|
1
|
Binte Hanafi Z, Mei Y, Teo HY, Zhu Y, Yong Lionel CC, Chiu JW, Lu J, Liu H. Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment. Oncoimmunology 2025; 14:2451444. [PMID: 39803956 PMCID: PMC11730618 DOI: 10.1080/2162402x.2025.2451444] [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: 09/21/2024] [Revised: 12/26/2024] [Accepted: 01/06/2025] [Indexed: 01/16/2025] Open
Abstract
Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1α, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1α is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1α for mature IL-1α secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1α secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1α-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1α secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment.
Collapse
Affiliation(s)
- Zuhairah Binte Hanafi
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yu Mei
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Huey Yee Teo
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ying Zhu
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chew Chin Yong Lionel
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jing Wen Chiu
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jinhua Lu
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Haiyan Liu
- Immunology Programme, Life Sciences Institute; Centre for Life Sciences, National University of Singapore, Singapore, Singapore
- Immunology Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| |
Collapse
|
|
2
|
Kohl LM, Sumpter TL. Melanomas and mast cells: an ambiguous relationship. Melanoma Res 2024; 34:1-8. [PMID: 37924526 DOI: 10.1097/cmr.0000000000000932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2023]
Abstract
Mast cells (MCs) accumulate in a broad range of tumors, including melanomas. While MCs are potent initiators of immunity in infection, and in allergic inflammation, the function of MCs in anti-melanoma immunity is unclear. MCs have the potential to release tumoricidal cytokines and proteases, to activate antigen-presenting cells and to promote anti-tumor adaptive immunity. However, within the immunosuppressive tumor microenvironment (TME), MC activation may promote angiogenesis and contribute to tumor growth. In this review, the relationship between MCs and melanomas is discussed with a focus on the impact of the TME on MC activation.
Collapse
Affiliation(s)
- Lisa M Kohl
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
- Departments of Dermatology
| | - Tina L Sumpter
- Departments of Dermatology
- Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| |
Collapse
|
|
3
|
Ostrand-Rosenberg S, Lamb TJ, Pawelec G. Here, There, and Everywhere: Myeloid-Derived Suppressor Cells in Immunology. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:1183-1197. [PMID: 37068300 PMCID: PMC10111205 DOI: 10.4049/jimmunol.2200914] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/06/2023] [Indexed: 04/19/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) were initially identified in humans and mice with cancer where they profoundly suppress T cell- and NK cell-mediated antitumor immunity. Inflammation is a central feature of many pathologies and normal physiological conditions and is the dominant driving force for the accumulation and function of MDSCs. Therefore, MDSCs are present in conditions where inflammation is present. Although MDSCs are detrimental in cancer and conditions where cellular immunity is desirable, they are beneficial in settings where cellular immunity is hyperactive. Because MDSCs can be generated ex vivo, they are being exploited as therapeutic agents to reduce damaging cellular immunity. In this review, we discuss the detrimental and beneficial roles of MDSCs in disease settings such as bacterial, viral, and parasitic infections, sepsis, obesity, trauma, stress, autoimmunity, transplantation and graft-versus-host disease, and normal physiological settings, including pregnancy and neonates as well as aging. The impact of MDSCs on vaccination is also discussed.
Collapse
Affiliation(s)
- Suzanne Ostrand-Rosenberg
- Division of Microbiology and Immunology, Department of Pathology, University of Utah 84112, Salt Lake City, UT
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Tracey J. Lamb
- Division of Microbiology and Immunology, Department of Pathology, University of Utah 84112, Salt Lake City, UT
| | - Graham Pawelec
- Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany, and Health Sciences North Research Institute, Sudbury, ON, Canada
| |
Collapse
|
|
4
|
The Controversial Role of Intestinal Mast Cells in Colon Cancer. Cells 2023; 12:cells12030459. [PMID: 36766801 PMCID: PMC9914221 DOI: 10.3390/cells12030459] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/24/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
Mast cells are tissue-resident sentinels involved in large number of physiological and pathological processes, such as infection and allergic response, thanks to the expression of a wide array of receptors. Mast cells are also frequently observed in a tumor microenvironment, suggesting their contribution in the transition from chronic inflammation to cancer. In particular, the link between inflammation and colorectal cancer development is becoming increasingly clear. It has long been recognized that patients with inflammatory bowel disease have an increased risk of developing colon cancer. Evidence from experimental animals also implicates the innate immune system in the development of sporadically occurring intestinal adenomas, the precursors to colorectal cancer. However, the exact role of mast cells in tumor initiation and growth remains controversial: mast cell-derived mediators can either exert pro-tumorigenic functions, causing the progression and spread of the tumor, or anti-tumorigenic functions, limiting the tumor's growth. Here, we review the multifaceted and often contrasting findings regarding the role of the intestinal mast cells in colon cancer progression focusing on the molecular pathways mainly involved in the regulation of mast cell plasticity/functions during tumor progression.
