|
1
|
Antunes FTT, Gandini MA, Garcia-Caballero A, Huang S, Ali MY, Gambeta E, Souza IA, Harding EK, Ferron L, Stray-Pedersen A, Gadotti VM, Zamponi GW. A pathological missense mutation in the deubiquitinase USP5 leads to insensitivity to pain. J Exp Med 2025; 222:e20241877. [PMID: 40377597 DOI: 10.1084/jem.20241877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 03/06/2025] [Accepted: 04/22/2025] [Indexed: 05/18/2025] Open
Abstract
Cav3.2 T-type calcium channels and their dysregulation by the deubiquitinase USP5 contribute to development of inflammatory and neuropathic pain. We report on a pediatric patient with a de novo heterozygous missense mutation R24W in USP5 who exhibits pain insensitivity. We created a CRISPR knock-in mouse harboring this mutation and performed detailed behavioral analyses in acute and chronic pain models. Heterozygous R24W mice of both sexes are resistant to acute pain and to thermal hypersensitivity in chronic inflammatory and neuropathic pain models. In contrast, only male R24W mice confer resistance to development of mechanical hypersensitivity. R24W mice lack upregulation of Cav3.2 and USP5 that is normally observed with CFA-induced inflammation. Moreover, mutant USP5 exhibits a dramatic reduction in enzymatic activity but stronger interactions with Cav3.2. Hence, R24W mutant USP5 is a critical regulator of chronic and acute pain states in humans by acting as a dominant-negative regulator of Cav3.2. Our data validate USP5 as a potential therapeutic target for chronic pain in humans.
Collapse
Affiliation(s)
- Flavia T T Antunes
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Maria A Gandini
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Agustin Garcia-Caballero
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Sun Huang
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Md Yousof Ali
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
- Zymedyne Therapeutics , Calgary, Canada
| | - Eder Gambeta
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Ivana A Souza
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Erika K Harding
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
- Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada
| | - Laurent Ferron
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Asbjorg Stray-Pedersen
- Norwegian National Unit for Newborn Screening, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
| | - Vinicius M Gadotti
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
- School of Health Sciences, Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí (UNIVALI) , Itajaí, Brazil
| | - Gerald W Zamponi
- Department of Clinical Neurosciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| |
Collapse
|
|
2
|
Ma Y, Fan X, Han J, Cheng Y, Zhao J, Fang W, Gao L. Critical illness and sex hormones: response and impact of the hypothalamic-pituitary-gonadal axis. Ther Adv Endocrinol Metab 2025; 16:20420188251328192. [PMID: 40183031 PMCID: PMC11967225 DOI: 10.1177/20420188251328192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 02/19/2025] [Indexed: 04/05/2025] Open
Abstract
Understanding the hypothalamic-pituitary-gonadal (HPG) axis is essential for grasping human responses under extreme physiological and pathological conditions. The HPG axis regulates reproductive and gonadal hormone activities and significantly impacts the body's response to acute and chronic illnesses. This review explores the fundamental functions of the HPG axis, modifications under critical conditions, and impacts on disease progression and treatment outcomes. In addition, it examines interactions between sex hormones and biomolecules like cytokines and gastrointestinal microorganisms, highlighting their roles in immune response regulation. Clinically, this knowledge can enhance patient prognoses. The review aims to provide a comprehensive framework, based on existing research, for understanding and applying the functions of the HPG axis in managing critical diseases, thereby broadening clinical applications and guiding future research.
Collapse
Affiliation(s)
- Yicheng Ma
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Key Laboratory of Endocrine Glucose and Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Xiude Fan
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Junming Han
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Yiping Cheng
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Jiajun Zhao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China
| | - Wei Fang
- Department of Critical-Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong First Medical University, Jinan, No. 9677, Jingshi Road, Lixia District, Jinan, Shandong 250000, China
| | - Ling Gao
- Department of Endocrinology, Shandong Provincial Hospital, Shandong University, No. 544, Jingsi Road, Xishichang Subdistrict, Huaiyin District, Jinan, Shandong 250000, China
- Key Laboratory of Endocrine Glucose and Lipids Metabolism and Brain Aging, Ministry of Education, Jinan, Shandong, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
- Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Jinan, Shandong, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China
- Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, No. 544, Jingsi Road, Xishichang Subdistrict, Huaiyin District, Jinan, Shandong 250000, China
| |
Collapse
|
|
3
|
Trager RJ, Haering CP, Baumann AN, Wright DS. Association between combined oral contraceptive prescription and cervical artery dissection: A retrospective cohort study. Thromb Res 2025; 247:109279. [PMID: 39923282 DOI: 10.1016/j.thromres.2025.109279] [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: 12/02/2024] [Revised: 01/01/2025] [Accepted: 02/01/2025] [Indexed: 02/11/2025]
Abstract
BACKGROUND To date, research has identified positive associations between combined oral contraceptives (COCs) and adverse vascular events, however, evidence regarding the possible association with cervical artery dissection (CeAD) remains limited. We tested the hypothesis of a positive association between COCs and CeAD within one year following COC initiation compared to matched controls initiating intrauterine devices (IUDs), as measured by risk ratio (RR). METHODS We queried de-identified United States health records data (TriNetX, Inc.) from 2014 to 2024 for females aged 15-50 years without previous cerebrovascular disease or CeAD, creating mutually exclusive cohorts initiating either COCs or IUDs. We used propensity matching to control for variables associated with CeAD. Our primary outcome included the RR for CeAD within one year follow-up. We secondarily explored cumulative CeAD incidence and RR of stroke, also examining outcomes for females with ≥2 COC prescriptions (COC2). RESULTS After matching there were 214,020 patients per cohort (mean age 31 years). The incidence and risk of CeAD was greater among those prescribed COCs compared to matched controls with IUDs [95 % CI] (COCs: 0.016 %, IUDs: 0.008 %; RR 1.94 [1.10,3.43]; P = 0.0195). A similar association was observed for stroke (COCs: 0.106 %, IUDs: 0.057 %; RR = 1.86 [1.49,2.32]; P < 0.0001). The secondary COC2 analysis revealed similar findings. CONCLUSIONS The present findings suggest that females prescribed COCs have an increased risk of CeAD and stroke compared to matched controls using IUDs. These observations should be viewed as preliminary, require corroboration by other studies, and in isolation do not replace the broader clinical and shared decision-making regarding contraceptive use.
Collapse
Affiliation(s)
- Robert J Trager
- Connor Whole Health, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Family Medicine and Community Health, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Biostatistics and Bioinformatics Clinical Research Training Program, Duke University School of Medicine, Durham, NC, USA.
| | - Catherine P Haering
- Department of Reproductive Endocrinology and Infertility, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Anthony N Baumann
- College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA; Department of Rehabilitation Services, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Debbie S Wright
- MSCR Student, Parker University, Dallas, TX, USA; Private practice, The Grove Health and Wellness, Courtenay, BC, Canada
| |
Collapse
|
|
4
|
Brown AC, Carroll OR, Mayall JR, Zounemat-Kermani N, Vinzenz SLE, Gomez HM, Mills EF, Kim RY, Donovan C, Baines KJ, Williams EJ, Berthon BS, Wynne K, Scott HA, Pinkerton JW, Guo Y, Hansbro PM, Foster PS, Wark PAB, Dahlen SE, Adcock IM, Wood LG, Horvat JC. Female sex hormones and the oral contraceptive pill modulate asthma severity through GLUT-1. Mucosal Immunol 2025:S1933-0219(25)00024-8. [PMID: 40021011 DOI: 10.1016/j.mucimm.2025.02.006] [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: 09/27/2024] [Revised: 02/20/2025] [Accepted: 02/20/2025] [Indexed: 03/03/2025]
Abstract
Females are disproportionately affected by asthma. An increased understanding of how female sex hormones influence key pathophysiological processes that underpin asthma may identify new, more effective asthma therapies, particularly for females with severe, poorly controlled asthma. We assessed the effects of oral ethinylestradiol/levonorgestrel (representing OCP use) and depot-medroxyprogesterone acetate (DMPA) and estradiol injections on key features of experimental asthma, and determined their effects on glucose transporter-1 (GLUT-1). The effects of OCP use on clinical asthma outcomes, and the relationships between estrogen receptors and type 2 (T2), non-T2, and GLUT-1 responses, in clinical asthma were also determined. OCP and DMPA reduce T2 responses, disease features, and lung expression of GLUT-1, whereas estradiol increases lung expression of GLUT-1, and results in severe, corticosteroid-insensitive, neutrophil-enriched disease, in experimental asthma. OCP use is associated with reduced T2 cytokine and GLUT-1 responses in clinical asthma. GLUT-1 expression is increased in sputum of severe asthmatics, and positively correlates with estrogen receptor expression and both T2 and non-T2 inflammatory responses. Significantly, OCP or GLUT-1 inhibition protects against obesity-associated or estradiol-induced, severe, experimental asthma, respectively. Together, these data show how female sex hormones and the OCP likely modulate asthma severity by modifying GLUT-1 responses in the airways.
Collapse
Affiliation(s)
- Alexandra C Brown
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Olivia R Carroll
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Jemma R Mayall
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | | | - Samantha L E Vinzenz
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Henry M Gomez
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Ed F Mills
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Richard Y Kim
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia; School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia; Woolcock Institute of Medical Research, Sydney, New South Wales, Australia
| | - Chantal Donovan
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia; School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia; Woolcock Institute of Medical Research, Sydney, New South Wales, Australia
| | - Katherine J Baines
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Evan J Williams
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Bronwyn S Berthon
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Katie Wynne
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Hayley A Scott
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - James W Pinkerton
- Respiratory Pharmacology & Toxicology Group, National Heart & Lung Institute, Imperial College London, London, United Kingdom
| | - Yike Guo
- Hong Kong University of Science and Technology, Hong Kong
| | - Philip M Hansbro
- Centre for Inflammation, Centenary Institute, and Faculty of Science, University of Technology Sydney, Sydney, New South Wales, Australia
| | - Paul S Foster
- Woolcock Institute of Medical Research and Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia
| | - Peter A B Wark
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia; School of Translational Medicine, Monash University, Melbourne, Victoria, Australia
| | - Sven-Erik Dahlen
- Clinical Lung and Allergy Research Unit, Department of Medicine Huddinge, Karolinska Institutet, and, Department of Respiratory Medicine and Allergy, Karolinska University Hospital Huddinge, and Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ian M Adcock
- The Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom
| | - Lisa G Wood
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Jay C Horvat
- The University of Newcastle and Immune Health Program, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
| |
Collapse
|
|
5
|
Zheng H, Mizokami A, Romera-Giner S, Llera-Oyola J, Yamawaki Y, Sano T, Jimi E, García-García F, Kanematsu T. Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia. Biol Sex Differ 2025; 16:9. [PMID: 39905477 PMCID: PMC11792555 DOI: 10.1186/s13293-025-00686-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 01/13/2025] [Indexed: 02/06/2025] Open
Abstract
BACKGROUND Significant sex differences exist in the prevalence and incidence of Alzheimer's disease (AD). Notably, testosterone has been reported to regulate cognitive functions in the brain, with low serum testosterone levels correlating with increased AD risk. However, the specific mechanisms underlying this relationship remain unclear. Recent studies have demonstrated that microglia, the primary innate immune cells in the brain, play a crucial role in AD development. Therefore, this study aimed to explore sex differences in microglial function, specifically focusing on the role of testosterone in miRNA-mediated regulation of microglial gene expression. METHODS Microglia were isolated from pooled hippocampal tissue of five 8-month-old male and female mice. Total RNA was extracted and subjected to miRNA microarray analysis. The mouse microglial cell line MG6 was used for in vitro experiments. Following testosterone treatment, miRNA, gene, and protein expression levels were investigated. An inflammatory response was induced using lipopolysaccharide (LPS) stimulation, and subsequent p65 phosphorylation was assessed. RESULTS Sex-dependent differences were observed in miRNA-mediated biological processes, with males exhibiting greater changes. Male-enriched miRNAs were associated with fatty acid synthesis and metabolism pathways. In MG6 cells, testosterone treatment upregulated the expression of several miRNAs enriched in male microglia, particularly those targeting genes related to fatty acid synthesis. Additionally, testosterone significantly reduced the gene expression of fatty acid synthase (FASN). This testosterone-induced inhibition of FASN expression attenuated NF-κB/p65 phosphorylation. Consequently, the suppression of FASN expression led to reduced expression and secretion of tumor necrosis factor-alpha following LPS stimulation in MG6 cells. CONCLUSIONS These findings suggest that testosterone modulates inflammation in male microglia by regulating fatty acid synthesis, potentially contributing to the observed sex differences in AD pathogenesis.
Collapse
Affiliation(s)
- Haolin Zheng
- Department of Cell Biology, Aging Science, and Pharmacology, Division of Oral Biological Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Akiko Mizokami
- OBT Research Center, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
| | - Sergio Romera-Giner
- Computational Biomedicine Laboratory, Prince Felipe Research Center (CIPF), 46012, Valencia, Spain
| | - Jaime Llera-Oyola
- Computational Biomedicine Laboratory, Prince Felipe Research Center (CIPF), 46012, Valencia, Spain
| | - Yosuke Yamawaki
- Department of Advanced Pharmacology, Daiichi University of Pharmacy, 22-1 Tamagawa-Cho, Minami-Ku, Fukuoka, 815-8511, Japan
| | - Tomomi Sano
- Department of Cell Biology, Aging Science, and Pharmacology, Division of Oral Biological Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Eijiro Jimi
- OBT Research Center, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
- Laboratory of Molecular and Cellular Biochemistry, Division of Oral Biological Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Francisco García-García
- Computational Biomedicine Laboratory, Prince Felipe Research Center (CIPF), 46012, Valencia, Spain
| | - Takashi Kanematsu
- Department of Cell Biology, Aging Science, and Pharmacology, Division of Oral Biological Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| |
Collapse
|
|
6
|
Huang SC, Liu KL, Chen P, Xu BW, Ding WL, Yue TJ, Lu YN, Li SY, Li JK, Jian FC. New insights into the combined effects of aflatoxin B1 and Eimeria ovinoidalis on uterine function by disrupting the gut-blood-reproductive axis in sheep. MICROBIOME 2024; 12:269. [PMID: 39707461 DOI: 10.1186/s40168-024-01966-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 11/03/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND Sheep coccidiosis is an infectious parasitic disease that primarily causes diarrhea and growth retardation in young animals, significantly hindering the development of the sheep breeding industry. Cereal grains and animal feeds are frequently contaminated with mycotoxins worldwide, with aflatoxin B1 (AFB1) being the most common form. AFB1 poses a serious threat to gastrointestinal health upon ingestion and affects the function of parenteral organs, thus endangering livestock health. However, the impact of the combined effects of coccidia and AFB1 on the reproductive system of sheep has not been reported. Therefore, this study utilized sheep as an animal model to investigate the mechanisms underlying the reproductive toxicity induced by the individual or combined effects of AFB1 and Eimeria ovinoidalis (E. ovinoidalis) on the gut-blood-reproductive axis. RESULTS The results showed that AFB1 and coccidia adversely affect the reproductive system defense of sheep by altering uterine histopathology and hormone levels and triggering inflammation, which is associated with changes in the gut microbiota and metabolites. Moreover, co-exposure to AFB1 and coccidia disrupted the intestinal structure of the colon, resulting in reduced crypt depth. The impaired barrier function of the colon manifests primarily through the suppression of barrier protein expression, changes in the gut microbiome composition, and disruptions in gut metabolism. Importantly, the levels of blood inflammatory factors (IL-6, IL-10, TNF-α, and LPS) increased, suggesting that exposure to AFB1 and coccidia compromises the function of uterine organs in sheep by perturbing the gut-blood-reproductive axis. Blood metabolomics analysis further revealed that the differential metabolites predominantly concentrate in the amino acid pathway, particularly N-acetyl-L-phenylalanine. This metabolite is significantly correlated with IL-6, TNF-α, LPS, ERα, and ERβ, and it influences hormone levels while inducing uterine damage through the regulation of the downstream genes PI3K, AKT, and eNOS in the relaxin signaling pathway, as demonstrated by RNA sequencing. CONCLUSIONS These findings reveal for the first time that the combined effects of AFB1 and E. ovinoidalis on sheep uterine function operate at the level of the gut-blood-reproductive axis. This suggests that regulating gut microbiota and its metabolites may represent a potential therapeutic strategy for addressing mycotoxins and coccidia-co-induced female reproductive toxicity.
Collapse
Affiliation(s)
- Shu-Cheng Huang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, People's Republic of China
| | - Kai-Li Liu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, People's Republic of China
| | - Pan Chen
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, People's Republic of China
| | - Bo-Wen Xu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, People's Republic of China
| | - Wen-Li Ding
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, People's Republic of China
| | - Tao-Jing Yue
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, People's Republic of China
| | - Ya-Nan Lu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, People's Republic of China
| | - Sen-Yang Li
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, People's Republic of China
| | - Jia-Kui Li
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, People's Republic of China.
| | - Fu-Chun Jian
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450046, People's Republic of China.
| |
Collapse
|
|
7
|
Topham B, Hock B, Phillips E, Wiggins G, Currie M. The Role of Innate Priming in Modifying Tumor-associated Macrophage Phenotype. FRONT BIOSCI-LANDMRK 2024; 29:418. [PMID: 39735978 DOI: 10.31083/j.fbl2912418] [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: 07/08/2024] [Revised: 08/07/2024] [Accepted: 08/19/2024] [Indexed: 12/31/2024]
Abstract
Tumor-associated macrophages (TAMs) are innate immune cells that exert far reaching influence over the tumor microenvironment (TME). Depending on cues within the local environment, TAMs may promote tumor angiogenesis, cancer cell invasion and immunosuppression, or, alternatively, inhibit tumor progression via neoantigen presentation, tumoricidal reactive oxygen species generation and pro-inflammatory cytokine secretion. Therefore, TAMs have a pivotal role in determining tumor progression and response to therapy. TAM phenotypes are driven by cytokines and physical cues produced by tumor cells, adipocytes, fibroblasts, pericytes, immune cells, and other cells within the TME. Research has shown that TAMs can be primed by environmental stimuli, adding another layer of complexity to the environmental context that determines TAM phenotype. Innate priming is a functional consequence of metabolic and epigenetic reprogramming of innate cells by a primary stimulant, resulting in altered cellular response to future secondary stimulation. Innate priming offers a novel target for development of cancer immunotherapy and improved prognosis of disease, but also raises the risk of exacerbating existing inflammatory pathologies. This review will discuss the mechanisms underlying innate priming including metabolic and epigenetic modification, its relevance to TAMs and tumor progression, and possible clinical implications for cancer treatment.
Collapse
Affiliation(s)
- Ben Topham
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, 8011 Christchurch, Aotearoa New Zealand
| | - Barry Hock
- Haematology Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, 8011 Christchurch, Aotearoa New Zealand
| | - Elisabeth Phillips
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, 8011 Christchurch, Aotearoa New Zealand
| | - George Wiggins
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, 8011 Christchurch, Aotearoa New Zealand
| | - Margaret Currie
- Mackenzie Cancer Research Group, Department of Pathology and Biomedical Science, University of Otago Christchurch, 8011 Christchurch, Aotearoa New Zealand
| |
Collapse
|
|
8
|
McGovern M, Kelly L, Finnegan R, McGrath R, Kelleher J, El-Khuffash A, Murphy J, Greene CM, Molloy EJ. Gender and sex hormone effects on neonatal innate immune function. J Matern Fetal Neonatal Med 2024; 37:2334850. [PMID: 38839425 DOI: 10.1080/14767058.2024.2334850] [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: 10/05/2023] [Accepted: 03/15/2024] [Indexed: 06/07/2024]
Abstract
OBJECTIVES Scientific evidence provides a widened view of differences in immune response between male and female neonates. The X-chromosome codes for several genes important in the innate immune response and neonatal innate immune cells express receptors for, and are inhibited by, maternal sex hormones. We hypothesized that sex differences in innate immune responses may be present in the neonatal population which may contribute to the increased susceptibility of premature males to sepsis. We aimed to examine the in vitro effect of pro-inflammatory stimuli and hormones in neutrophils and monocytes of male and female neonates, to examine the expression of X-linked genes involved in innate immunity and the miRNA profiles in these populations. METHODS Preterm infants (n = 21) and term control (n = 19) infants were recruited from the Coombe Women and Infants University Hospital Dublin with ethical approval and explicit consent. The preterm neonates (eight female, 13 male) were recruited with a mean gestation at birth (mean ± SD) of 28 ± 2 weeks and corrected gestation at the time of sampling was 30 + 2.6 weeks. The mean birth weight of preterm neonates was 1084 ± 246 g. Peripheral blood samples were used to analyze immune cell phenotypes, miRNA human panel, and RNA profiles for inflammasome and inflammatory genes. RESULTS Dividing neutrophil results by sex showed no differences in baseline CD11b between sexes among either term or preterm neonates. Examining monocyte CD11b by sex shows, that at baseline, total and classical monocytes have higher CD11b in preterm females than preterm males. Neutrophil TLR2 did not differ between sexes at baseline or following lipopolysaccharide (LPS) exposure. CD11b expression was higher in preterm male non-classical monocytes following Pam3CSK treatment when compared to females, a finding which is unique to our study. Preterm neonates had higher TLR2 expression at baseline in total monocytes, classical monocytes and non-classical monocytes than term. A sex difference was evident between preterm females and term females in TLR2 expression only. Hormone treatment showed no sex differences and there was no detectable difference between males and females in X-linked gene expression. Two miRNAs, miR-212-3p and miR-218-2-3p had significantly higher expression in preterm female than preterm male neonates. CONCLUSIONS This study examined immune cell phenotypes and x-linked gene expression in preterm neonates and stratified according to gender. Our findings suggest that the responses of females mature with advancing gestation, whereas male term and preterm neonates have very similar responses. Female preterm neonates have improved monocyte activation than males, which likely reflects improved innate immune function as reflected clinically by their lower risk of sepsis. Dividing results by sex showed changes in preterm and term infants at baseline and following LPS stimulation, a difference which is reflected clinically by infection susceptibility. The sex difference noted is novel and may be limited to the preterm or early neonatal population as TLR2 expression on monocytes of older children does not differ between males and females. The differences shown in female and male innate immune cells likely reflect a superior innate immune defense system in females with sex differences in immune cell maturation. Existing human studies on sex differences in miRNA expression do not include preterm patients, and most frequently use either adult blood or cord blood. Our findings suggest that miRNA profiles are similar in neonates of opposite sexes at term but require further investigation in the preterm population. Our findings, while novel, provide only very limited insights into sex differences in infection susceptibility in the preterm population leaving many areas that require further study. These represent important areas for ongoing clinical and laboratory study and our findings represent an important contribution to exiting literature.
Collapse
Affiliation(s)
- Matthew McGovern
- Paediatrics, Academic Centre, Tallaght University Hospital, Trinity College, The University of Dublin, Dublin, Ireland
| | - Lynne Kelly
- Trinity Translational Medicine Institute (TTMI) & Trinity Research in Childhood Centre (TRICC), Trinity College Dublin, Dublin, Ireland
| | - Rebecca Finnegan
- Paediatrics, Academic Centre, Tallaght University Hospital, Trinity College, The University of Dublin, Dublin, Ireland
| | - Roisin McGrath
- Trinity Translational Medicine Institute (TTMI) & Trinity Research in Childhood Centre (TRICC), Trinity College Dublin, Dublin, Ireland
| | - John Kelleher
- Neonatology, Coombe Women and Infants' University Hospital, Dublin, Ireland
| | - Afif El-Khuffash
- Department of Neonatology, The Rotunda Hospital, Dublin, Ireland
| | - John Murphy
- Department of Neonatology, National Maternity Hospital, Dublin, Ireland
| | | | - Eleanor J Molloy
- Paediatrics, Academic Centre, Tallaght University Hospital, Trinity College, The University of Dublin, Dublin, Ireland
- Trinity Translational Medicine Institute (TTMI) & Trinity Research in Childhood Centre (TRICC), Trinity College Dublin, Dublin, Ireland
- Neonatology, Coombe Women and Infants' University Hospital, Dublin, Ireland
- Department of Neonatology, The Rotunda Hospital, Dublin, Ireland
| |
Collapse
|
|
9
|
Hutcherson C, Luke B, Khader K, Dhaher YY. Unraveling the complex interplay of sex, endocrinology, and inflammation in post-Injury articular cartilage breakdown through in silico modeling. Sci Rep 2024; 14:28654. [PMID: 39562596 PMCID: PMC11576913 DOI: 10.1038/s41598-024-77730-x] [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: 09/02/2024] [Accepted: 10/24/2024] [Indexed: 11/21/2024] Open
Abstract
The onset of degenerative joint diseases such as post-traumatic osteoarthritis (PTOA) are associated with joint injury, biomechanical changes, and synovial biochemical anomalies. Sex and reproductive endocrinology have been emerging as potential risk factors, with epidemiological evidence revealing that female's exhibit higher PTOA risk and poorer outcomes post-injury compared to males. Sex hormones, including estradiol, progesterone, and testosterone, have been shown to regulate inflammatory signaling in immune and synovial cells, yet their collective impact on injury-induced joint inflammation and catabolism is poorly understood. Using an in silico kinetic model, we investigated the effects of sex-specific endocrine states on post-injury mechanisms in the human synovial joint. Our model results reveal that heightened estradiol levels in pre-menopausal females during the peri-ovulatory phase increase interleukin (IL)-1β expression and suppress IL-10 expression within the synovium after a simulated injury. Conversely, elevated testosterone levels in males decrease post-injury IL-1β, tumor necrosis factor alpha (TNF)-α, and stromelysin (MMP)-3 expression while increasing IL-10 production compared to females. Gaining insight into the effects of sex hormones on injury-induced inflammation and cartilage degradation provides a basis for designing future experimental and clinical studies to explore their effects on the synovial system, with a particular focus on the female sex.
Collapse
Affiliation(s)
- C Hutcherson
- Department of Physical Medicine and Rehabilitation, University of Texas Southwestern, Dallas, TX, USA
- Department of Orthopaedic Surgery, University of Texas Southwestern, Dallas, TX, USA
| | - B Luke
- Department of Mechanical Engineering, Valparaiso University, Valparaiso, IN, USA
| | - K Khader
- Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Y Y Dhaher
- Department of Physical Medicine and Rehabilitation, University of Texas Southwestern, Dallas, TX, USA.
- Department of Orthopaedic Surgery, University of Texas Southwestern, Dallas, TX, USA.
| |
Collapse
|
|
10
|
Kiss O, Bahri R, Watson REB, Chike C, Langton AK, Newton VL, Bell M, Griffiths CEM, Bulfone-Paus S, Pilkington SM. The impact of irritant challenge on the skin barrier and myeloid-resident immune cells in women who are postmenopausal is modulated by hormone replacement therapy. Br J Dermatol 2024; 191:746-759. [PMID: 38819239 DOI: 10.1093/bjd/ljae226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/15/2024] [Accepted: 05/18/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND Sex hormone changes during menopausal transition contribute to declining skin health. However, how menopause and its treatment by hormone replacement therapy (HRT) impact the skin barrier and immune system is unclear. OBJECTIVES To examine how menopause and HRT affect the skin barrier and immune cell composition in postmenopausal women following irritant challenge. METHODS Two cohorts of postmenopausal women were recruited to the study. The first cohort consisted of 10 untreated women [HRT-; mean (SEM) age 56.5 (1.6) years (range 48-63)] and the second was composed of 8 women receiving HRT [HRT+; mean (SEM) age 54.0 (2.1) years (range 48-63)]. Skin irritation was induced by applying topical sodium lauryl sulfate (SLS) 1.25% to occluded buttock skin for 48 h. Clinical assessment was conducted after 24 h, followed by biopsy of both SLS-challenged and unchallenged skin for analysis of skin barrier proteins and immune cell distribution using immunofluorescence. RESULTS Clinically, there were no significant differences in skin irritant responses between those taking or not taking HRT (including increased skin redness and blood flow). In response to SLS challenge a significant increase in transepidermal water loss (P < 0.05), filaggrin deposition and cytokeratin 10 (K10)+ cell layers (P < 0.01) was observed in individuals receiving HRT compared with the HRT- group. Following SLS challenge in individuals taking HRT, a significant (P < 0.01) reduction in CD207+ cells in the epidermis was observed, accompanied by an increase of CD207+ cells in the dermis, indicative of migrating Langerhans cells (LCs). Significantly fewer migrating LCs were found in those who were not receiving HRT (P < 0.01). Furthermore, the numbers of dermal dendritic cells (DCs), macrophages, and CD11c+CD206- and CD68+CD206- subsets were found to be significantly (P < 0.05) higher in those taking HRT following SLS challenge. CONCLUSIONS Individuals receiving HRT displayed enhanced skin barrier response to SLS challenge with thicker filaggrin and increased K10+ epidermal cell layers. Following challenge, HRT users exhibited elevated LC, inflammatory DC and macrophage counts in the dermis. These may render skin both more prone to inflammation and more capable of resolving it, while also promoting skin repair.
Collapse
Affiliation(s)
- Orsolya Kiss
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Rajia Bahri
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- Lydia Becker Institute of Immunology and Inflammation and Manchester Collaborative Centre for Inflammation Research, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - Rachel E B Watson
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology and Research (A*STAR), National Skin Centre and Skin Research Institute of Singapore (SRIS), Republic of Singapore
| | - Chidera Chike
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Abigail K Langton
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | | | - Mike Bell
- No7 Beauty Company, Walgreens Boots Alliance, Nottingham, UK
| | - Christopher E M Griffiths
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- Department of Dermatology, King's College Hospital NHS Foundation Trust, King's College London, London, UK
| | - Silvia Bulfone-Paus
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- Lydia Becker Institute of Immunology and Inflammation and Manchester Collaborative Centre for Inflammation Research, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester, UK
| | - Suzanne M Pilkington
- Centre for Dermatology Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| |
Collapse
|
|
11
|
Rodríguez-Palma EJ, Huerta de la Cruz S, Islas-Espinoza AM, Castañeda-Corral G, Granados-Soto V, Khanna R. Nociplastic pain mechanisms and toll-like receptors as promising targets for its management. Pain 2024; 165:2150-2164. [PMID: 38595206 DOI: 10.1097/j.pain.0000000000003238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 02/29/2024] [Indexed: 04/11/2024]
Abstract
ABSTRACT Nociplastic pain, characterized by abnormal pain processing without an identifiable organic cause, affects a significant portion of the global population. Unfortunately, current pharmacological treatments for this condition often prove ineffective, prompting the need to explore new potential targets for inducing analgesic effects in patients with nociplastic pain. In this context, toll-like receptors (TLRs), known for their role in the immune response to infections, represent promising opportunities for pharmacological intervention because they play a relevant role in both the development and maintenance of pain. Although TLRs have been extensively studied in neuropathic and inflammatory pain, their specific contributions to nociplastic pain remain less clear, demanding further investigation. This review consolidates current evidence on the connection between TLRs and nociplastic pain, with a specific focus on prevalent conditions like fibromyalgia, stress-induced pain, sleep deprivation-related pain, and irritable bowel syndrome. In addition, we explore the association between nociplastic pain and psychiatric comorbidities, proposing that modulating TLRs can potentially alleviate both pain syndromes and related psychiatric disorders. Finally, we discuss the potential sex differences in TLR signaling, considering the higher prevalence of nociplastic pain among women. Altogether, this review aims to shed light on nociplastic pain, its underlying mechanisms, and its intriguing relationship with TLR signaling pathways, ultimately framing the potential therapeutic role of TLRs in addressing this challenging condition.
Collapse
Affiliation(s)
- Erick J Rodríguez-Palma
- Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, United States
- Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, South Campus, Mexico City, Mexico
| | | | - Ana M Islas-Espinoza
- Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, South Campus, Mexico City, Mexico
| | | | - Vinicio Granados-Soto
- Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Cinvestav, South Campus, Mexico City, Mexico
| | - Rajesh Khanna
- Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL, United States
| |
Collapse
|
|
12
|
Khaksari M, Pourali M, Rezaei Talabon S, Gholizadeh Navashenaq J, Bashiri H, Amiresmaili S. Protective effects of 17-β-estradiol on liver injury: The role of TLR4 signaling pathway and inflammatory response. Cytokine 2024; 181:156686. [PMID: 38991382 DOI: 10.1016/j.cyto.2024.156686] [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: 04/20/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/13/2024]
Abstract
Liver injury, a major global health issue, stems from various causes such as alcohol consumption, nonalcoholic steatohepatitis, obesity, diabetes, metabolic syndrome, hepatitis, and certain medications. The liver's unique susceptibility to ischemia and hypoxia, coupled with the critical role of the gut-liver axis in inflammation, underscores the need for effective therapeutic interventions. The study highlights E2's interaction with estrogen receptors (ERs) and its modulation of the Toll-like receptor 4 (TLR4) signaling pathway as key mechanisms in mitigating liver injury. Activation of TLR4 leads to the release of pro-inflammatory cytokines and chemokines, exacerbating liver inflammation and injury. E2 down-regulates TLR4 expression, reduces oxidative stress, and inhibits pro-inflammatory cytokines, thereby protecting the liver. Both classic (ERα and ERβ) and non-classic [G protein-coupled estrogen receptor (GPER)] receptors are influenced by E2. ERα is particularly crucial for liver regeneration, preventing liver failure by promoting hepatocyte proliferation. Furthermore, E2 exerts anti-inflammatory, antioxidant, and anti-apoptotic effects by inhibiting cytokines such as IL-6, IL-1β, TNF-α, and IL-17, and by reducing lipid peroxidation and free radical damage. The article calls for further clinical research to validate these findings and to develop estrogen-based treatments for liver injuries. Overall, the research emphasizes the significant potential of E2 as a therapeutic agent for liver injuries. It advocates for extensive clinical studies to validate E2 hepatoprotective properties and develop effective estrogen-based treatments.
Collapse
Affiliation(s)
- Mohammad Khaksari
- Neuroscince and Endocrinology and Metabolism Research Centers, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | | | | | | | - Hamideh Bashiri
- Neuroscience Research Center, Institute of Neuropharmacology, Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Ira
| | | |
Collapse
|
|
13
|
Leucuța DC, Anton D, Almășan O. Estrogen Hormones' Implications on the Physiopathology of Temporomandibular Dysfunction. J Clin Med 2024; 13:4406. [PMID: 39124673 PMCID: PMC11313074 DOI: 10.3390/jcm13154406] [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: 07/15/2024] [Revised: 07/24/2024] [Accepted: 07/26/2024] [Indexed: 08/12/2024] Open
Abstract
Background/Objectives: Temporomandibular dysfunction syndrome consists of several disorders of the masticatory system, namely those of the muscles, the joint itself, as well as the dental and periodontal system. This syndrome is often characterized by pain and an inability to perform functions within the dental-maxillary apparatus, which creates a certain degree of disability in patients. Women are more susceptible to this syndrome than men and hormonal factors, particularly estrogen, are central to its etiology and physiopathology. Methods: A comprehensive literature search was conducted using PubMed/MEDLINE, Scopus, Embase, and Web of Science databases regarding articles published from January 2008 to December 2023. Two authors conducted searches in the mentioned databases based on a pre-established search strategy using agreed-upon keywords. Additionally, each review author performed the selection process of eligible studies based on established inclusion criteria. The Newcastle-Ottawa scale and Risk of Bias tool 2 were used to assess each article for its methodological quality. Results: Of the 1030 records found in the four bibliographic databases, 22 studies were included in this review. Polymorphism in the alpha estrogen receptor appears to be significantly more prevalent in women with temporomandibular dysfunction, suggesting a genetic predisposition. There is a significant role of estrogen in the physiopathology of TMD-related pain. Women with polycystic ovary syndrome (PCOS) have a significantly higher incidence of TMD, accompanied by elevated inflammatory factors and decreased progesterone levels. In premenopausal women, there is scientific relevance to the association between beta-estradiol levels and TMD development and progression. The effects of estrogen hormones on temporomandibular dysfunction remain highly debated and challenging. Conclusions: These findings emphasize the importance of considering hormonal factors, genetic predisposition, and reproductive life stages in understanding and managing temporomandibular dysfunction. Further research is needed to elucidate the specific mechanisms underlying these associations.
Collapse
Affiliation(s)
- Daniel-Corneliu Leucuța
- Department of Medical Informatics and Biostatistics, Iuliu Hațieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Damaris Anton
- Department of Prosthetic Dentistry and Dental Materials, Iuliu Hațieganu University of Medicine and Pharmacy, 32 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Oana Almășan
- Department of Prosthetic Dentistry and Dental Materials, Iuliu Hațieganu University of Medicine and Pharmacy, 32 Clinicilor Street, 400006 Cluj-Napoca, Romania
| |
Collapse
|
|
14
|
Baudo G, Flinn H, Holcomb M, Tiwari A, Soriano S, Taraballi F, Godin B, Zinger A, Villapol S. Sex-dependent improvement in traumatic brain injury outcomes after liposomal delivery of dexamethasone in mice. Bioeng Transl Med 2024; 9:e10647. [PMID: 39036088 PMCID: PMC11256133 DOI: 10.1002/btm2.10647] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 12/02/2023] [Accepted: 01/11/2024] [Indexed: 07/23/2024] Open
Abstract
Traumatic brain injury (TBI) can have long-lasting physical, emotional, and cognitive consequences due to the neurodegeneration caused by its robust inflammatory response. Despite advances in rehabilitation care, effective neuroprotective treatments for TBI patients are lacking. Furthermore, current drug delivery methods for TBI treatment are inefficient in targeting inflamed brain areas. To address this issue, we have developed a liposomal nanocarrier (Lipo) encapsulating dexamethasone (Dex), an agonist for the glucocorticoid receptor utilized to alleviate inflammation and swelling in various conditions. In vitro studies show that Lipo-Dex were well tolerated in human and murine neural cells. Lipo-Dex showed significant suppression of inflammatory cytokines, IL-6 and TNF-α, release after induction of neural inflammation with lipopolysaccharide. Further, the Lipo-Dex were administered to young adult male and female C57BL/6 mice immediately after controlled cortical impact injury (a TBI model). Our findings demonstrate that Lipo-Dex can selectively target the injured brain, thereby reducing lesion volume, cell death, astrogliosis, the release of pro-inflammatory cytokines, and microglial activation compared to Lipo-treated mice in a sex-dependent manner, showing a major impact only in male mice. This highlights the importance of considering sex as a crucial variable in developing and evaluating new nano-therapies for brain injury. These results suggest that Lipo-Dex administration may effectively treat acute TBI.
Collapse
Affiliation(s)
- Gherardo Baudo
- Department of NanomedicineHouston Methodist Research InstituteHoustonTexasUSA
| | - Hannah Flinn
- Department of Neurosurgery and Center for NeuroregenerationHouston Methodist Research InstituteHoustonTexasUSA
| | - Morgan Holcomb
- Department of Neurosurgery and Center for NeuroregenerationHouston Methodist Research InstituteHoustonTexasUSA
| | - Anjana Tiwari
- Department of NanomedicineHouston Methodist Research InstituteHoustonTexasUSA
| | - Sirena Soriano
- Department of Neurosurgery and Center for NeuroregenerationHouston Methodist Research InstituteHoustonTexasUSA
| | - Francesca Taraballi
- Department of Orthopedics and Sports Medicine and Center for Musculoskeletal RegenerationHouston Methodist HospitalHoustonTexasUSA
| | - Biana Godin
- Department of NanomedicineHouston Methodist Research InstituteHoustonTexasUSA
- Department of Obstetrics and GynecologyHouston Methodist Research InstituteHoustonTexasUSA
- Department of Obstetrics and GynecologyWeill Cornell Medicine College (WCMC)New YorkNew YorkUSA
- Department of Biomedical EngineeringTexas A&M UniversityCollege StationTexasUSA
| | - Assaf Zinger
- Department of Cardiovascular SciencesHouston Methodist Research InstituteHoustonTexasUSA
- Department of Chemical EngineeringTechnion−Israel Institute of TechnologyHaifaIsrael
| | - Sonia Villapol
- Department of Neurosurgery and Center for NeuroregenerationHouston Methodist Research InstituteHoustonTexasUSA
- Department of Neuroscience in Neurological SurgeryWeill Cornell Medicine College (WCMC)New YorkNew YorkUSA
| |
Collapse
|
|
15
|
Xiao T, Lee J, Gauntner TD, Velegraki M, Lathia JD, Li Z. Hallmarks of sex bias in immuno-oncology: mechanisms and therapeutic implications. Nat Rev Cancer 2024; 24:338-355. [PMID: 38589557 DOI: 10.1038/s41568-024-00680-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/26/2024] [Indexed: 04/10/2024]
Abstract
Sex differences are present across multiple non-reproductive organ cancers, with male individuals generally experiencing higher incidence of cancer with poorer outcomes. Although some mechanisms underlying these differences are emerging, the immunological basis is not well understood. Observations from clinical trials also suggest a sex bias in conventional immunotherapies with male individuals experiencing a more favourable response and female individuals experiencing more severe adverse events to immune checkpoint blockade. In this Perspective article, we summarize the major biological hallmarks underlying sex bias in immuno-oncology. We focus on signalling from sex hormones and chromosome-encoded gene products, along with sex hormone-independent and chromosome-independent epigenetic mechanisms in tumour and immune cells such as myeloid cells and T cells. Finally, we highlight opportunities for future studies on sex differences that integrate sex hormones and chromosomes and other emerging cancer hallmarks such as ageing and the microbiome to provide a more comprehensive view of how sex differences underlie the response in cancer that can be leveraged for more effective immuno-oncology approaches.
Collapse
Affiliation(s)
- Tong Xiao
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-The James, Columbus, OH, USA
| | - Juyeun Lee
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Timothy D Gauntner
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-The James, Columbus, OH, USA
| | - Maria Velegraki
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-The James, Columbus, OH, USA
| | - Justin D Lathia
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Case Comprehensive Cancer Center, Cleveland, OH, USA.
- Rose Ella Burkhardt Brain Tumour Center, Cleveland Clinic, Cleveland, OH, USA.
| | - Zihai Li
- Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center-The James, Columbus, OH, USA.
| |
Collapse
|
|
16
|
Balan I, Boero G, Chéry SL, McFarland MH, Lopez AG, Morrow AL. Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders. Life (Basel) 2024; 14:582. [PMID: 38792602 PMCID: PMC11122352 DOI: 10.3390/life14050582] [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: 03/11/2024] [Revised: 04/18/2024] [Accepted: 04/28/2024] [Indexed: 05/26/2024] Open
Abstract
Pregnane neuroactive steroids, notably allopregnanolone and pregnenolone, exhibit efficacy in mitigating inflammatory signals triggered by toll-like receptor (TLR) activation, thus attenuating the production of inflammatory factors. Clinical studies highlight their therapeutic potential, particularly in conditions like postpartum depression (PPD), where the FDA-approved compound brexanolone, an intravenous formulation of allopregnanolone, effectively suppresses TLR-mediated inflammatory pathways, predicting symptom improvement. Additionally, pregnane neurosteroids exhibit trophic and anti-inflammatory properties, stimulating the production of vital trophic proteins and anti-inflammatory factors. Androstane neuroactive steroids, including estrogens and androgens, along with dehydroepiandrosterone (DHEA), display diverse effects on TLR expression and activation. Notably, androstenediol (ADIOL), an androstane neurosteroid, emerges as a potent anti-inflammatory agent, promising for therapeutic interventions. The dysregulation of immune responses via TLR signaling alongside reduced levels of endogenous neurosteroids significantly contributes to symptom severity across various neuropsychiatric disorders. Neuroactive steroids, such as allopregnanolone, demonstrate efficacy in alleviating symptoms of various neuropsychiatric disorders and modulating neuroimmune responses, offering potential intervention avenues. This review emphasizes the significant therapeutic potential of neuroactive steroids in modulating TLR signaling pathways, particularly in addressing inflammatory processes associated with neuropsychiatric disorders. It advances our understanding of the complex interplay between neuroactive steroids and immune responses, paving the way for personalized treatment strategies tailored to individual needs and providing insights for future research aimed at unraveling the intricacies of neuropsychiatric disorders.
Collapse
Affiliation(s)
- Irina Balan
- Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (I.B.); (S.L.C.); (M.H.M.); (A.G.L.)
- Department of Psychiatry, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Giorgia Boero
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA;
| | - Samantha Lucenell Chéry
- Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (I.B.); (S.L.C.); (M.H.M.); (A.G.L.)
- Neuroscience Curriculum, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Minna H. McFarland
- Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (I.B.); (S.L.C.); (M.H.M.); (A.G.L.)
- Neuroscience Curriculum, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Alejandro G. Lopez
- Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (I.B.); (S.L.C.); (M.H.M.); (A.G.L.)
- Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - A. Leslie Morrow
- Bowles Center for Alcohol Studies, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (I.B.); (S.L.C.); (M.H.M.); (A.G.L.)
- Department of Psychiatry, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Pharmacology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| |
Collapse
|
|
17
|
Li Z, Li M, Li D, Chen Y, Feng W, Zhao T, Yang L, Mao G, Wu X. A review of cumulative toxic effects of environmental endocrine disruptors on the zebrafish immune system: Characterization methods, toxic effects and mechanisms. ENVIRONMENTAL RESEARCH 2024; 246:118010. [PMID: 38157964 DOI: 10.1016/j.envres.2023.118010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/03/2024]
Abstract
Environmental endocrine disrupting chemicals (EDCs), are a type of exogenous organic pollutants, are ubiquitous in natural aquatic environments. Currently, in addition to neurological, endocrine, developmental and reproductive toxicity, ecotoxicology studies on immunotoxicity are receiving increasing attention. In this review, the composition of immune system of zebrafish, the common indicators of immunotoxicity, the immunotoxicity of EDCs and their molecular mechanism were summarized. We reviewed the immunotoxicity of EDCs on zebrafish mainly in terms of immune organs, immunocytes, immune molecules and immune functions, meanwhile, the possible molecular mechanisms driving these effects were elucidated in terms of endocrine disruption, dysregulation of signaling pathways, and oxidative damage. Hopefully, this review will provide a reference for further investigation of the immunotoxicity of EDCs.
Collapse
Affiliation(s)
- Zixu Li
- School of the Environment and Safety Engineering, School of Emergency Management, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China
| | - Muge Li
- School of the Environment and Safety Engineering, School of Emergency Management, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China
| | - Dan Li
- School of the Environment and Safety Engineering, School of Emergency Management, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China
| | - Yao Chen
- School of the Environment and Safety Engineering, School of Emergency Management, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China; Institute of Environmental Health and Ecological Safety, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China
| | - Weiwei Feng
- School of the Environment and Safety Engineering, School of Emergency Management, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China; Institute of Environmental Health and Ecological Safety, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China
| | - Ting Zhao
- School of Chemistry and Chemical Engineering, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China
| | - Liuqing Yang
- School of Chemistry and Chemical Engineering, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China
| | - Guanghua Mao
- School of the Environment and Safety Engineering, School of Emergency Management, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China.
| | - Xiangyang Wu
- School of the Environment and Safety Engineering, School of Emergency Management, Jiangsu University, 301 Xuefu Rd, Zhenjiang, 212013, China.
| |
Collapse
|
|
18
|
Braga Tibaes JR, Barreto Silva MI, Wollin B, Vine D, Tsai S, Richard C. Sex differences in systemic inflammation and immune function in diet-induced obesity rodent models: A systematic review. Obes Rev 2024; 25:e13665. [PMID: 38072656 DOI: 10.1111/obr.13665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/27/2023] [Accepted: 10/05/2023] [Indexed: 02/28/2024]
Abstract
Understanding sex differences in immunological responses in the context of obesity is important to improve health outcomes. This systematic review aimed to investigate sex differences in systemic inflammation, immune cell phenotype, and function in diet-induced obesity (DIO) animal models. A systematic search in Medline, Embase, and CINAHL from inception to April 2023 was conducted, using a combination of the following concepts: sex, obesity, cytokines, and immune cell phenotypes/function. Forty-one publications reporting on systemic inflammation (61%), cell phenotype (44%), and/or function (7%) were included. Females had lower systemic inflammation compared with males in response to DIO intervention and a higher proportion of macrophage (M)2-like cells compared with males that had a higher proportion of M1-like in adipose tissue. Although there were no clear sex differences in immune function, high-fat DIO intervention remains an important factor in the development of immune dysfunction in both males and females, including disturbances in cytokine production, proliferation, and migration of immune cells. Yet, the mechanistic links between diet and obesity on such immune dysfunction remain unclear. Future studies should investigate the role of diet and obesity in the functionality of immune cells and employ adequate methods for a high-quality investigation of sex differences in this context.
Collapse
Affiliation(s)
| | - Maria Ines Barreto Silva
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
- Department of Applied Nutrition, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Bethany Wollin
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Donna Vine
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Sue Tsai
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Caroline Richard
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
19
|
Joshi NP, Madiwale SD, Sundrani DP, Joshi SR. Fatty acids, inflammation and angiogenesis in women with gestational diabetes mellitus. Biochimie 2023; 212:31-40. [PMID: 37059350 DOI: 10.1016/j.biochi.2023.04.005] [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: 11/14/2022] [Revised: 03/01/2023] [Accepted: 04/11/2023] [Indexed: 04/16/2023]
Abstract
Gestational diabetes mellitus (GDM) is a metabolic disorder in pregnancy whose prevalence is on the rise. Reports suggest a likely association between inflammation and maternal GDM. A balance between pro and anti-inflammatory cytokines is necessary for the regulation of maternal inflammation system throughout pregnancy. Along with various inflammatory markers, fatty acids also act as pro-inflammatory molecules. However, studies reporting the role of inflammatory markers in GDM are contradictory, suggesting the need of more studies to better understand the role of inflammation in pregnancies complicated by GDM. Inflammatory response can be regulated by angiopoietins suggesting a link between inflammation and angiogenesis. Placental angiogenesis is a normal physiological process which is tightly regulated during pregnancy. Various pro and anti-angiogenic factors influence the regulation of the feto-placental vascular development. Studies evaluating the levels of angiogenic markers in women with GDM are limited and the findings are inconsistent. This review summarizes the available literature on fatty acids, inflammatory markers and angiogenesis in women with GDM. We also discuss the possible link between them and their influence on placental development in GDM.
Collapse
Affiliation(s)
- Nikita P Joshi
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India
| | - Shweta D Madiwale
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India
| | - Deepali P Sundrani
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India
| | - Sadhana R Joshi
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune, India.
| |
Collapse
|
|
20
|
Hayashi K, Lesnak JB, Plumb AN, Rasmussen LA, Sluka KA. P2X7-NLRP3-Caspase-1 signaling mediates activity-induced muscle pain in male but not female mice. Pain 2023; 164:1860-1873. [PMID: 36930885 PMCID: PMC10363217 DOI: 10.1097/j.pain.0000000000002887] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/23/2022] [Indexed: 03/19/2023]
Abstract
ABSTRACT We developed an animal model of activity-induced muscle pain that is dependent on local macrophage activation and release of interleukin-1β (IL-1β). Activation of purinergic type 2X (P2X) 7 receptors recruits the NOD-like receptor protein (NLRP) 3 and activates Caspase-1 to release IL-1β. We hypothesized that pharmacological blockade of P2X7, NLRP3, and Caspase-1 would prevent development of activity-induced muscle pain in vivo and release of IL-1β from macrophages in vitro. The decrease in muscle withdrawal thresholds in male, but not female, mice was prevented by the administration of P2X7, NLRP3, and Caspase-1 inhibitors before induction of the model, whereas blockade of IL-1β before induction prevented muscle hyperalgesia in both male and female mice. Blockade of P2X7, NLRP3, Capsase-1, or IL-1β 24 hours, but not 1 week, after induction of the model alleviated muscle hyperalgesia in male, but not female, mice. mRNA expression of P2X7, NLRP3, Caspase-1, and IL-1β from muscle was increased 24 hours after induction of the model in both male and female mice. Using multiplex, increases in IL-1β induced by combining adenosine triphosphate with pH 6.5 in lipopolysaccharide-primed male and female macrophages were significantly lower with the presence of inhibitors of P2X7 (A740003), NLRP3 (MCC950), and Caspase-1 (Z-WEHD-FMK) when compared with the vehicle. The current data suggest the P2X7/NLRP3/Caspase-1 pathway contributed to activity-induced muscle pain initiation and early maintenance phases in male but not female, and not in late maintenance phases in male mice.
Collapse
Affiliation(s)
- Kazuhiro Hayashi
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, USA
| | - Joseph B. Lesnak
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, USA
| | - Ashley N. Plumb
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, USA
| | - Lynn A. Rasmussen
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, USA
| | - Kathleen A. Sluka
- Department of Physical Therapy and Rehabilitation Science, University of Iowa, Iowa City, IA, USA
| |
Collapse
|
|
21
|
Branyan TE, Aleksa J, Lepe E, Kosel K, Sohrabji F. The aging ovary impairs acute stroke outcomes. J Neuroinflammation 2023; 20:159. [PMID: 37408003 DOI: 10.1186/s12974-023-02839-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 06/20/2023] [Indexed: 07/07/2023] Open
Abstract
In experimental stroke, ovariectomized (OVX) adult rats have larger infarct volumes and greater sensory-motor impairment as compared to ovary-intact females and is usually interpreted to indicate that ovarian hormones are neuroprotective for stroke. Previous work from our lab shows that middle-aged, acyclic reproductively senescent (RS) females have worse stroke outcomes as compared to adult (normally cycling) females. We hypothesized that if loss of ovarian estrogen is the critical determinant of stroke outcomes, then ovary-intact middle-aged acyclic females, who have reduced levels of estradiol, should have similar stroke outcomes as age-matched OVX. Instead, the data demonstrated that OVX RS animals showed better sensory-motor function after stroke and reduced infarct volume as compared to ovary-intact females. Inflammatory cytokines were decreased in the aging ovary after stroke as compared to non-stroke shams, which led to the hypothesis that immune cells may be extravasated from the ovaries post-stroke. Flow cytometry indicated reduced overall T cell populations in the aging ovary after middle cerebral artery occlusion (MCAo), with a paradoxical increase in regulatory T cells (Tregs) and M2-like macrophages. Moreover, in the brain, OVX RS animals showed increased Tregs, increased M2-like macrophages, and increased MHC II + cells as compared to intact RS animals, which have all been shown to be correlated with better prognosis after stroke. Depletion of ovary-resident immune cells after stroke suggests that there may be an exaggerated response to ischemia and possible increased burden of the inflammatory response via extravasation of these cells into circulation. Increased anti-inflammatory cells in the brain of OVX RS animals further supports this hypothesis. These data suggest that stroke severity in aging females may be exacerbated by the aging ovary and underscore the need to assess immunological changes in this organ after stroke.
Collapse
Affiliation(s)
- Taylor E Branyan
- Department of Neuroscience and Experimental Therapeutics, Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, 8447 Riverside Pkwy, Bryan, TX, 77807, USA
- Texas A&M Institute for Neuroscience, College Station, TX, 77840, USA
| | - Jocelyn Aleksa
- Department of Neuroscience and Experimental Therapeutics, Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, 8447 Riverside Pkwy, Bryan, TX, 77807, USA
| | - Esteban Lepe
- Department of Neuroscience and Experimental Therapeutics, Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, 8447 Riverside Pkwy, Bryan, TX, 77807, USA
| | - Kelby Kosel
- Department of Neuroscience and Experimental Therapeutics, Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, 8447 Riverside Pkwy, Bryan, TX, 77807, USA
| | - Farida Sohrabji
- Department of Neuroscience and Experimental Therapeutics, Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, 8447 Riverside Pkwy, