Cells by Targeting CRISPR/Cas9-Based Genome-Editing Tools: A New Era of Cancer Management. Int J Nanomedicine 2023; 18:5531-5559. [PMID: 37795042 PMCID: PMC10547015 DOI: 10.2147/ijn.s424872] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 09/16/2023] [Indexed: 10/06/2023] Open
Abstract
The recent developments in the study of clustered regularly interspaced short palindromic repeats/associated protein 9 (CRISPR/Cas9) system have revolutionized the art of genome-editing and its applications for cellular differentiation and immune response behavior. This technology has further helped in understanding the mysteries of cancer progression and possible designing of novel antitumor immunotherapies. CRISPR/Cas9-based genome-editing is now often used to engineer universal T-cells, equipped with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR). In addition, this technology is used in cytokine stimulation, antibody designing, natural killer (NK) cell transfer, and to overcome immune checkpoints. The innovative potential of CRISPR/Cas9 in preparing the building blocks of adoptive cell transfer (ACT) immunotherapy has opened a new window of antitumor immunotherapy and some of them have gained FDA approval. The manipulation of immunogenetic regulators has opened a new interface for designing, implementation and interpretation of CRISPR/Cas9-based screening in immuno-oncology. Several cancers like lymphoma, melanoma, lung, and liver malignancies have been treated with this strategy, once thought to be impossible. The safe and efficient delivery of CRISPR/Cas9 system within the immune cells for the genome-editing strategy is a challenging task which needs to be sorted out for efficient immunotherapy. Several targeting approaches like virus-mediated, electroporation, microinjection and nanoformulation-based methods have been used, but each procedure offers some limitations. Here, we elaborate the recent updates of cancer management through immunotherapy in partnership with CRISPR/Cas9 technology. Further, some innovative methods of targeting this genome-editing system within the immune system cells for reprogramming them, as a novel strategy of anticancer immunotherapy is elaborated. In addition, future prospects and clinical trials are also discussed.
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Affiliation(s)
- Khaled S Allemailem
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Mohammed A Alsahli
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Faris Alrumaihi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Amira A Moawad
- Friedrich-Loeffler-Institut, Institute of Bacterial Infections and Zoonoses, Jena, Germany
| | - Wanian M Alwanian
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Nahlah Makki Almansour
- Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin, Saudi Arabia
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Amjad Ali Khan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
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15
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Wang RM, Mesfin JM, Karkanitsa M, Ungerleider JL, Zelus E, Zhang Y, Kawakami Y, Kawakami Y, Kawakami T, Christman KL. Immunomodulatory contribution of mast cells to the regenerative biomaterial microenvironment. NPJ Regen Med 2023; 8:53. [PMID: 37730736 PMCID: PMC10511634 DOI: 10.1038/s41536-023-00324-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 08/31/2023] [Indexed: 09/22/2023] Open
Abstract
Bioactive immunomodulatory biomaterials have shown promise for influencing the immune response to promote tissue repair and regeneration. Macrophages and T cells have been associated with this response; however, other immune cell types have been traditionally overlooked. In this study, we investigated the role of mast cells in the regulation of the immune response to decellularized biomaterial scaffolds using a subcutaneous implant model. In mast cell-deficient mice, there was dysregulation of the expected M1 to M2 macrophage transition typically induced by the biomaterial scaffold. Polarization progression deviated in a sex-specific manner with an early transition to an M2 profile in female mice, while the male response was unable to properly transition past a pro-inflammatory M1 state. Both were reversed with adoptive mast cell transfer. Further investigation of the later-stage immune response in male mice determined a greater sustained pro-inflammatory gene expression profile, including the IL-1 cytokine family, IL-6, alarmins, and chemokines. These results highlight mast cells as another important cell type that influences the immune response to pro-regenerative biomaterials.
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Affiliation(s)
- Raymond M Wang
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
| | - Joshua M Mesfin
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
| | - Maria Karkanitsa
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
| | - Jessica L Ungerleider
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
| | - Emma Zelus
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA
| | - Yuxue Zhang
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yu Kawakami
- Laboratory of Allergic Diseases, Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, California, 92037, USA
- Department of Dermatology, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Yuko Kawakami
- Laboratory of Allergic Diseases, Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, California, 92037, USA
- Department of Dermatology, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Toshiaki Kawakami
- Laboratory of Allergic Diseases, Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, California, 92037, USA
- Department of Dermatology, University of California San Diego, School of Medicine, La Jolla, CA, 92093, USA
| | - Karen L Christman
- Shu Chien-Gene Lay Department of Bioengineering, Sanford Consortium of Regenerative Medicine, University of California San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA, 92037, USA.
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16
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Zhu M, Cao L, Melino S, Candi E, Wang Y, Shao C, Melino G, Shi Y, Chen X. Orchestration of Mesenchymal Stem/Stromal Cells and Inflammation During Wound Healing. Stem Cells Transl Med 2023; 12:576-587. [PMID: 37487541 PMCID: PMC10502569 DOI: 10.1093/stcltm/szad043] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 06/13/2023] [Indexed: 07/26/2023] Open
Abstract
Wound healing is a complex process and encompasses a number of overlapping phases, during which coordinated inflammatory responses following tissue injury play dominant roles in triggering evolutionarily highly conserved principals governing tissue repair and regeneration. Among all nonimmune cells involved in the process, mesenchymal stem/stromal cells (MSCs) are most intensely investigated and have been shown to play fundamental roles in orchestrating wound healing and regeneration through interaction with the ordered inflammatory processes. Despite recent progress and encouraging results, an informed view of the scope of this evolutionarily conserved biological process requires a clear understanding of the dynamic interplay between MSCs and the immune systems in the process of wound healing. In this review, we outline current insights into the ways in which MSCs sense and modulate inflammation undergoing the process of wound healing, highlighting the central role of neutrophils, macrophages, and T cells during the interaction. We also draw attention to the specific effects of MSC-based therapy on different pathological wound healing. Finally, we discuss how ongoing scientific advances in MSCs could be efficiently translated into clinical strategies, focusing on the current limitations and gaps that remain to be overcome for achieving preferred functional tissue regeneration.
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Affiliation(s)
- Mengting Zhu
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People’s Republic of China
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Lijuan Cao
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People’s Republic of China
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Sonia Melino
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Shanghai, People’s Republic of China
| | - Changshun Shao
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People’s Republic of China
| | - Gerry Melino
- Department of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata,”Rome, Italy
| | - Yufang Shi
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, People’s Republic of China
| | - Xiaodong Chen
- Wuxi Sinotide New Drug Discovery Institutes, Huishan Economic and Technological Development Zone, Wuxi, Jiangsu, People’s Republic of China
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17
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Dileepan KN, Raveendran VV, Sharma R, Abraham H, Barua R, Singh V, Sharma R, Sharma M. Mast cell-mediated immune regulation in health and disease. Front Med (Lausanne) 2023; 10:1213320. [PMID: 37663654 PMCID: PMC10470157 DOI: 10.3389/fmed.2023.1213320] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/17/2023] [Indexed: 09/05/2023] Open
Abstract
Mast cells are important components of the immune system, and they perform pro-inflammatory as well as anti-inflammatory roles in the complex process of immune regulation in health and disease. Because of their strategic perivascular localization, sensitivity and adaptability to the microenvironment, and ability to release a variety of preformed and newly synthesized effector molecules, mast cells perform unique functions in almost all organs. Additionally, Mast cells express a wide range of surface and cytoplasmic receptors which enable them to respond to a variety of cytokines, chemicals, and pathogens. The mast cell's role as a cellular interface between external and internal environments as well as between vasculature and tissues is critical for protection and repair. Mast cell interactions with different immune and nonimmune cells through secreted inflammatory mediators may also turn in favor of disease promoting agents. First and forefront, mast cells are well recognized for their multifaceted functions in allergic diseases. Reciprocal communication between mast cells and endothelial cells in the presence of bacterial toxins in chronic/sub-clinical infections induce persistent vascular inflammation. We have shown that mast cell proteases and histamine induce endothelial inflammatory responses that are synergistically amplified by bacterial toxins. Mast cells have been shown to exacerbate vascular changes in normal states as well as in chronic or subclinical infections, particularly among cigarette smokers. Furthermore, a potential role of mast cells in SARS-CoV-2-induced dysfunction of the capillary-alveolar interface adds to the growing understanding of mast cells in viral infections. The interaction between mast cells and microglial cells in the brain further highlights their significance in neuroinflammation. This review highlights the significant role of mast cells as the interface that acts as sensor and early responder through interactions with cells in systemic organs and the nervous system.
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Affiliation(s)
- Kottarappat N. Dileepan
- Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Vineesh V. Raveendran
- Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Rishi Sharma
- Department of Medicine, School of Medicine, University of Missouri, Kansas City, MO, United States
| | - Harita Abraham
- Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, The University of Kansas Medical Center, Kansas City, KS, United States
| | - Rajat Barua
- Cardiology Section, Kansas City Veterans Affairs Medical Center, Kansas City, MO, United States
| | - Vikas Singh
- Neurology Section, Kansas City Veterans Affairs Medical Center, Kansas City, MO, United States
| | - Ram Sharma
- Research and Development Service, Kansas City Veterans Affairs Medical Center, Kansas City, MO, United States
| | - Mukut Sharma
- Research and Development Service, Kansas City Veterans Affairs Medical Center, Kansas City, MO, United States
- Midwest Veterans’ Biomedical Research Foundation (MVBRF), Kansas City VA Medical Center, Kansas, MO, United States
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18
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Keith YH, Egawa G, Honda T, Kabashima K. Mast cells in type 2 skin inflammation: Maintenance and function. Eur J Immunol 2023; 53:e2250359. [PMID: 36933268 DOI: 10.1002/eji.202250359] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/24/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023]
Abstract
Mast cells (MCs) are immune cells residing in tissues and playing indispensable roles in maintaining homeostasis and inflammatory states. Skin lesions associated with atopic dermatitis (AD) and type 2 skin inflammation display an increment in MCs, which have both pro- and anti-inflammatory effects. The direct and indirect activations of skin MCs by environmental factors such as Staphylococcus aureus can instigate type 2 skin inflammation in AD with poorly understood mechanisms. Furthermore, both IgE-dependent and -independent degranulation of MCs contribute to pruritus in AD. Conversely, MCs suppress type 2 skin inflammation by promoting Treg expansion through IL-2 secretion in the spleen. Moreover, skin MCs can upregulate gene expression involved in skin barrier function, thus mitigating AD-like inflammation. These functional variances of MCs in AD could stem from differences in experimental systems, their localization, and origins. In this review, we will focus on how MCs are maintained in the skin under homeostatic and inflammatory conditions, and how they are involved in the pathogenesis of type 2 skin inflammation.
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Affiliation(s)
- Yuki Honda Keith
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Intravital Microscopy Laboratory and Gene Expression (IMAGE) Lab, Precision Immunology Program, Garvan Institute of Medical Research, Sydney, Australia
| | - Gyohei Egawa
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Tetsuya Honda
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kenji Kabashima
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
- A*Star Skin Research Labs (A*SRL), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore
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19
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Ni H, Xi J, Tang J, Yan Y, Chu Y, Zhou J. Therapeutic Potential of Extracellular Vesicles from Different Stem Cells in Chronic Wound Healing. Stem Cell Rev Rep 2023; 19:1596-1614. [PMID: 37178227 DOI: 10.1007/s12015-023-10540-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/31/2023] [Indexed: 05/15/2023]
Abstract
Wound healing has long been a complex problem, especially in chronic wounds. Although debridement, skin grafting, and antimicrobial dressings have been used to treat chronic wounds, their treatment period is long, expensive, and has specific rejection reactions. The poor treatment results of traditional methods have caused psychological stress to patients and a substantial economic burden to society. Extracellular vesicles (EVs) are nanoscale vesicles secreted by cells. They play an essential role in intercellular communication. Numerous studies have confirmed that stem cell-derived extracellular vesicles (SC-EVs) can inhibit overactive inflammation, induce angiogenesis, promote re-epithelization, and reduce scar formation. Therefore, SC-EVs are expected to be a novel cell-free strategy for chronic wound treatment. We first summarize the pathological factors that hinder wound healing and discuss how SC-EVs accelerate chronic wound repair. And then, we also compare the advantages and disadvantages of different SC-EVs for chronic wound treatment. Finally, we discuss the limitations of SC-EVs usage and provide new thoughts for future SC-EVs research in chronic wound treatment.
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Affiliation(s)
- Haoxi Ni
- School of Medicine, Jiangsu University, Zhenjiang, 212013, China
| | - Jianbo Xi
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China
| | - Jianjun Tang
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China
- Department of General Surgery, Wujin Clinical College of Xuzhou Medical University, Changzhou, 213017, China
| | - Yongmin Yan
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Changzhou, 213017, China
| | - Ying Chu
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China.
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China.
| | - Jing Zhou
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, 213017, China.
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Changzhou, 213017, China.
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20
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Kidzeru EB, Lebeko M, Sharma JR, Nkengazong L, Adeola HA, Ndlovu H, P Khumalo N, Bayat A. Immune cells and associated molecular markers in dermal fibrosis with focus on raised cutaneous scars. Exp Dermatol 2023; 32:570-587. [PMID: 36562321 PMCID: PMC10947010 DOI: 10.1111/exd.14734] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 08/04/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022]
Abstract
Raised dermal scars including hypertrophic, and keloid scars as well as scalp-associated fibrosing Folliculitis Keloidalis Nuchae (FKN) are a group of fibrotic raised dermal lesions that mostly occur following cutaneous injury. They are characterized by increased extracellular matrix (ECM) deposition, primarily excessive collagen type 1 production by hyperproliferative fibroblasts. The extent of ECM deposition is thought to be proportional to the severity of local skin inflammation leading to excessive fibrosis of the dermis. Due to a lack of suitable study models, therapy for raised dermal scars remains ill-defined. Immune cells and their associated markers have been strongly associated with dermal fibrosis. Therefore, modulation of the immune system and use of anti-inflammatory cytokines are of potential interest in the management of dermal fibrosis. In this review, we will discuss the importance of immune factors in the pathogenesis of raised dermal scarring. The aim here is to provide an up-to-date comprehensive review of the literature, from PubMed, Scopus, and other relevant search engines in order to describe the known immunological factors associated with raised dermal scarring. The importance of immune cells including mast cells, macrophages, lymphocytes, and relevant molecules such as cytokines, chemokines, and growth factors, antibodies, transcription factors, and other immune-associated molecules as well as tissue lymphoid aggregates identified within raised dermal scars will be presented. A growing body of evidence points to a shift from proinflammatory Th1 response to regulatory/anti-inflammatory Th2 response being associated with the development of fibrogenesis in raised dermal scarring. In summary, a better understanding of immune cells and associated molecular markers in dermal fibrosis will likely enable future development of potential immune-modulated therapeutic, diagnostic, and theranostic targets in raised dermal scarring.
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Affiliation(s)
- Elvis Banboye Kidzeru
- Wound Healing And Keloid Scar Unit, Medical Research Council (South Africa), Hair and Skin Research Laboratory, Division of Dermatology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
- Microbiology, Infectious Diseases, and Immunology Laboratory (LAMMII)Centre for Research on Health and Priority Pathologies (CRSPP)Institute of Medical Research and Medicinal Plant Studies (IMPM), Ministry of Scientific Research and InnovationYaoundéCameroon
| | - Maribanyana Lebeko
- Wound Healing And Keloid Scar Unit, Medical Research Council (South Africa), Hair and Skin Research Laboratory, Division of Dermatology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
- Present address:
Cape Biologix Technologies (PTY, LTD)Cape TownSouth Africa
| | - Jyoti Rajan Sharma
- Wound Healing And Keloid Scar Unit, Medical Research Council (South Africa), Hair and Skin Research Laboratory, Division of Dermatology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
- Biomedical Research and Innovation Platform, South African Medical Research Council, Francie van Zijl Drive, Parow ValleyCape TownSouth Africa
- Present address:
Biomedical Research and Innovation Platform, South African Medical Research Council, Francie van Zijl Drive, Parow ValleyCape TownSouth Africa
| | - Lucia Nkengazong
- Microbiology, Infectious Diseases, and Immunology Laboratory (LAMMII)Centre for Research on Health and Priority Pathologies (CRSPP)Institute of Medical Research and Medicinal Plant Studies (IMPM), Ministry of Scientific Research and InnovationYaoundéCameroon
| | - Henry Ademola Adeola
- Wound Healing And Keloid Scar Unit, Medical Research Council (South Africa), Hair and Skin Research Laboratory, Division of Dermatology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
| | - Hlumani Ndlovu
- Department of Integrative Biomedical SciencesUniversity of Cape TownCape TownSouth Africa
| | - Nonhlanhla P Khumalo
- Wound Healing And Keloid Scar Unit, Medical Research Council (South Africa), Hair and Skin Research Laboratory, Division of Dermatology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
| | - Ardeshir Bayat
- Wound Healing And Keloid Scar Unit, Medical Research Council (South Africa), Hair and Skin Research Laboratory, Division of Dermatology, Department of MedicineUniversity of Cape TownCape TownSouth Africa
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21
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Leonardo TR, Chen L, Schrementi ME, Shi J, Marucha PT, Glass K, DiPietro LA. Transcriptional changes in human palate and skin healing. Wound Repair Regen 2023; 31:156-170. [PMID: 36571451 PMCID: PMC10006330 DOI: 10.1111/wrr.13068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/26/2022] [Accepted: 12/20/2022] [Indexed: 12/27/2022]
Abstract
Most human tissue injuries lead to the formation of a fibrous scar and result in the loss of functional tissue. One adult tissue that exhibits a more regenerative response to injury with minimal scarring is the oral mucosa. We generated a microarray gene expression dataset to examine the response to injury in human palate and skin excisional biopsies spanning the first 7 days after wounding. Differential expression analyses were performed in each tissue to identify genes overexpressed or underexpressed over time when compared to baseline unwounded tissue gene expression levels. To attribute biological processes of interest to these gene expression changes, gene set enrichment analysis was used to identify core gene sets that are enriched over the time-course of the wound healing process with respect to unwounded tissue. This analysis identified gene sets uniquely enriched in either palate or skin wounds and gene sets that are enriched in both tissues in at least one time point after injury. Finally, a cell type enrichment analysis was performed to better understand the cell type distribution in these tissues and how it changes over the time course of wound healing. This work provides a source of human wound gene expression data that includes two tissue types with distinct regenerative and scarring phenotypes.
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Affiliation(s)
- Trevor R Leonardo
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, USA
- Department of Periodontics, Center for Wound Healing and Tissue Regeneration, University of Illinois Chicago, Chicago, Illinois, USA
| | - Lin Chen
- Department of Periodontics, Center for Wound Healing and Tissue Regeneration, University of Illinois Chicago, Chicago, Illinois, USA
| | - Megan E Schrementi
- Department of Science and Health, DePaul University, Chicago, Illinois, USA
| | - Junhe Shi
- Department of Periodontics, Center for Wound Healing and Tissue Regeneration, University of Illinois Chicago, Chicago, Illinois, USA
- National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Traditional Chinese Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Phillip T Marucha
- Department of Periodontics, College of Dentistry, Oregon Health and Sciences University, Portland, Oregon, USA
| | - Kimberly Glass
- Channing Division of Network Medicine,Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Biostatistics, Harvard Chan School of Public Health, Boston, Massachusetts, USA
| | - Luisa A DiPietro
- Department of Periodontics, Center for Wound Healing and Tissue Regeneration, University of Illinois Chicago, Chicago, Illinois, USA
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22
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Ili P, Sari F. Egg yolk oil accelerates wound healing in streptozotocin induced diabetic rats. Biotech Histochem 2023; 98:94-111. [PMID: 36040350 DOI: 10.1080/10520295.2022.2115554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Impaired diabetic wound healing causes foot ulcers. We investigated egg yolk oil for skin wound healing in streptozotocin (STZ) induced diabetic rats. Rats were allocated into three groups of six. Group 1, nondiabetic control group, was treated topically with 2% fusidic acid ointment. Group 2, STZ diabetic control, was treated topically with 2% fusidic acid ointment. Group 3, STZ diabetic group, was treated topically with egg yolk oil. Three days after STZ injection, two full thickness excisional skin wounds were created on the back of each animal. Wound diameter was measured for 14 days and wound contraction was calculated. Re-epithelization time also was determined. Three rats from each group were sacrificed on experimental day 7 and the remaining rats on day 14. Wound samples were examined using hematoxylin and eosin, periodic acid-Schiff, Masson's trichrome, Taenzer-Unna orcein and toluidine blue staining. Expression of endoglin (CD105), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) were investigated using immunohistochemistry. Egg yolk oil increased the proliferation of epithelial cells and angiogenesis, and stimulated collagen deposition in the lesion area. Egg yolk oil increased CD105, EGF and VEGF expression in blood vessels, and EGF and VEGF expression in epidermis of the lesions. The predominant fatty acids in egg yolk oil are oleic, palmitic and linoleic, which likely were responsible for the beneficial effects of egg yolk oil on diabetic wound healing. Egg yolk oil appears to be a promising therapeutic agent for healing of diabetic wounds.
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Affiliation(s)
- Pinar Ili
- Department of Medical Services and Techniques, Denizli Vocational School of Health Services, Pamukkale University, Denizli, Turkey
| | - Fikret Sari
- Department of Plant and Animal Production, Tavas Vocational School, Pamukkale University, Denizli, Turkey
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23
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Soliman AM, Barreda DR. Acute Inflammation in Tissue Healing. Int J Mol Sci 2022; 24:ijms24010641. [PMID: 36614083 PMCID: PMC9820461 DOI: 10.3390/ijms24010641] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/19/2022] [Accepted: 12/28/2022] [Indexed: 12/31/2022] Open
Abstract
There are well-established links between acute inflammation and successful tissue repair across evolution. Innate immune reactions contribute significantly to pathogen clearance and activation of subsequent reparative events. A network of molecular and cellular regulators supports antimicrobial and tissue repair functions throughout the healing process. A delicate balance must be achieved between protection and the potential for collateral tissue damage associated with overt inflammation. In this review, we summarize the contributions of key cellular and molecular components to the acute inflammatory process and the effective and timely transition toward activation of tissue repair mechanisms. We further discuss how the disruption of inflammatory responses ultimately results in chronic non-healing injuries.
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Affiliation(s)
- Amro M. Soliman
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Daniel R. Barreda
- Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Correspondence: ; Tel.: +1-(780)492-0375
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24
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Norrby K. Do mast cells contribute to the continued survival of vertebrates? APMIS 2022; 130:618-624. [PMID: 35869669 PMCID: PMC9545593 DOI: 10.1111/apm.13264] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/20/2022] [Indexed: 11/30/2022]
Abstract
This study is an attempt to shed light on why the connective tissue mast cell (MC) is preserved in all species with a blood circulatory system, i.e., the vertebrates since >500 million years, which suggests that the MC performs as yet not understood indispensible life-promoting actions. The literature survey focuses on data in published papers on MC functions in immunological and nonimmunological reactions, host protection, pregnancy, inflammation, and wound healing. All data are thus accessible to the reader. The MC is a secretory cell with a unique mediator profile. A distinctive role for MCs is defined not only by their extensive mediator composition but also by their prominent ability to affect the vasculature to expedite selective cell recruitment and permeability changes and to set the stage for an appropriate acquired response. MCs, harboring a wide range of surface membrane receptors, are activated by the major female sex hormones as well as by diverse potentially adverse stimuli. MC activation/degranulation creates a presumably unique triad tissue response in physiological and pathological situations alike: extracellular matrix degradation and tissue remodeling, de novo cell proliferation, and de novo angiogenesis. As shown in the literature, MC-activation is crucial for successful female reproduction in the mouse, implying one of possibly several yet unidentified physiological roles of MCs. Moreover, the activated MC aids newborns to survive to reproductive age owing to its key beneficial actions in inflammation and wound healing. Thus, a not previously described life-perpetuating loop spanning generations are apparently formed, which, hypothetically, could contribute to the continued survival of the vertebrates.
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Affiliation(s)
- Klas Norrby
- Department of Pathology, Institute of Biomedicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
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25
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Hossain R, Quispe C, Khan RA, Saikat ASM, Ray P, Ongalbek D, Yeskaliyeva B, Jain D, Smeriglio A, Trombetta D, Kiani R, Kobarfard F, Mojgani N, Saffarian P, Ayatollahi SA, Sarkar C, Islam MT, Keriman D, Uçar A, Martorell M, Sureda A, Pintus G, Butnariu M, Sharifi-Rad J, Cho WC. Propolis: An update on its chemistry and pharmacological applications. Chin Med 2022; 17:100. [PMID: 36028892 PMCID: PMC9412804 DOI: 10.1186/s13020-022-00651-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 08/02/2022] [Indexed: 12/23/2022] Open
Abstract
Propolis, a resinous substance produced by honeybees from various plant sources, has been used for thousands of years in traditional medicine for several purposes all over the world. The precise composition of propolis varies according to plant source, seasons harvesting, geography, type of bee flora, climate changes, and honeybee species at the site of collection. This apiary product has broad clinical applications such as antioxidant, anti-inflammatory, antimicrobial, anticancer, analgesic, antidepressant, and anxiolytic as well asimmunomodulatory effects. It is also well known from traditional uses in treating purulent disorders, improving the wound healing, and alleviating many of the related discomforts. Even if its use was already widespread since ancient times, after the First and Second World War, it has grown even more as well as the studies to identify its chemical and pharmacological features, allowing to discriminate the qualities of propolis in terms of the chemical profile and relative biological activity based on the geographic place of origin. Recently, several in vitro and in vivo studies have been carried out and new insights into the pharmaceutical prospects of this bee product in the management of different disorders, have been highlighted. Specifically, the available literature confirms the efficacy of propolis and its bioactive compounds in the reduction of cancer progression, inhibition of bacterial and viral infections as well as mitigation of parasitic-related symptoms, paving the way to the use of propolis as an alternative approach to improve the human health. However, a more conscious use of propolis in terms of standardized extracts as well as new clinical studies are needed to substantiate these health claims.
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Affiliation(s)
- Rajib Hossain
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Dhaka 8100 Bangladesh
| | - Cristina Quispe
- Facultad de Ciencias de La Salud, Universidad Arturo Prat, Avda. Arturo Prat 2120, 1110939 Iquique, Chile
| | - Rasel Ahmed Khan
- Pharmacy Discipline, Life Science School, Khulna University, Khulna, 9280 Bangladesh
| | - Abu Saim Mohammad Saikat
- Department of Biochemistry and Molecular Biology, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100 Bangladesh
| | - Pranta Ray
- Department of Biomedical Engineering, Huazhong University of Science and Technology, Wuhan, China
| | - Damira Ongalbek
- Faculty of Chemistry and Chemical Technology, Al-Farabi Kazakh National University, 050040 Almaty, Kazakhstan
| | - Balakyz Yeskaliyeva
- Faculty of Chemistry and Chemical Technology, Al-Farabi Kazakh National University, 050040 Almaty, Kazakhstan
| | - Divya Jain
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Rajasthan 304022 India
| | - Antonella Smeriglio
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences (ChiBioFarAm), University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy
| | - Domenico Trombetta
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences (ChiBioFarAm), University of Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy
| | - Roghayeh Kiani
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Farzad Kobarfard
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Naheed Mojgani
- Department of Biotechnology, Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Parvaneh Saffarian
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Seyed Abdulmajid Ayatollahi
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Pharmacognosy and Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Chandan Sarkar
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Dhaka 8100 Bangladesh
| | - Mohammad Torequl Islam
- Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Dhaka 8100 Bangladesh
| | - Dılhun Keriman
- Food Processing Department, Vocational School of Technical Sciences, Bingöl University, Bingöl, Turkey
| | - Arserim Uçar
- Food Processing Department, Vocational School of Technical Sciences, Bingöl University, Bingöl, Turkey
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, and Centre for Healthy Living, University of Concepción, Concepción, Chile
- Universidad de Concepción, Unidad de Desarrollo Tecnológico, UDT, 4070386 Concepción, Chile
| | - Antoni Sureda
- Research Group on Community Nutrition and Oxidative Stress, Laboratory of Physical Activity Sciences, and CIBEROBN - Physiopathology of Obesity and Nutrition, CB12/03/30038, University of Balearic Islands, Palma, Spain
| | - Gianfranco Pintus
- Department of Medical Laboratory Sciences, College of Health Sciences and Sharjah Institute for Medical Research, University of Sharjah, 22272 Sharjah, United Arab Emirates
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
| | - Monica Butnariu
- Chemistry & Biochemistry Discipline, University of Life Sciences King Mihai I from Timisoara, Calea Aradului 119, 300645 Timis, Romania
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
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26
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Numata T, Harada K, Nakae S. Roles of Mast Cells in Cutaneous Diseases. Front Immunol 2022; 13:923495. [PMID: 35874756 PMCID: PMC9298983 DOI: 10.3389/fimmu.2022.923495] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/16/2022] [Indexed: 01/05/2023] Open
Abstract
Mast cells are present in all vascularized tissues of the body. They are especially abundant in tissues that are in frequent contact with the surrounding environment and act as potential sources of inflammatory and/or regulatory mediators during development of various infections and diseases. Mature mast cells’ cytoplasm contains numerous granules that store a variety of chemical mediators, cytokines, proteoglycans, and proteases. Mast cells are activated via various cell surface receptors, including FcϵRI, toll-like receptors (TLR), Mas-related G-protein-coupled receptor X2 (MRGPRX2), and cytokine receptors. IgE-mediated mast cell activation results in release of histamine and other contents of their granules into the extracellular environment, contributing to host defense against pathogens. TLRs, play a crucial role in host defense against various types of pathogens by recognizing pathogen-associated molecular patterns. On the other hand, excessive/inappropriate mast cell activation can cause various disorders. Here, we review the published literature regarding the known and potential inflammatory and regulatory roles of mast cells in cutaneous inflammation, including atopic dermatitis, psoriasis, and contact dermatitis GVHD, as well as in host defense against pathogens.
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Affiliation(s)
- Takafumi Numata
- Department of Dermatology, Tokyo Medical University, Tokyo, Japan
| | - Kazutoshi Harada
- Department of Dermatology, Tokyo Medical University, Tokyo, Japan
| | - Susumu Nakae
- Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan.,Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan
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27
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Mousavi M, Khanifar A, Mousavi N, Anbari K, Chehelcheraghi F. Coactivity of Mast Cells and Stem Cells on Angiogenesis and Antioxidants' Potentials at Inflammation, Proliferation, and Tissue Remodeling Phases of Wound. Arch Plast Surg 2022; 49:462-470. [PMID: 35832143 PMCID: PMC9142223 DOI: 10.1055/s-0042-1748665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Background
Reactive oxygen species cause serious damage to the physiological function of tissues. Determination of total antioxidant capacity of skin tissue is one of the determinants of damaged tissue function. Mast cells (MCs) are one of the groups of cells that are invited to the site of injury. The healing process begins with the rapid release of various types of MCs' intermediate factors at the site of injury. Bone marrow mesenchymal stem cell (BMMSC) production and secretion have been shown to regenerate the skin. The aim of this research was to evaluate the wound-healing and antioxidant effects of BMMSCs per MCs.
Methods
Fifty-four albino Wistar male rats were divided into three groups: (1) nonsurgery, (2) surgery, and (3) surgery + BMMSCs. Groups 2 and 3 were operated with a 3 × 8 cm flap and in group 3, cell injections (7 × 10
9
cell injection at the time of surgery) were performed. After days 4, 7, and 15, percentage of the surviving tissue, histological characteristics, superoxide dismutase (SOD) activity, and amount of malondialdehyde (MDA) were measured in the groups. For results, Graph Pad Prism 8 software was used, and data were analyzed and compared by analysis of variance and Tukey test.
Results
BMMSCs' application decreased the amount of MDA, increased SOD activity and survival rate of the flaps, and improved the histological characteristics.
Conclusion
This study revealed the protective effects BMMSCs alongside MCs against oxidative stress on the survival of the flaps. However, for clinical use, more research is needed to determine its benefits.
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Affiliation(s)
- Mahshad Mousavi
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Ahmad Khanifar
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Nazanin Mousavi
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Khatereh Anbari
- Community Medicine Department, Lorestan University of Medical Sciences, Khorramabad, Iran
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28
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Mulder PPG, Koenen HJPM, Vlig M, Joosten I, de Vries RBM, Boekema BKHL. Burn-Induced Local and Systemic Immune Response: Systematic Review and Meta-Analysis of Animal Studies. J Invest Dermatol 2022; 142:3093-3109.e15. [PMID: 35623415 DOI: 10.1016/j.jid.2022.05.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/08/2022] [Accepted: 05/02/2022] [Indexed: 10/31/2022]
Abstract
As burn injuries are often followed by a derailed immune response and excessive inflammation, a thorough understanding of the occurring reactions is key to prevent secondary complications. This systematic review, that includes 247 animal studies, shows the post-burn response of 14 different immune cell types involved in immediate and long-term effects, in both wound tissue and circulation. Peripheral blood neutrophil and monocyte numbers increased directly after burns, whereas thrombocyte numbers increased near the end of the first week. Lymphocyte numbers, however, were decreased for at least two weeks. In burn wound tissue, neutrophil and macrophage numbers accumulated during the first three weeks. Burns also altered cellular functions as we found increased migratory potential of leukocytes, impaired antibacterial activity of neutrophils and enhanced inflammatory mediator production by macrophages. Neutrophil surges were positively associated with burn size and were highest in rats. Altogether, this comprehensive overview of the temporal immune cell dynamics shows that unlike normal wound healing, burn injury induces a long-lasting inflammatory response. It provides a fundamental research basis to improve experimental set-ups, burn care and outcome.
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Affiliation(s)
- Patrick P G Mulder
- Association of Dutch Burn Centres (ADBC), Preclinical Research, Beverwijk, the Netherlands; Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
| | - Hans J P M Koenen
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Marcel Vlig
- Association of Dutch Burn Centres (ADBC), Preclinical Research, Beverwijk, the Netherlands
| | - Irma Joosten
- Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Rob B M de Vries
- SYRCLE, Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Bouke K H L Boekema
- Association of Dutch Burn Centres (ADBC), Preclinical Research, Beverwijk, the Netherlands
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29
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Cutaneous Wound Healing: A Review about Innate Immune Response and Current Therapeutic Applications. Mediators Inflamm 2022; 2022:5344085. [PMID: 35509434 PMCID: PMC9061066 DOI: 10.1155/2022/5344085] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 12/22/2021] [Accepted: 03/25/2022] [Indexed: 12/22/2022] Open
Abstract
Skin wounds and compromised wound healing are major concerns for the public. Although skin wound healing has been studied for decades, the molecular and cellular mechanisms behind the process are still not completely clear. The systemic responses to trauma involve the body’s inflammatory and immunomodulatory cellular and humoral networks. Studies over the years provided essential insights into a complex and dynamic immunity during the cutaneous wound healing process. This review will focus on innate cell populations involved in the initial phase of this orchestrated process, including innate cells from both the skin and the immune system.
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30
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Jiang Y, Xu X, Xiao L, Wang L, Qiang S. The Role of microRNA in the Inflammatory Response of Wound Healing. Front Immunol 2022; 13:852419. [PMID: 35386721 PMCID: PMC8977525 DOI: 10.3389/fimmu.2022.852419] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/02/2022] [Indexed: 12/20/2022] Open
Abstract
Wound healing, a highly complex pathophysiological response to injury, includes four overlapping phases of hemostasis, inflammation, proliferation, and remodeling. Initiation and resolution of the inflammatory response are the primary requirements for wound healing, and are also key events that determines wound quality and healing time. Currently, the number of patients with persistent chronic wounds has generally increased, which imposes health and economic burden on patients and society. Recent studies have found that microRNA(miRNA) plays an essential role in the inflammation involved in wound healing and may provide a new therapeutic direction for wound treatment. Therefore, this review focused on the role and significance of miRNA in the inflammation phase of wound healing.
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Affiliation(s)
- Yuanyuan Jiang
- Center Laboratory, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China
| | - Xiang Xu
- Center Laboratory, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China
| | - Long Xiao
- Center Laboratory, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China
| | - Lihong Wang
- Center Laboratory, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China
| | - Sheng Qiang
- Center Laboratory, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China
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31
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Singer AJ. Healing Mechanisms in Cutaneous Wounds: Tipping the Balance. TISSUE ENGINEERING. PART B, REVIEWS 2022; 28:1151-1167. [PMID: 34915757 PMCID: PMC9587785 DOI: 10.1089/ten.teb.2021.0114] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Acute and chronic cutaneous wounds pose a significant health and economic burden. Cutaneous wound healing is a complex process that occurs in four distinct, yet overlapping, highly coordinated stages: hemostasis, inflammation, proliferation, and remodeling. Postnatal wound healing is reparative, which can lead to the formation of scar tissue. Regenerative wound healing occurs during fetal development and in restricted postnatal tissues. This process can restore the wound to an uninjured state by producing new skin cells from stem cell reservoirs, resulting in healing with minimal or no scarring. Focusing on the pathophysiology of acute burn wounds, this review highlights reparative and regenerative healing mechanisms (including the role of cells, signaling molecules, and the extracellular matrix) and discusses how components of regenerative healing are being used to drive the development of novel approaches and therapeutics aimed at improving clinical outcomes. Important components of regenerative healing, such as stem cells, growth factors, and decellularized dermal matrices, are all being evaluated to recapitulate more closely the natural regenerative healing process.
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Affiliation(s)
- Adam J Singer
- Department of Emergency Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA
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32
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Immune Cells in Cutaneous Wound Healing: A Review of Functional Data from Animal Models. Int J Mol Sci 2022; 23:ijms23052444. [PMID: 35269586 PMCID: PMC8910456 DOI: 10.3390/ijms23052444] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/10/2022] [Accepted: 02/18/2022] [Indexed: 11/17/2022] Open
Abstract
The healing of skin wounds involves the activation and recruitment of various immune cell types, many of which are believed to contribute significantly to different aspects of the repair process. Roles for immune cells have been described in practically all stages of wound healing, including hemostasis, inflammation, proliferation and scar formation/remodeling. Over the last decade, tools to deplete immune cell populations in animal models have become more advanced, leading to a surge in the number of studies examining the function of specific immune cell types in skin repair. In this review, we will summarize what is known about distinct immune cell types in cutaneous wound healing, with an emphasis on data from animal studies in which specific cell types have been targeted.
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33
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Alvarado D, Maurer M, Gedrich R, Seibel SB, Murphy MB, Crew L, Goldstein J, Crocker A, Vitale LA, Morani PA, Thomas LJ, Hawthorne TR, Keler T, Young D, Crowley E, Kankam M, Heath‐Chiozzi M. Anti-KIT monoclonal antibody CDX-0159 induces profound and durable mast cell suppression in a healthy volunteer study. Allergy 2022; 77:2393-2403. [PMID: 35184297 PMCID: PMC9544977 DOI: 10.1111/all.15262] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/25/2022] [Accepted: 01/31/2022] [Indexed: 12/18/2022]
Abstract
Background Mast cells (MC) are powerful inflammatory immune sentinel cells that drive numerous allergic, inflammatory, and pruritic disorders when activated. MC‐targeted therapies are approved in several disorders, yet many patients have limited benefit suggesting the need for approaches that more broadly inhibit MC activity. MCs require the KIT receptor and its ligand stem cell factor (SCF) for differentiation, maturation, and survival. Here we describe CDX‐0159, an anti‐KIT monoclonal antibody that potently suppresses MCs in human healthy volunteers. Methods CDX‐0159‐mediated KIT inhibition was tested in vitro using KIT‐expressing immortalized cells and primary human mast cells. CDX‐0159 safety and pharmacokinetics were evaluated in a 13‐week good laboratory practice (GLP)‐compliant cynomolgus macaque study. A single ascending dose (0.3, 1, 3, and 9 mg/kg), double‐blinded placebo‐controlled phase 1a human healthy volunteer study (n = 32) was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of CDX‐0159. Results CDX‐0159 inhibits SCF‐dependent KIT activation in vitro. Fc modifications in CDX‐0159 led to elimination of effector function and reduced serum clearance. In cynomolgus macaques, multiple high doses were safely administered without a significant impact on hematology, a potential concern for KIT inhibitors. A single dose of CDX‐0159 in healthy human subjects was generally well tolerated and demonstrated long antibody exposure. Importantly, CDX‐0159 led to dose‐dependent, profound suppression of plasma tryptase, a MC‐specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation. Conclusion CDX‐0159 administration leads to systemic mast cell ablation and may represent a safe and novel approach to treat mast cell‐driven disorders.
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Affiliation(s)
| | - Marcus Maurer
- Dermatological Allergology Allergie‐Centrum‐Charité Department of Dermatology and Allergy Charité ‐ Universtätsmedizin Berlin Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Allergology and Immunology Berlin Germany
| | | | | | | | - Linda Crew
- Celldex Therapeutics Hampton New Jersey USA
| | | | | | | | | | | | | | | | | | | | - Martin Kankam
- Altasciences Clinical Kansas Overland Park Kansas USA
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He X, Wang J, Wang Q, Liu J, Yang X, He L, Hu H, Zeng S, Yu L, Qiu Y, Lou Y. P38 MAPK, NF-κB, and JAK-STAT3 Signaling Pathways Involved in Capecitabine-Induced Hand-Foot Syndrome via Interleukin 6 or Interleukin 8 Abnormal Expression. Chem Res Toxicol 2022; 35:422-430. [PMID: 35147423 DOI: 10.1021/acs.chemrestox.1c00317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hand-foot syndrome (HFS) is a major adverse reaction to capecitabine (CAP). The exact pathogenesis of this disease remains unclear. In this study, metabolomics combined with cell RNA sequencing was used to study the mechanisms of CAP-induced HFS. The murine model of HFS was constructed by intragastric administration of CAP or its metabolites. Quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays were used to verify the mechanisms. Metabolomics showed the phosphatidylinositol signaling pathway and amino acid and fatty acid metabolism to be the major metabolic alterations related to the occurrence of HFS. Transcriptomics profiles further revealed that the cytokine-cytokine receptor interaction, IL17 signaling pathway, Toll-like receptor signaling pathway, arachidonic acid metabolism, MAPK signaling pathway, and JAK-STAT3 signaling pathway were the vital steps in skin toxicity induced by CAP or its metabolites. We also verified that the inflammation mechanisms were primarily mediated by the abnormal expression of interleukin (IL) 6 or IL8 and not exclusively by COX-2 overexpression. Finally, the P38 MAPK, NF-κB, and JAK-STAT3 signaling pathways, which mediate high levels of expression of IL6 or IL8, were identified as potential pathways underlying CAP-induced HFS.
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Affiliation(s)
- Xiaoying He
- Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, Department of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of China
| | - Jiali Wang
- Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, Department of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of China
| | - Qian Wang
- Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, Department of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of China
| | - Jing Liu
- Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, Department of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of China
| | - Xi Yang
- Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, Department of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of China
| | - Lingjuan He
- Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, Department of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of China
| | - Haihong Hu
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, People's Republic of China
| | - Su Zeng
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, People's Republic of China
| | - Lushan Yu
- Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, People's Republic of China
| | - Yunqing Qiu
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of China
| | - Yan Lou
- Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, Department of Clinical Pharmacy, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People's Republic of China
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Ozpinar EW, Frey AL, Cruse G, Freytes DO. Mast Cell-Biomaterial Interactions and Tissue Repair. TISSUE ENGINEERING. PART B, REVIEWS 2021; 27:590-603. [PMID: 33164714 PMCID: PMC8739845 DOI: 10.1089/ten.teb.2020.0275] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 11/03/2020] [Indexed: 12/12/2022]
Abstract
Tissue engineers often use biomaterials to provide structural support along with mechanical and chemical signals to modulate the wound healing process. Biomaterials that are implanted into the body interact with a heterogeneous and dynamic inflammatory environment that is present at the site of injury. Whether synthetically derived, naturally derived, or a combination of both, it is important to assess biomaterials for their ability to modulate inflammation to understand their potential clinical use. One important, but underexplored cell in the context of biomaterials is the mast cell (MC). MCs are granulocytic leukocytes that engage in a variety of events in both the innate and adaptive immune systems. Although highly recognized for their roles in allergic reactions, MCs play an important role in wound healing by recognizing antigens through pattern recognition receptors and the high-affinity immunoglobulin E receptor (FceRI) and releasing granules that affect cell recruitment, fibrosis, extracellular matrix deposition, angiogenesis, and vasculogenesis. MCs also mediate the foreign body response, contributing to the incorporation or rejection of implants. Studies of MC-biomaterial interactions can aid in the elucidation of MC roles during the host tissue response and tissue repair. This review is designed for those in the tissue engineering and biomaterial fields who are interested in exploring the role MCs may play in wound-biomaterial interactions and wound healing. With this review, we hope to inspire more research in the MC-biomaterial space to accelerate the design and construction of optimized implants. Impact statement Mast cells (MCs) are highly specialized inflammatory cells that have crucial, but not fully understood, roles in wound healing and tissue repair. Upon stimulation, they recognize foreign antigens and release granules that help orchestrate the inflammatory response after tissue damage or biomaterial implantation. This review summarizes the current use of MCs in biomaterial research along with literature from the past decade focusing on MC interactions with materials used for tissue repair and regeneration. Studying MC-biomaterial interactions will help (i) further understand the process of inflammation and (ii) design biomaterials and tissue-engineered constructs for optimal repair and regeneration.
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Affiliation(s)
- Emily W Ozpinar
- The Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina-Chapel Hill, Raleigh, North Carolina, USA
- The Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina, USA
| | - Ariana L Frey
- The Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina-Chapel Hill, Raleigh, North Carolina, USA
| | - Glenn Cruse
- The Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina, USA
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
| | - Donald O Freytes
- The Joint Department of Biomedical Engineering, North Carolina State University and University of North Carolina-Chapel Hill, Raleigh, North Carolina, USA
- The Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina, USA
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36
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Kaul A, Short WD, Keswani SG, Wang X. Immunologic Roles of Hyaluronan in Dermal Wound Healing. Biomolecules 2021; 11:1234. [PMID: 34439900 PMCID: PMC8394879 DOI: 10.3390/biom11081234] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
Hyaluronic acid (HA), a glycosaminoglycan ubiquitous in the skin, has come into the limelight in recent years for its role in facilitating dermal wound healing. Specifically, HA's length of linearly repeating disaccharides-in other words, its molecular weight (MW)-determines its effects. High molecular weight (HMW)-HA serves an immunosuppressive and anti-inflammatory role, whereas low molecular weight (LMW)-HA contributes to immunostimulation and thus inflammation. During the inflammatory stage of tissue repair, direct and indirect interactions between HA and the innate and adaptive immune systems are of particular interest for their long-lasting impact on wound repair. This review seeks to synthesize the literature on wound healing with a focus on HA's involvement in the immune subsystems.
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Affiliation(s)
| | | | - Sundeep G. Keswani
- Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Texas Children’s Hospital/Baylor College of Medicine, Houston, TX 77030, USA; (A.K.); (W.D.S.)
| | - Xinyi Wang
- Laboratory for Regenerative Tissue Repair, Division of Pediatric Surgery, Department of Surgery, Texas Children’s Hospital/Baylor College of Medicine, Houston, TX 77030, USA; (A.K.); (W.D.S.)
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Manabe T, Park H, Minami T. Calcineurin-nuclear factor for activated T cells (NFAT) signaling in pathophysiology of wound healing. Inflamm Regen 2021; 41:26. [PMID: 34407893 PMCID: PMC8371293 DOI: 10.1186/s41232-021-00176-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/02/2021] [Indexed: 12/26/2022] Open
Abstract
Wound healing occurred with serial coordinated processes via coagulation-fibrinolysis, inflammation following to immune-activation, angiogenesis, granulation, and the final re-epithelization. Since the dermis forms critical physical and biological barriers, the repair system should be rapidly and accurately functioned to keep homeostasis in our body. The wound healing is impaired or dysregulated via an inappropriate microenvironment, which is easy to lead to several diseases, including fibrosis in multiple organs and psoriasis. Such a disease led to the dysregulation of several types of cells: immune cells, fibroblasts, mural cells, and endothelial cells. Moreover, recent progress in medical studies uncovers the significant concept. The calcium signaling, typically the following calcineurin-NFAT signaling, essentially regulates not only immune cell activations, but also various healing steps via coagulation, inflammation, and angiogenesis. In this review, we summarize the role of the NFAT activation pathway in wound healing and discuss its overall impact on future therapeutic ways.
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Affiliation(s)
- Takahiro Manabe
- Division of Molecular and Vascular Biology, IRDA, Kumamoto University, 2-2-1 Honjyo Chuo-ku, Kumamoto, 860-0811, Japan
| | - Heamin Park
- Division of Molecular and Vascular Biology, IRDA, Kumamoto University, 2-2-1 Honjyo Chuo-ku, Kumamoto, 860-0811, Japan
| | - Takashi Minami
- Division of Molecular and Vascular Biology, IRDA, Kumamoto University, 2-2-1 Honjyo Chuo-ku, Kumamoto, 860-0811, Japan.
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Babaei-Jadidi R, Dongre A, Miller S, Castellanos Uribe M, Stewart ID, Thompson ZM, Nateri AS, Bradding P, May ST, Clements D, Johnson SR. Mast-Cell Tryptase Release Contributes to Disease Progression in Lymphangioleiomyomatosis. Am J Respir Crit Care Med 2021; 204:431-444. [PMID: 33882264 DOI: 10.1164/rccm.202007-2854oc] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Rationale: Lymphangioleiomyomatosis (LAM) is a multisystem disease that causes lung cysts and respiratory failure. Loss of TSC (tuberous sclerosis complex) gene function results in a clone of "LAM cells" with dysregulated mTOR (mechanistic target of rapamycin) activity. LAM cells and fibroblasts form lung nodules that also contain mast cells, although their significance is unknown. Objectives: To understand the mechanism of mast-cell accumulation and the role of mast cells in the pathogenesis of LAM. Methods: Gene expression was examined using transcriptional profiling and qRT-PCR. Mast cell/LAM nodule interactions were examined in vitro using spheroid TSC2-null cell/fibroblast cocultures and in vivo using an immunocompetent Tsc2-null murine homograft model. Measurements and Main Results: LAM-derived cell/fibroblast cocultures induced multiple CXC chemokines in fibroblasts. LAM lungs had increased tryptase-positive mast cells expressing CXCRs (CXC chemokine receptors) (P < 0.05). Mast cells located around the periphery of LAM nodules were positively associated with the rate of lung function loss (P = 0.016). LAM spheroids attracted mast cells, and this process was inhibited by pharmacologic and CRISPR/cas9 inhibition of CXCR1 and CXCR2. LAM spheroids caused mast-cell tryptase release, which induced fibroblast proliferation and increased LAM-spheroid size (1.36 ± 0.24-fold; P = 0.0019). The tryptase inhibitor APC366 and sodium cromoglycate (SCG) inhibited mast cell-induced spheroid growth. In vivo, SCG reduced mast-cell activation and Tsc2-null lung tumor burden (vehicle: 32.5.3% ± 23.6%; SCG: 5.5% ± 4.3%; P = 0.0035). Conclusions: LAM-cell/fibroblast interactions attract mast cells where tryptase release contributes to disease progression. Repurposing SCG for use in LAM should be studied as an alternative or adjunct to mTOR inhibitor therapy.
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Affiliation(s)
- Roya Babaei-Jadidi
- Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute
| | - Arundhati Dongre
- Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute
| | - Suzanne Miller
- Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute
| | | | - Ian D Stewart
- Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute
| | - Zoe M Thompson
- Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute
| | - Abdolrahman S Nateri
- Cancer Genetics & Stem Cell Group, Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Peter Bradding
- Department of Respiratory Sciences, Institute for Lung Health, University of Leicester, Leicester, United Kingdom.,Respiratory Theme, National Institute for Health Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom; and
| | - Sean T May
- Nottingham Arabidopsis Stock Centre, and
| | - Debbie Clements
- Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute
| | - Simon R Johnson
- Division of Respiratory Medicine, National Institute for Health Research Biomedical Research Centre and Biodiscovery Institute.,National Centre for Lymphangioleiomyomatosis, Nottingham University Hospitals National Health Service Trust, Nottingham, United Kingdom
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Abstract
Historically, understanding of the human mast cell (MC) compartment has lagged behind the appreciation of other cell lineages. MCs exist in vascularised tissues but do not under normal circumstances circulate in blood, and there has been no pharmacological agent identified that totally and selectively inhibits human MC function. There are no substantiated accounts of an apparently healthy individual who is severely lacking in MCs. Thus, some of the approaches employed to understand the function of a specific immune cell are not available to the MC biologist. The disease categories that have provided the greatest insight into MC biology have been monoclonal and IgE-mediated MC disorders. This has led to the categorisation of MC diseases as intrinsic or extrinsic to the MC compartment and to the recognition of the role of mediators in MC activation disorders. Mastocytosis as a clonal disorder not only impacts the MC compartment through changes intrinsic to the MC, but also by the effects of episodes of significant release of MC mediators. The availability of newer therapeutic approaches developed to treat monoclonal MC disorders offer insights into how to more selectively approach management of MC centric diseases.
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Affiliation(s)
- Melody C Carter
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Dean D Metcalfe
- Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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40
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Roy S, Chompunud Na Ayudhya C, Thapaliya M, Deepak V, Ali H. Multifaceted MRGPRX2: New insight into the role of mast cells in health and disease. J Allergy Clin Immunol 2021; 148:293-308. [PMID: 33957166 PMCID: PMC8355064 DOI: 10.1016/j.jaci.2021.03.049] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 03/03/2021] [Accepted: 03/16/2021] [Indexed: 02/07/2023]
Abstract
Cutaneous mast cells (MCs) express Mas-related G protein-coupled receptor-X2 (MRGPRX2; mouse ortholog MrgprB2), which is activated by an ever-increasing number of cationic ligands. Antimicrobial host defense peptides (HDPs) generated by keratinocytes contribute to host defense likely by 2 mechanisms, one involving direct killing of microbes and the other via MC activation through MRGPRX2. However, its inappropriate activation may cause pseudoallergy and likely contribute to the pathogenesis of rosacea, atopic dermatitis, allergic contact dermatitis, urticaria, and mastocytosis. Gain- and loss-of-function missense single nucleotide polymorphisms in MRGPRX2 have been identified. The ability of certain ligands to serve as balanced or G protein-biased agonists has been defined. Small-molecule HDP mimetics that display both direct antimicrobial activity and activate MCs via MRGPRX2 have been developed. In addition, antibodies and reagents that modulate MRGPRX2 expression and signaling have been generated. In this article, we provide a comprehensive update on MrgprB2 and MRGPRX2 biology. We propose that harnessing MRGPRX2's host defense function by small-molecule HDP mimetics may provide a novel approach for the treatment of antibiotic-resistant cutaneous infections. In contrast, MRGPRX2-specific antibodies and inhibitors could be used for the modulation of allergic and inflammatory diseases that are mediated via this receptor.
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Affiliation(s)
- Saptarshi Roy
- Department of Basic and Translational Sciences, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pa
| | - Chalatip Chompunud Na Ayudhya
- Department of Basic and Translational Sciences, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pa
| | - Monica Thapaliya
- Department of Basic and Translational Sciences, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pa
| | - Vishwa Deepak
- Department of Basic and Translational Sciences, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pa
| | - Hydar Ali
- Department of Basic and Translational Sciences, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pa.
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41
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Amponnawarat A, Chompunud Na Ayudhya C, Ali H. Murepavadin, a Small Molecule Host Defense Peptide Mimetic, Activates Mast Cells via MRGPRX2 and MrgprB2. Front Immunol 2021; 12:689410. [PMID: 34248979 PMCID: PMC8261236 DOI: 10.3389/fimmu.2021.689410] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022] Open
Abstract
Pseudomonas aeruginosa is a frequent cause of hospital-acquired wound infection and is difficult to treat because it forms biofilms and displays antibiotic resistance. Previous studies in mice demonstrated that mast cells (MCs) not only contribute to P. aeruginosa eradication but also promote wound healing via an unknown mechanism. We recently reported that host defense peptides (HDPs) induce human MC degranulation via Mas-related G protein-coupled receptor-X2 (MRGPRX2). Small molecule HDP mimetics have distinct advantages over HDPs because they are inexpensive to synthesize and display high stability, bioavailability, and low toxicity. Murepavadin is a lipidated HDP mimetic, (also known as POL7080), which displays antibacterial activity against a broad panel of multi-drug-resistant P. aeruginosa. We found that murepavadin induces Ca2+ mobilization, degranulation, chemokine IL-8 and CCL3 production in a human MC line (LAD2 cells) endogenously expressing MRGPRX2. Murepavadin also caused degranulation in RBL-2H3 cells expressing MRGPRX2 but this response was significantly reduced in cells expressing missense variants within the receptor's ligand binding (G165E) or G protein coupling (V282M) domains. Compound 48/80 induced β-arrestin recruitment and promoted receptor internalization, which resulted in substantial decrease in the subsequent responsiveness to the MRGPRX2 agonist. By contrast, murepavadin did not cause β-arrestin-mediated MRGPRX2 regulation. Murepavadin induced degranulation in mouse peritoneal MCs via MrgprB2 (ortholog of human MRGPRX2) and caused increased vascular permeability in wild-type mice but not in MrgprB2-/- mice. The data presented herein demonstrate that murepavadin activates human MCs via MRGPRX2 and murine MCs via MrgprB2 and that MRGPRX2 is resistant to β-arrestin-mediated receptor regulation. Thus, besides its direct activity against P. aeruginosa, murepavadin may contribute to bacterial clearance and promote wound healing by harnessing MC's immunomodulatory property via the activation of MRGPRX2.
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Affiliation(s)
- Aetas Amponnawarat
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Family and Community Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
| | - Chalatip Chompunud Na Ayudhya
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Department of Oral Diagnosis, Faculty of Dentistry, Naresuan University, Phitsanulok, Thailand
| | - Hydar Ali
- Department of Basic and Translational Sciences, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
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Jiménez M, Cervantes-García D, Córdova-Dávalos LE, Pérez-Rodríguez MJ, Gonzalez-Espinosa C, Salinas E. Responses of Mast Cells to Pathogens: Beneficial and Detrimental Roles. Front Immunol 2021; 12:685865. [PMID: 34211473 PMCID: PMC8240065 DOI: 10.3389/fimmu.2021.685865] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/28/2021] [Indexed: 12/19/2022] Open
Abstract
Mast cells (MCs) are strategically located in tissues close to the external environment, being one of the first immune cells to interact with invading pathogens. They are long living effector cells equipped with different receptors that allow microbial recognition. Once activated, MCs release numerous biologically active mediators in the site of pathogen contact, which induce vascular endothelium modification, inflammation development and extracellular matrix remodeling. Efficient and direct antimicrobial mechanisms of MCs involve phagocytosis with oxidative and non-oxidative microbial destruction, extracellular trap formation, and the release of antimicrobial substances. MCs also contribute to host defense through the attraction and activation of phagocytic and inflammatory cells, shaping the innate and adaptive immune responses. However, as part of their response to pathogens and under an impaired, sustained, or systemic activation, MCs may contribute to tissue damage. This review will focus on the current knowledge about direct and indirect contribution of MCs to pathogen clearance. Antimicrobial mechanisms of MCs are addressed with special attention to signaling pathways involved and molecular weapons implicated. The role of MCs in a dysregulated host response that can increase morbidity and mortality is also reviewed and discussed, highlighting the complexity of MCs biology in the context of host-pathogen interactions.
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Affiliation(s)
- Mariela Jiménez
- Laboratory of Immunology, Department of Microbiology, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Daniel Cervantes-García
- Laboratory of Immunology, Department of Microbiology, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico.,Cátedras CONACYT, National Council of Science and Technology, Mexico City, Mexico
| | - Laura E Córdova-Dávalos
- Laboratory of Immunology, Department of Microbiology, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
| | - Marian Jesabel Pérez-Rodríguez
- Department of Pharmacobiology, Centro de Investigación y de Estudios Avanzados (Cinvestav), Unidad Sede Sur, Mexico City, Mexico
| | - Claudia Gonzalez-Espinosa
- Department of Pharmacobiology, Centro de Investigación y de Estudios Avanzados (Cinvestav), Unidad Sede Sur, Mexico City, Mexico
| | - Eva Salinas
- Laboratory of Immunology, Department of Microbiology, Universidad Autónoma de Aguascalientes, Aguascalientes, Mexico
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Borges PA, Waclawiak I, Georgii JL, Fraga-Junior VDS, Barros JF, Lemos FS, Russo-Abrahão T, Saraiva EM, Takiya CM, Coutinho-Silva R, Penido C, Mermelstein C, Meyer-Fernandes JR, Canto FB, Neves JS, Melo PA, Canetti C, Benjamim CF. Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y 12 Receptor Activation. Front Immunol 2021; 12:651740. [PMID: 33828561 PMCID: PMC8019717 DOI: 10.3389/fimmu.2021.651740] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 03/01/2021] [Indexed: 01/13/2023] Open
Abstract
Chronic wounds are a public health problem worldwide, especially those related to diabetes. Besides being an enormous burden to patients, it challenges wound care professionals and causes a great financial cost to health system. Considering the absence of effective treatments for chronic wounds, our aim was to better understand the pathophysiology of tissue repair in diabetes in order to find alternative strategies to accelerate wound healing. Nucleotides have been described as extracellular signaling molecules in different inflammatory processes, including tissue repair. Adenosine-5'-diphosphate (ADP) plays important roles in vascular and cellular response and is immediately released after tissue injury, mainly from platelets. However, despite the well described effect on platelet aggregation during inflammation and injury, little is known about the role of ADP on the multiple steps of tissue repair, particularly in skin wounds. Therefore, we used the full-thickness excisional wound model to evaluate the effect of local ADP application in wounds of diabetic mice. ADP accelerated cutaneous wound healing, improved new tissue formation, and increased both collagen deposition and transforming growth factor-β (TGF-β) production in the wound. These effects were mediated by P2Y12 receptor activation since they were inhibited by Clopidogrel (Clop) treatment, a P2Y12 receptor antagonist. Furthermore, P2Y1 receptor antagonist also blocked ADP-induced wound closure until day 7, suggesting its involvement early in repair process. Interestingly, ADP treatment increased the expression of P2Y12 and P2Y1 receptors in the wound. In parallel, ADP reduced reactive oxygen species (ROS) formation and tumor necrosis factor-α (TNF-α) levels, while increased IL-13 levels in the skin. Also, ADP increased the counts of neutrophils, eosinophils, mast cells, and gamma delta (γδ) T cells (Vγ4+ and Vγ5+ cells subtypes of γδ+ T cells), although reduced regulatory T (Tregs) cells in the lesion. In accordance, ADP increased fibroblast proliferation and migration, myofibroblast differentiation, and keratinocyte proliferation. In conclusion, we provide strong evidence that ADP acts as a pro-resolution mediator in diabetes-associated skin wounds and is a promising intervention target for this worldwide problem.
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Affiliation(s)
- Paula Alvarenga Borges
- Institute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
- Fluminense Federal Institute (IFF), Rio de Janeiro, Brazil
| | - Ingrid Waclawiak
- Institute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Janaína Lima Georgii
- Institute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | | | - Janaína Figueiredo Barros
- Institute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Felipe Simões Lemos
- Institute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Thaís Russo-Abrahão
- Institute of Medical Biochemistry Leopoldo de Meis, Center of Health Sciences, UFRJ, Rio de Janeiro, Brazil
| | - Elvira Maria Saraiva
- Institute of Microbiology Paulo de Góes, Center of Health Sciences, UFRJ, Rio de Janeiro, Brazil
| | - Christina M. Takiya
- Institute of Biophysics Carlos Chagas Filho (IBCCF), Center of Health Sciences, UFRJ, Rio de Janeiro, Brazil
| | - Robson Coutinho-Silva
- Institute of Biophysics Carlos Chagas Filho (IBCCF), Center of Health Sciences, UFRJ, Rio de Janeiro, Brazil
| | - Carmen Penido
- Center for Technological Development in Health, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
- Laboratory of Applied Pharmacology, Institute of Drug Technology, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| | - Claudia Mermelstein
- Institute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | | | - Fábio B. Canto
- Department of Immunobiology, Institute of Biology, Fluminense Federal University (UFF), Niterói, Brazil
| | - Josiane Sabbadini Neves
- Institute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Paulo A. Melo
- Institute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Claudio Canetti
- Institute of Biophysics Carlos Chagas Filho (IBCCF), Center of Health Sciences, UFRJ, Rio de Janeiro, Brazil
| | - Claudia Farias Benjamim
- Institute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
- Institute of Biophysics Carlos Chagas Filho (IBCCF), Center of Health Sciences, UFRJ, Rio de Janeiro, Brazil
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Soleimani H, Amini A, Abdollahifar MA, Norouzian M, Kouhkheil R, Mostafavinia A, Ghoreishi SK, Bayat S, Chien S, Bayat M. Combined effects of photobiomodulation and curcumin on mast cells and wound strength in wound healing of streptozotocin-induced diabetes in rats. Lasers Med Sci 2021; 36:375-386. [PMID: 32696423 DOI: 10.1007/s10103-020-03053-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 06/02/2020] [Indexed: 12/24/2022]
Abstract
We investigated the probable involvement of mast cell degranulation and their numbers in the remodeling step of wound healing in a diabetic ischemic skin wound model treated with photobiomodulation plus curcumin. A total of 108 adult male Wistar rats were randomized into one healthy control and five diabetic groups. Type I diabetes was inflicted in 90 of the 108 rats. After 1 month, an excisional wound was generated in each of the 108 rats. There were one healthy group (group 1) and five diabetic groups as follows: group 2 was the untreated diabetic control group and group 3 rats were treated with sesame oil. Rats in group 4 were treated with photobiomodulation (890 nm, 890 ± 10 nm, 80 Hz, 0.2 J/cm2) and those in group 5 received curcumin dissolved in sesame oil. Group 6 rats were treated with photobiomodulation and curcumin. We conducted stereological and tensiometric tests on days 4, 7, and 15 after treatment. The results indicated that photobiomodulation significantly improved wound strength in the diabetic rats and significantly decreased the total numbers of mast cells. The diabetic control group had significantly reduced tensiometric properties of the healing wounds and a significant increase in the total numbers of mast cells. Photobiomodulation significantly improved the healing process in diabetic animals and significantly decreased the total number of mast cells. The increased numbers of mast cells in the diabetic control group negatively affected tensiometric properties of the ischemic skin wound.
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Affiliation(s)
- Hasan Soleimani
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abdollah Amini
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad-Amin Abdollahifar
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohsen Norouzian
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Kouhkheil
- Department of Anatomical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Atarodsadat Mostafavinia
- Department of Anatomy, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Sahar Bayat
- Illinois Institute of Technology, Chicago, IL, USA
| | - Sufan Chien
- Price Institute of Surgical Research, University of Louisville, Louisville, KY, USA.
- Noveratech LLC of Louisville, Louisville, KY, USA.
| | - Mohammad Bayat
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Price Institute of Surgical Research, University of Louisville, Louisville, KY, USA.
- Noveratech LLC of Louisville, Louisville, KY, USA.
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Han B, Fang J, Yang Z, Zhao S, Fang W, Hoang BX. PEGylated Coating Affects DBM Osteoinductivity In Vivo by Changing Inflammatory Responses. ACS APPLIED BIO MATERIALS 2020; 3:8722-8730. [PMID: 35019643 DOI: 10.1021/acsabm.0c01113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
PEGylation is a widely used modification in device coating or drug delivery by combing materials with poly(ethylene glycol) (PEG). In the present study, a well-established rat ectopic bone formation model was used to elucidate how PEGylated coating affects demineralized bone matrix (DBM) osteoinductivity in vivo by changing the inflammation events at the early phase of implantation. A range of cell-matrix interactions was characterized at the cellular and functional levels, including growth factor activity and kinetics, immune cell migration and activation, and bone formation in vivo. After 28 days, DBM's bone formation potential decreased in groups with increasing PEG concentration in the gelatin carrier. The increasing PEG concentration did not affect DBM's osteoinductive growth factor release or activity. However, increasing PEG cross-linking concentration resulted in decreased DBM-related early phase inflammatory reactions, reduced neutrophil infiltration, decreased coating material degradation, lowered the total number and active mast cells, and decreased CD80+ macrophage expression. Understanding and controlling cell-material responses may improve the design and development of functional medical devices.
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Affiliation(s)
- Bo Han
- Department of Surgery and Biomedical Engineering, Keck School of Medicine of USC, Los Angeles, California 90089, United States
| | - Josephine Fang
- Department of Surgery and Biomedical Engineering, Keck School of Medicine of USC, Los Angeles, California 90089, United States
| | - Zhi Yang
- Department of Surgery and Biomedical Engineering, Keck School of Medicine of USC, Los Angeles, California 90089, United States
| | - Shuqing Zhao
- Department of Surgery and Biomedical Engineering, Keck School of Medicine of USC, Los Angeles, California 90089, United States
| | - William Fang
- Western University of Health Sciences, Pomona, California 91766, United States
| | - Ba Xuan Hoang
- Department of Surgery and Biomedical Engineering, Keck School of Medicine of USC, Los Angeles, California 90089, United States
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Willows S, Kulka M. Harnessing the Power of Mast Cells in unconventional Immunotherapy Strategies and Vaccine Adjuvants. Cells 2020; 9:cells9122713. [PMID: 33352850 PMCID: PMC7766453 DOI: 10.3390/cells9122713] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/03/2020] [Accepted: 12/17/2020] [Indexed: 02/06/2023] Open
Abstract
Mast cells are long-lived, granular, myeloid-derived leukocytes that have significant protective and repair functions in tissues. Mast cells sense disruptions in the local microenvironment and are first responders to physical, chemical and biological insults. When activated, mast cells release growth factors, proteases, chemotactic proteins and cytokines thereby mobilizing and amplifying the reactions of the innate and adaptive immune system. Mast cells are therefore significant regulators of homeostatic functions and may be essential in microenvironmental changes during pathogen invasion and disease. During infection by helminths, bacteria and viruses, mast cells release antimicrobial factors to facilitate pathogen expulsion and eradication. Mast cell-derived proteases and growth factors protect tissues from insect/snake bites and exposure to ultraviolet radiation. Finally, mast cells release mediators that promote wound healing in the inflammatory, proliferative and remodelling stages. Since mast cells have such a powerful repertoire of functions, targeting mast cells may be an effective new strategy for immunotherapy of disease and design of novel vaccine adjuvants. In this review, we will examine how certain strategies that specifically target and activate mast cells can be used to treat and resolve infections, augment vaccines and heal wounds. Although these strategies may be protective in certain circumstances, mast cells activation may be deleterious if not carefully controlled and any therapeutic strategy using mast cell activators must be carefully explored.
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Affiliation(s)
- Steven Willows
- Nanotechnology Research Centre, National Research Council Canada, 11421 Saskatchewan Dr, Edmonton, AB T6G 2M9, Canada;
| | - Marianna Kulka
- Nanotechnology Research Centre, National Research Council Canada, 11421 Saskatchewan Dr, Edmonton, AB T6G 2M9, Canada;
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Correspondence: ; Tel.: +1-780-641-1687
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Dong J, Chen L, Zhang Y, Jayaswal N, Mezghani I, Zhang W, Veves A. Mast Cells in Diabetes and Diabetic Wound Healing. Adv Ther 2020; 37:4519-4537. [PMID: 32935286 PMCID: PMC7547971 DOI: 10.1007/s12325-020-01499-4] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 09/04/2020] [Indexed: 12/11/2022]
Abstract
Mast cells (MCs) are granulated, immune cells of the myeloid lineage that are present in connective tissues. Apart from their classical role in allergies, MCs also mediate various inflammatory responses due to the nature of their secretory products. They are involved in important physiological and pathophysiological responses related to inflammation, chronic wounds, and autoimmune diseases. There are also indications that MCs are associated with diabetes and its complications. MCs and MC-derived mediators participate in all wound healing stages and are involved in the pathogenesis of non-healing, chronic diabetic foot ulcers (DFUs). More specifically, recent work has shown increased degranulation of skin MCs in human diabetes and diabetic mice, which is associated with impaired wound healing. Furthermore, MC stabilization, either systemic or local at the skin level, improves wound healing in diabetic mice. Understanding the precise role of MCs in wound progression and healing processes can be of critical importance as it can lead to the development of new targeted therapies for diabetic foot ulceration, one of the most devastating complications of diabetes.
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Affiliation(s)
- Jie Dong
- Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA
| | - Lihong Chen
- Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA
| | - Ying Zhang
- Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA
| | - Navin Jayaswal
- Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA
| | - Ikram Mezghani
- Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA
| | - Weijie Zhang
- Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA
- LanZhou University of Technology, 287 Langongping Road, Qilihe District, Lanzhou, Gansu, China
| | - Aristidis Veves
- Joslin-Beth Israel Deaconess Foot Center and The Rongxiang Xu, MD, Center for Regenerative Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.
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The Protective Effects of Pre- and Post-Administration of Micronized Palmitoylethanolamide Formulation on Postoperative Pain in Rats. Int J Mol Sci 2020; 21:ijms21207700. [PMID: 33080989 PMCID: PMC7589788 DOI: 10.3390/ijms21207700] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/16/2020] [Accepted: 10/16/2020] [Indexed: 02/07/2023] Open
Abstract
Background: Postoperative pain (PO) is a common form of acute pain. Inadequate PO treatment is an important health problem, as it leads to worse outcomes, such as chronic post-surgical pain. Therefore, it is necessary to acquire new knowledge on PO mechanisms to develop therapeutic options with greater efficacy than those available today and to lower the risk of adverse effects. For this reason, we evaluated the ability of micronized palmitoylethanolamide (PEA-m) to resolve the pain and inflammatory processes activated after incision of the hind paw in an animal model of PO. Methods: The animals were subjected to surgical paw incision and randomized into different groups. PEA-m was administered orally at 10 mg/kg at different time points before or after incision. Results: Our research demonstrated that the pre- and post-treatment with PEA-m reduced the activation of mast cells at the incision site and the expression of its algogenic mediator nerve growth factor (NGF) in the lumbar spinal cord. Furthermore, again at the spinal level, it was able to decrease the activation of phospho-extracellular signal-regulated kinases (p-ERK), ionized calcium binding adaptor molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and the expression of brain-derived neurotrophic factor (BDNF). PEA-m also reduced the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) spinal pathway, showing a protective effect in a rat model of PO. Conclusion: The results obtained reinforce the idea that PEA-m may be a potential treatment for the control of pain and inflammatory processes associated with PO. In addition, pre- and post-treatment with PEA-m is more effective than treatment alone after the surgery and this limits the time of taking the compound and the abuse of analgesics.
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Abstract
Wound healing is a complex, dynamic process supported by a myriad of cellular events that must be tightly coordinated to efficiently repair damaged tissue. Derangement in wound-linked cellular behaviours, as occurs with diabetes and ageing, can lead to healing impairment and the formation of chronic, non-healing wounds. These wounds are a significant socioeconomic burden due to their high prevalence and recurrence. Thus, there is an urgent requirement for the improved biological and clinical understanding of the mechanisms that underpin wound repair. Here, we review the cellular basis of tissue repair and discuss how current and emerging understanding of wound pathology could inform future development of efficacious wound therapies.
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Affiliation(s)
- Holly N Wilkinson
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, The University of Hull, Hull HU6 7RX, United Kingdom
| | - Matthew J Hardman
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, The University of Hull, Hull HU6 7RX, United Kingdom
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Ud-Din S, Wilgus TA, Bayat A. Mast Cells in Skin Scarring: A Review of Animal and Human Research. Front Immunol 2020; 11:552205. [PMID: 33117341 PMCID: PMC7561364 DOI: 10.3389/fimmu.2020.552205] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 08/27/2020] [Indexed: 01/05/2023] Open
Abstract
Mast cells (MCs) are an important immune cell type in the skin and play an active role during wound healing. MCs produce mediators that can enhance acute inflammation, stimulate re-epithelialisation as well as angiogenesis, and promote skin scarring. There is also a link between MCs and abnormal pathological cutaneous scarring, with increased numbers of MCs found in hypertrophic scars and keloid disease. However, there has been conflicting data regarding the specific role of MCs in scar formation in both animal and human studies. Whilst animal studies have proved to be valuable in studying the MC phenomenon in wound healing, the appropriate translation of these findings to cutaneous wound healing and scar formation in human subjects remains crucial to elucidate the role of these cells and target treatment effectively. Therefore, this perspective paper will focus on evaluation of the current evidence for the role of MCs in skin scarring in both animals and humans in order to identify common themes and future areas for translational research.
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Affiliation(s)
- Sara Ud-Din
- Plastic and Reconstructive Surgery Research, Centre for Dermatology Research, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, United Kingdom
| | - Traci A Wilgus
- Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, United States
| | - Ardeshir Bayat
- Plastic and Reconstructive Surgery Research, Centre for Dermatology Research, NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, United Kingdom.,MRC-SA Wound Healing Unit, Division of Dermatology, University of Cape Town, Cape Town, South Africa
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