Collapse
|
|
5
|
Stevenson MM, Valanparambil RM, Tam M. Myeloid-Derived Suppressor Cells: The Expanding World of Helminth Modulation of the Immune System. Front Immunol 2022; 13:874308. [PMID: 35757733 PMCID: PMC9229775 DOI: 10.3389/fimmu.2022.874308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 05/02/2022] [Indexed: 01/09/2023] Open
Abstract
Infection with helminths or parasitic worms are highly prevalent worldwide especially in developing regions. Helminths cause chronic infections that are associated with suppression of immune responses to unrelated pathogens, vaccines, and by-stander antigens responsible for dysregulated immune responses as occurs in diseases such as allergies. Helminths use multiple mechanisms to modulate the immune system to evade the highly polarized type 2 immune response required to expel adult worms and for immunity to reinfection. Anthelmintic drugs are efficient in reducing adult worm burdens in helminth-infected individuals, but resistance to these drugs is rapidly increasing and vaccines against these pathogens are not available. Emerging evidence indicate that helminths induce myeloid-derived suppressor cells (MDSC), originally described in tumor-bearing mice and cancer patients. MDSC are a heterogenous population of immature cells that consist of two distinct sub-populations, polymorphonuclear (PMN)-MDSC and monocytic (M)-MDSC based on morphology and phenotype. MDSC suppress the function of T cells and other innate and adaptive immune cells including NK cells and B cells. During cancer or infection with bacteria or viruses, there is marked expansion of MDSC. Furthermore, the frequencies of MDSC correlate inversely with the prognosis and survival of tumor-bearing hosts as well as bacterial and viral burdens, persistence, and outcome in infected hosts. Currently, there is a paucity of data on MDSC and helminth infections. Here, we provide a survey of the evidence accumulated so far that overall support a role for MDSC in modulating immune responses during helminth infections. We review data from studies in various helminths, including those that infect humans. Finally, we summarize the progress to date in understanding the role of MDSC in helminth infections and briefly discuss potential host-directed strategies to target MDSC-mediated suppression of immune responses to helminths in favor of development of immunity to eliminate adult worms and possibly induce protection against reinfection.
Collapse
Affiliation(s)
- Mary M Stevenson
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.,Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, Canada
| | - Rajesh M Valanparambil
- Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, Canada
| | - Mifong Tam
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| |
Collapse
|
|
6
|
Goretzki A, Zimmermann J, Lin YJ, Schülke S. Immune Metabolism–An Opportunity to Better Understand Allergic Pathology and Improve Treatment of Allergic Diseases? FRONTIERS IN ALLERGY 2022; 3:825931. [PMID: 35386646 PMCID: PMC8974690 DOI: 10.3389/falgy.2022.825931] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/25/2022] [Indexed: 01/16/2023] Open
|
|
7
|
The diverse roles of myeloid derived suppressor cells in mucosal immunity. Cell Immunol 2021; 365:104361. [PMID: 33984533 DOI: 10.1016/j.cellimm.2021.104361] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 03/21/2021] [Accepted: 04/06/2021] [Indexed: 12/12/2022]
Abstract
The mucosal immune system plays a vital role in protecting the host from the external environment. Its major challenge is to balance immune responses against harmful and harmless agents and serve as a 'homeostatic gate keeper'. Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of undifferentiated cells that are characterized by an immunoregulatory and immunosuppressive phenotype. Herein we postulate that MDSCs may be involved in shaping immune responses related to mucosal immunity, due to their immunomodulatory and tissue remodeling functions. Until recently, MDSCs were investigated mainly in cancerous diseases, where they induce and contribute to an immunosuppressive and inflammatory environment that favors tumor development. However, it is now becoming clear that MDSCs participate in non-cancerous conditions such as chronic infections, autoimmune diseases, pregnancy, aging processes and immune tolerance to commensal microbiota at mucosal sites. Since MDSCs are found in the periphery only in small numbers under normal conditions, their role is highlighted during pathologies characterized by acute or chronic inflammation, when they accumulate and become activated. In this review, we describe several aspects of the current knowledge characterizing MDSCs and their involvement in the regulation of the mucosal epithelial barrier, their crosstalk with commensal microbiota and pathogenic microorganisms, and their complex interactions with a variety of surrounding regulatory and effector immune cells. Finally, we discuss the beneficial and harmful outcomes of the MDSC regulatory functions in diseases affecting mucosal tissues. We wish to illuminate the pivotal role of MDSCs in mucosal immunity, the limitations in our understanding of all the players and the intricate challenges stemming from the complex interactions of MDSCs with their environment.
Collapse
|
|
8
|
Ostrand-Rosenberg S. Myeloid-Derived Suppressor Cells: Facilitators of Cancer and Obesity-Induced Cancer. ANNUAL REVIEW OF CANCER BIOLOGY-SERIES 2021. [DOI: 10.1146/annurev-cancerbio-042120-105240] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Immature myeloid cells at varied stages of differentiation, known as myeloid-derived suppressor cells (MDSC), are present in virtually all cancer patients. MDSC are profoundly immune-suppressive cells that impair adaptive and innate antitumor immunity and promote tumor progression through nonimmune mechanisms. Their widespread presence combined with their multitude of protumor activities makes MDSC a major obstacle to cancer immunotherapies. MDSC are derived from progenitor cells in the bone marrow and traffic through the blood to infiltrate solid tumors. Their accumulation and suppressive potency are driven by multiple tumor- and host-secreted proinflammatory factors and adrenergic signals that act via diverse but sometimes overlapping transcriptional pathways. MDSC also accumulate in response to the chronic inflammation and lipid deposition characteristic of obesity and contribute to the more rapid progression of cancers in obese individuals. This article summarizes the key aspects of tumor-induced MDSC with a focus on recent progress in the MDSC field.
Collapse
Affiliation(s)
- Suzanne Ostrand-Rosenberg
- Department of Pathology and Huntsman Cancer Institute (HCI), University of Utah, Salt Lake City, Utah 84112, USA
- Emeritus at: Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland 21250, USA
| |
Collapse
|
|
9
|
Dorhoi A, Kotzé LA, Berzofsky JA, Sui Y, Gabrilovich DI, Garg A, Hafner R, Khader SA, Schaible UE, Kaufmann SH, Walzl G, Lutz MB, Mahon RN, Ostrand-Rosenberg S, Bishai W, du Plessis N. Therapies for tuberculosis and AIDS: myeloid-derived suppressor cells in focus. J Clin Invest 2021; 130:2789-2799. [PMID: 32420917 DOI: 10.1172/jci136288] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The critical role of suppressive myeloid cells in immune regulation has come to the forefront in cancer research, with myeloid-derived suppressor cells (MDSCs) as a main oncology immunotherapeutic target. Recent improvement and standardization of criteria classifying tumor-induced MDSCs have led to unified descriptions and also promoted MDSC research in tuberculosis (TB) and AIDS. Despite convincing evidence on the induction of MDSCs by pathogen-derived molecules and inflammatory mediators in TB and AIDS, very little attention has been given to their therapeutic modulation or roles in vaccination in these diseases. Clinical manifestations in TB are consequences of complex host-pathogen interactions and are substantially affected by HIV infection. Here we summarize the current understanding and knowledge gaps regarding the role of MDSCs in HIV and Mycobacterium tuberculosis (co)infections. We discuss key scientific priorities to enable application of this knowledge to the development of novel strategies to improve vaccine efficacy and/or implementation of enhanced treatment approaches. Building on recent findings and potential for cross-fertilization between oncology and infection biology, we highlight current challenges and untapped opportunities for translating new advances in MDSC research into clinical applications for TB and AIDS.
Collapse
Affiliation(s)
- Anca Dorhoi
- Institute of Immunology, Friedrich-Loeffler-Institute, Greifswald-Insel Riems, Germany.,Faculty of Mathematics and Natural Sciences, University of Greifswald, Greifswald, Germany
| | - Leigh A Kotzé
- Centre for Tuberculosis Research, South African Medical Research Council, Cape Town, South Africa.,DST-NRF Centre of Excellence for Biomedical Tuberculosis Research (CBTBR) and.,Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Jay A Berzofsky
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Yongjun Sui
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | | | - Ankita Garg
- Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA
| | - Richard Hafner
- Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Shabaana A Khader
- Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Ulrich E Schaible
- Cellular Microbiology, Priority Program Infections.,Thematic Translation Unit Tuberculosis, German Center for Infection Research, and.,Leibniz Research Alliance INFECTIONS'21, Research Center Borstel, Borstel, Germany
| | - Stefan He Kaufmann
- Max Planck Institute for Infection Biology, Berlin, Germany.,Hagler Institute for Advanced Study, Texas A&M University, College Station, Texas, USA
| | - Gerhard Walzl
- Centre for Tuberculosis Research, South African Medical Research Council, Cape Town, South Africa.,DST-NRF Centre of Excellence for Biomedical Tuberculosis Research (CBTBR) and.,Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Manfred B Lutz
- Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
| | - Robert N Mahon
- Division of AIDS, Columbus Technologies & Services Inc., Contractor to National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Suzanne Ostrand-Rosenberg
- Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | - William Bishai
- Center for Tuberculosis Research, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Nelita du Plessis
- Centre for Tuberculosis Research, South African Medical Research Council, Cape Town, South Africa.,DST-NRF Centre of Excellence for Biomedical Tuberculosis Research (CBTBR) and.,Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| |
Collapse
|
|
10
|
Xue F, Yu M, Li L, Zhang W, Ma Y, Dong L, Shan W, Zheng Y, Wang T, Feng D, Lv J, Wang X. Elevated granulocytic myeloid-derived suppressor cells are closely related with elevation of Th17 cells in mice with experimental asthma. Int J Biol Sci 2020; 16:2072-2083. [PMID: 32549755 PMCID: PMC7294949 DOI: 10.7150/ijbs.43596] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 05/02/2020] [Indexed: 02/03/2023] Open
Abstract
Asthma is a complex and heterogeneous inflammatory response characterized by various immune cells, including myeloid-derived suppressor cells (MDSCs) and CD4+ T-cell subsets. However, few studies on MDSC subsets and the association between MDSCs and CD4+ T-cell subsets in asthma are reported. In the present study, we detected CD4+ T cells and MDSC subsets and evaluated the relationship of these cells in mice with ovalbumin-induced asthma. We found that asthmatic mice showed severe airway inflammatory response and inflammatory cell infiltration in the lungs and bronchoalveolar lavage fluid. We also noted increased numbers of Th2, Th17, and MDSCs; decreased proportion of Th1 and Treg cells in the splenocytes and lungs; and increased expression of pro-inflammatory cytokines in splenocytes and lungs. Granulocytic MDSCs (G-MDSCs) and Th17 cells were closely related. Gemcitabine treatment reduced the G-MDSC level and the iNOS expression, alleviated the inflammatory response, and decreased the proportion and number of Th2 and Th17 cells in asthmatic mice. Besides the increase in Th2 and Th17 cells, the findings indicate that G-MDSC elevation plays a crucial role in asthmatic mice.
Collapse
Affiliation(s)
- Fei Xue
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.,Department of Pediatrics, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Mengzhu Yu
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.,Department of Pediatrics, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Li Li
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Wenzhe Zhang
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Yongbin Ma
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.,Department of Neurology Laboratory, Jintan Hospital, Jiangsu University, Jintan 213200, China
| | - Liyang Dong
- Department of Nuclear Medicine and Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Wenqi Shan
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China.,Department of Pediatrics, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Yu Zheng
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Ting Wang
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Dingqi Feng
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Jianping Lv
- Department of Pediatrics, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| | - Xuefeng Wang
- Department of Central Laboratory, The Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China
| |
Collapse
|
|
11
|
Lyons DO, Pullen NA. Beyond IgE: Alternative Mast Cell Activation Across Different Disease States. Int J Mol Sci 2020; 21:ijms21041498. [PMID: 32098318 PMCID: PMC7073060 DOI: 10.3390/ijms21041498] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 02/20/2020] [Accepted: 02/21/2020] [Indexed: 12/14/2022] Open
Abstract
Mast cells are often regarded through the lens of IgE-dependent reactions as a cell specialized only for anti-parasitic and type I hypersensitive responses. However, recently many researchers have begun to appreciate the expansive repertoire of stimuli that mast cells can respond to. After the characterization of the interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) axis of mast cell activation-a pathway that is independent of the adaptive immune system-researchers are revisiting other stimuli to induce mast cell activation and/or subsequent degranulation independent of IgE. This discovery also underscores that mast cells act as important mediators in maintaining body wide homeostasis, especially through barrier defense, and can thus be the source of disease as well. Particularly in the gut, inflammatory bowel diseases (Crohn's disease, ulcerative colitis, etc.) are characterized with enhanced mast cell activity in the context of autoimmune disease. Mast cells show phenotypic differences based on tissue residency, which could manifest as different receptor expression profiles, allowing for unique mast cell responses (both IgE and non-IgE mediated) across varying tissues as well. This variety in receptor expression suggests mast cells respond differently, such as in the gut where immunosuppressive IL-10 stimulates the development of food allergy or in the lungs where transforming growth factor-β1 (TGF-β1) can enhance mast cell IL-6 production. Such differences in receptor expression illustrate the truly diverse effector capabilities of mast cells, and careful consideration must be given toward the phenotype of mast cells observed in vitro. Given mast cells' ubiquitous tissue presence and their capability to respond to a broad spectrum of non-IgE stimuli, it is expected that mast cells may also contribute to the progression of autoimmune disorders and other disease states such as metastatic cancer through promoting chronic inflammation in the local tissue microenvironment and ultimately polarizing toward a unique Th17 immune response. Furthermore, these interconnected, atypical activation pathways may crosstalk with IgE-mediated signaling differently across disorders such as parasitism, food allergies, and autoimmune disorders of the gut. In this review, we summarize recent research into familiar and novel pathways of mast cells activation and draw connections to clinical human disease.
Collapse
|
|
12
|
Zahran AM, Saad K, Elsayh KI, Abdelmoghny A, Aboul-Khair MD, Sobhy A, Abdel-Raheem YF, El-Asheer OM, El-Houfey AA, Alblihed MA, Al-Neami I. Myeloid-Derived Suppressor Cells and Costimulatory Molecules in Children With Allergic Rhinitis. Ann Otol Rhinol Laryngol 2019; 128:128-134. [PMID: 30449135 DOI: 10.1177/0003489418812902] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES: The aim of this study is to assess the level of myeloid-derived suppressor cells (MDSCs) and the expression of costimulatory molecules CD80 and CD86 on monocytes and their ligands (CD28) on T-lymphocytes in children with allergic rhinitis (AR). METHODS: The study included 60 children with AR and 50 controls. Flow cytometry was performed to analyze MDSCs and the expression of costimulatory molecules CD80 and CD86 on monocytes and their ligands (CD28) on T-lymphocytes. RESULTS: The percentages of total and monocytic MDSCs and the expression of costimulatory molecule CD86 on monocytes were significantly higher in children with AR than in healthy controls. In addition, the expressions of CD28 on CD4+ and CD8+ were significantly elevated in AR patients. CONCLUSION: The present study demonstrated that the percentages of MDSCs were significantly elevated in AR children. Moreover, the expressions of CD28 on CD4+ and CD8+ were significantly higher in children with AR.
Collapse
Affiliation(s)
- Asmaa M Zahran
- 1 Clinical Pathology Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Khaled Saad
- 2 Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Khalid I Elsayh
- 2 Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Abobakr Abdelmoghny
- 3 Department of ENT, Faculty of Medicine, Al-Azhar University, Assiut, Egypt
| | | | - Ali Sobhy
- 5 Department of Clinical Pathology, Faculty of Medicine, Alazhar University, Assiut, Egypt
| | | | - Osama M El-Asheer
- 2 Pediatric Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Amira A El-Houfey
- 6 Department of Community Health Nursing, Faculty of Nursing, Assiut University, Egypt
- 7 Department of Community Health Nursing, Sabia University College, Jazan University, Kingdom of Saudi Arabia
| | - Mohamd A Alblihed
- 8 Department of Medical Biochemistry, School of Medicine, Taif University, Taif, Kingdom of Saudi Arabia
| | - Ibrahim Al-Neami
- 9 Director of Training and Scholarship Administration, MOH, Gizan, Kingdom of Saudi Arabia
| |
Collapse
|
|
13
|
Lyons DO, Plewes MR, Pullen NA. Soluble transforming growth factor beta-1 enhances murine mast cell release of Interleukin 6 in IgE-independent and Interleukin 13 in IgE-dependent settings in vitro. PLoS One 2018; 13:e0207704. [PMID: 30444930 PMCID: PMC6239331 DOI: 10.1371/journal.pone.0207704] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 11/03/2018] [Indexed: 12/05/2022] Open
Abstract
INTRODUCTION For immune cells transforming growth factor beta-1 (TGF-β1) can enhance or repress effector functions. Here, we characterize the effects of TGF-β1 on IgE-mediated and IL-33-mediated activation of primary murine mast cells derived from hematopoietic stem cells (bone marrow derived mast cells; BMMC). We also investigated potential interactions between TGF-β1 and stem cell factor (SCF). We conclude TGF-β1 plays a selectively stimulatory role for mast cell cultures in vitro. METHODS BMMCs from C57BL/6 mice were differentiated with IL-3 and then treated with TGF-β1. BMMCs were exposed to TGF-β1, primed with IgE, activated with antigen, and then IL-6 and IL-13 cytokine release was quantified using ELISA. Additionally, the effects of TGF-β1 on both IgE and IL-33-mediated short term activation were observed via flow cytometric analysis of both surface LAMP-1 expression and intracellular IL-6. Receptor colocalization was visualized using fluorescence confocal microscopy and individual receptor expression levels were also quantified. RESULTS Resting IL-6 production increased with TGF-β1 but significance was lost following BMMC activation via IgE receptor (FcεRI) crosslinking. This was similar to a comparison effect due to SCF treatment alone, which also enhanced resting levels of IL-6. TGF-β1 treatment enhanced release of IL-13 only with FcεRI-IgE-mediated activation. TGF-β1 suppressed mobilization of IL-6 with short-term BMMC activation when stimulated with IL-33. Lastly, colocalization patterns of the SCF receptor (CD117) and FcεRI with IgE crosslinking were unaffected by TGF-β1 treatment, but individual expression levels for FcεRI, CD117, and TGFβRII were all reduced following either IgE activation or TGF-β1 treatment; this reduction was partially recovered in BMMCs that were both activated by IgE and treated with TGF-β1. DISCUSSION These data reveal a novel positive effect of soluble TGF-β1 on mast cell activation in vitro, suggesting mast cells may be activated through a non-canonical pathway by TGF-β1. Understanding this interaction will provide insight into the potential role of mast cells in settings where TGF-β1 is produced in an aberrant manner, such as in and around high grade tumors.
Collapse
Affiliation(s)
- David O. Lyons
- School of Biological Sciences, University of Northern Colorado, Greeley, Colorado, United States of America
| | - Michele R. Plewes
- Olson Center for Women's Health, Department of Obstetrics and Gynecology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
| | - Nicholas A. Pullen
- School of Biological Sciences, University of Northern Colorado, Greeley, Colorado, United States of America
| |
Collapse
|
|
14
|
Abstract
Many major tropical diseases are caused by long-lived helminth parasites that are able to survive by modulation of the host immune system, including the innate compartment of myeloid cells. In particular, dendritic cells and macrophages show markedly altered phenotypes during parasite infections. In addition, many specialized subsets such as eosinophils and basophils expand dramatically in response to these pathogens. The changes in phenotype and function, and their effects on both immunity to infection and reactivity to bystander antigens such as allergens, are discussed.
Collapse
|
|
15
|
The role of rare innate immune cells in Type 2 immune activation against parasitic helminths. Parasitology 2017; 144:1288-1301. [PMID: 28583216 DOI: 10.1017/s0031182017000488] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The complexity of helminth macroparasites is reflected in the intricate network of host cell types that participate in the Type 2 immune response needed to battle these organisms. In this context, adaptive T helper 2 cells and the Type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have been the focus of research for years, but recent work has demonstrated that the innate immune system plays an essential role. Some innate immune cells that promote Type 2 immunity are relatively abundant, such as macrophages and eosinophils. However, we now appreciate that more rare cell types including group 2 innate lymphoid cells, basophils, mast cells and dendritic cells make significant contributions to these responses. These cells are found at low frequency but they are specialized to their roles - located at sites such as the skin, lung and gut, where the host combats helminth parasites. These cells respond rapidly and robustly to worm antigens and worm-induced damage to produce essential cytokines, chemokines, eicosanoids and histamine to activate damaged epithelium and to recruit other effectors. Thus, a greater understanding of how these cells operate is essential to understand how the host protects itself during helminth infection.
Collapse
|
|
16
|
Primary Heligmosomoides polygyrus bakeri infection induces myeloid-derived suppressor cells that suppress CD4 + Th2 responses and promote chronic infection. Mucosal Immunol 2017; 10:238-249. [PMID: 27072608 DOI: 10.1038/mi.2016.36] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 03/15/2016] [Indexed: 02/08/2023]
Abstract
Primary infection with the gastrointestinal nematode Heligmosomoides polygyrus bakeri is chronic in C57BL/6 (B6) mice whereas challenge infection is rapidly eliminated. F4/80-CD11b+Gr+ cells, presumed to be neutrophils, were reported to accumulate around encysting larvae in intestinal tissue during primary infection, but their exact identity and role remain unclear. We observed significant increases in F4/80-CD11bhiGr1hi cells in mesenteric lymph nodes (MLNs) and spleen after primary but not challenge infection; a high proportion of these cells expressed Ly6G and Ly6C. These cells, which phenotypically resemble myeloid-derived suppressor cells (MDSC), increased in lamina propria (LP) early during primary infection. Increased MDSC were associated with low numbers of alternatively activated macrophages (AAMØ) in LP and CD4+GATA3+ T cells and AAMØ in MLN and spleen. Purified CD11c-CD11b+Gr1+ cells from H. polygyrus bakeri-infected mice suppressed OVA-specific CD4+ T-cell proliferation via a nitric oxide-dependent mechanism and parasite-specific IL-4 secretion in vitro. Adoptive transfer of CD11c-CD11b+Gr1+ cells from mice with primary infection resulted in significantly higher adult worm burdens and increased egg production in naïve B6 recipients infected with H. polygyrus bakeri. Altogether, these findings indicate that primary H. polygyrus bakeri infection induces a novel subset of MDSC that suppress CD4+ Th2 responses and promote chronic infection.
Collapse
|
|
17
|
Maizels RM, McSorley HJ. Regulation of the host immune system by helminth parasites. J Allergy Clin Immunol 2016; 138:666-675. [PMID: 27476889 PMCID: PMC5010150 DOI: 10.1016/j.jaci.2016.07.007] [Citation(s) in RCA: 376] [Impact Index Per Article: 41.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 07/25/2016] [Accepted: 07/25/2016] [Indexed: 01/01/2023]
Abstract
Helminth parasite infections are associated with a battery of immunomodulatory mechanisms that affect all facets of the host immune response to ensure their persistence within the host. This broad-spectrum modulation of host immunity has intended and unintended consequences, both advantageous and disadvantageous. Thus the host can benefit from suppression of collateral damage during parasite infection and from reduced allergic, autoimmune, and inflammatory reactions. However, helminth infection can also be detrimental in reducing vaccine responses, increasing susceptibility to coinfection and potentially reducing tumor immunosurveillance. In this review we will summarize the panoply of immunomodulatory mechanisms used by helminths, their potential utility in human disease, and prospective areas of future research.
Collapse
Affiliation(s)
- Rick M Maizels
- Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
| | - Henry J McSorley
- Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom
| |
Collapse
|
|
18
|
Kolahian S, Öz HH, Zhou B, Griessinger CM, Rieber N, Hartl D. The emerging role of myeloid-derived suppressor cells in lung diseases. Eur Respir J 2016; 47:967-77. [PMID: 26846830 DOI: 10.1183/13993003.01572-2015] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 12/15/2015] [Indexed: 02/06/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) are innate immune cells characterised by their potential to control T-cell responses and to dampen inflammation. While the role of MDSCs in cancer has been studied in depth, our understanding of their relevance for infectious and inflammatory disease conditions has just begun to evolve. Recent studies highlight an emerging and complex role for MDSCs in pulmonary diseases. In this review, we discuss the potential contribution of MDSCs as biomarkers and therapeutic targets in lung diseases, particularly lung cancer, tuberculosis, chronic obstructive pulmonary disease, asthma and cystic fibrosis.
Collapse
Affiliation(s)
- Saeed Kolahian
- Children's Hospital of the University of Tübingen, Pediatric Infectiology, Immunology & Cystic Fibrosis, Tübingen, Germany Dept of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Hasan Halit Öz
- Children's Hospital of the University of Tübingen, Pediatric Infectiology, Immunology & Cystic Fibrosis, Tübingen, Germany
| | - Benyuan Zhou
- Children's Hospital of the University of Tübingen, Pediatric Infectiology, Immunology & Cystic Fibrosis, Tübingen, Germany
| | - Christoph M Griessinger
- Werner Siemens Imaging Center, Dept of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Nikolaus Rieber
- Children's Hospital of the University of Tübingen, Pediatric Infectiology, Immunology & Cystic Fibrosis, Tübingen, Germany Dept of Pediatrics, Kinderklinik München Schwabing, Klinikum rechts der Isar, Technische Universität München, Munich Germany
| | - Dominik Hartl
- Children's Hospital of the University of Tübingen, Pediatric Infectiology, Immunology & Cystic Fibrosis, Tübingen, Germany
| |
Collapse
|
|
19
|
Danelli L, Frossi B, Pucillo CE. Mast cell/MDSC a liaison immunosuppressive for tumor microenvironment. Oncoimmunology 2015; 4:e1001232. [PMID: 26137400 DOI: 10.1080/2162402x.2014.1001232] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 12/17/2014] [Indexed: 12/11/2022] Open
Abstract
The instauration of an immunosuppressive microenvironment is a key event in cancer development and progression. Here, we discuss increasing evidences of the crosstalk between myeloid-derived suppressor cells (MDSCs) and mast cells (MCs) as a new fuel for the cancer immunosuppressive machinery.
Collapse
Affiliation(s)
- Luca Danelli
- Department of Medical and Biological Science; University of Udine ; Udine, Italy ; Inserm UMRS-1149; CNRS ERL 8252; Laboratoire d'excellence INFLAMEX; Université Paris Diderot; Sorbonne Paris Cite ; Paris, France
| | - Barbara Frossi
- Department of Medical and Biological Science; University of Udine ; Udine, Italy
| | - Carlo E Pucillo
- Department of Medical and Biological Science; University of Udine ; Udine, Italy
| |
Collapse
|
|
20
|
Danelli L, Frossi B, Gri G, Mion F, Guarnotta C, Bongiovanni L, Tripodo C, Mariuzzi L, Marzinotto S, Rigoni A, Blank U, Colombo MP, Pucillo CE. Mast cells boost myeloid-derived suppressor cell activity and contribute to the development of tumor-favoring microenvironment. Cancer Immunol Res 2014; 3:85-95. [PMID: 25351848 DOI: 10.1158/2326-6066.cir-14-0102] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Inflammation plays crucial roles at different stages of tumor development and may lead to the failure of immune surveillance and immunotherapy. Myeloid-derived suppressor cells (MDSC) are one of the major components of the immune-suppressive network that favors tumor growth, and their interaction with mast cells is emerging as critical for the outcome of the tumor-associated immune response. Herein, we showed the occurrence of cell-to-cell interactions between MDSCs and mast cells in the mucosa of patients with colon carcinoma and in the colon and spleen of tumor-bearing mice. Furthermore, we demonstrated that the CT-26 colon cancer cells induced the accumulation of CD11b(+)Gr1(+) immature MDSCs and the recruitment of protumoral mast cells at the tumor site. Using ex vivo analyses, we showed that mast cells have the ability to increase the suppressive properties of spleen-derived monocytic MDSCs, through a mechanism involving IFNγ and nitric oxide production. In addition, we demonstrated that the CD40:CD40L cross-talk between the two cell populations is responsible for the instauration of a proinflammatory microenvironment and for the increase in the production of mediators that can further support MDSC mobilization and tumor growth. In light of these results, interfering with the MDSC:mast cell axis could be a promising approach to abrogate MDSC-related immune suppression and to improve the antitumor immune response.
Collapse
Affiliation(s)
- Luca Danelli
- Department of Medical and Biological Science, University of Udine, Udine, Italy. Inserm UMRS-1149; CNRS ERL 8252; Université Paris Diderot, Sorbonne Paris Cite, Laboratoire d'excellence INFLAMEX, 75018 Paris, France
| | - Barbara Frossi
- Department of Medical and Biological Science, University of Udine, Udine, Italy
| | - Giorgia Gri
- Department of Medical and Biological Science, University of Udine, Udine, Italy
| | - Francesca Mion
- Department of Medical and Biological Science, University of Udine, Udine, Italy
| | - Carla Guarnotta
- Department of Health Science, University of Palermo, Palermo, Italy
| | | | - Claudio Tripodo
- Department of Health Science, University of Palermo, Palermo, Italy
| | - Laura Mariuzzi
- Department of Medical and Biological Science, University of Udine, Udine, Italy
| | - Stefania Marzinotto
- Department of Medical and Biological Science, University of Udine, Udine, Italy
| | - Alice Rigoni
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Ulrich Blank
- Inserm UMRS-1149; CNRS ERL 8252; Université Paris Diderot, Sorbonne Paris Cite, Laboratoire d'excellence INFLAMEX, 75018 Paris, France
| | - Mario P Colombo
- Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
| | - Carlo E Pucillo
- Department of Medical and Biological Science, University of Udine, Udine, Italy.
| |
Collapse
|
|
21
|
Beury DW, Parker KH, Nyandjo M, Sinha P, Carter KA, Ostrand-Rosenberg S. Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors. J Leukoc Biol 2014; 96:1109-18. [PMID: 25170116 DOI: 10.1189/jlb.3a0414-210r] [Citation(s) in RCA: 149] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
MDSC and macrophages are present in most solid tumors and are important drivers of immune suppression and inflammation. It is established that cross-talk between MDSC and macrophages impacts anti-tumor immunity; however, interactions between tumor cells and MDSC or macrophages are less well studied. To examine potential interactions between these cells, we studied the impact of MDSC, macrophages, and four murine tumor cell lines on each other, both in vitro and in vivo. We focused on IL-6, IL-10, IL-12, TNF-α, and NO, as these molecules are produced by macrophages, MDSC, and many tumor cells; are present in most solid tumors; and regulate inflammation. In vitro studies demonstrated that MDSC-produced IL-10 decreased macrophage IL-6 and TNF-α and increased NO. IL-6 indirectly regulated MDSC IL-10. Tumor cells increased MDSC IL-6 and vice versa. Tumor cells also increased macrophage IL-6 and NO and decreased macrophage TNF-α. Tumor cell-driven macrophage IL-6 was reduced by MDSC, and tumor cells and MDSC enhanced macrophage NO. In vivo analysis of solid tumors identified IL-6 and IL-10 as the dominant cytokines and demonstrated that these molecules were produced predominantly by stromal cells. These results suggest that inflammation within solid tumors is regulated by the ratio of tumor cells to MDSC and macrophages and that interactions of these cells have the potential to alter significantly the inflammatory milieu within the tumor microenvironment.
Collapse
Affiliation(s)
- Daniel W Beury
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland, USA
| | - Katherine H Parker
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland, USA
| | - Maeva Nyandjo
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland, USA
| | - Pratima Sinha
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland, USA
| | - Kayla A Carter
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland, USA
| | - Suzanne Ostrand-Rosenberg
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland, USA
| |
Collapse
|
|
22
|
Yan C, Du H. Lysosomal acid lipase is critical for myeloid-derived suppressive cell differentiation, development, and homeostasis. World J Immunol 2014; 4:42-51. [DOI: 10.5411/wji.v4.i2.42] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 04/02/2014] [Accepted: 06/18/2014] [Indexed: 02/05/2023] Open
Abstract
Lysosomal acid lipase (LAL) cleaves cholesteryl esters (CE) and triglycerides (TG) to generate cholesterol and free fatty acid in lysosomes of cells. The downstream metabolic products of fatty acids are ligands for activation of peroxisome proliferator-activated receptor gamma (PPARγ). Accumulation of CEs and TGs is resulted from lack of functional LAL in lysosomes of cells, especially in myeloid cells. One characteristic phenotype in LAL knock-out (lal-/-) mice is systemic elevation of myeloid-derived suppressive cells (MDSCs). MDSCs infiltrate into multiple distal organs, alter T cell development, and suppress T cell proliferation and lymphokine production in lal-/- mice, which lead to severe pathogeneses in multiple organs. The gene transcriptional profile analysis in MDSCs from the bone marrow has identified multiple defects responsible for MDSCs malformation and malfunction in lal-/- mice, including G protein signaling, cell cycles, glycolysis metabolism, mitochondrial bioenergetics, mTOR pathway etc. In a separate gene transcriptional profile analysis in the lung of lal-/- mice, matrix metalloproteinase 12 (MMP12) and apoptosis inhibitor 6 (Api6) are highly overexpressed due to lack of ligand synthesis for PPARγ. PPARγ negatively regulates MMP12 and Api6. Blocking the PPAR signaling by overexpression of a dominant negative PPARγ (dnPPARγ) form, or overexpressing MMP12 or Api6 in myeloid or lung epithelial cells in inducible transgenic mouse models results in elevated MDSCs and inflammation-induced tumorigenesis. These studies demonstrate that LAL and its downstream effectors are critical for MDSCs development, differentiation and malfunction.
Collapse
|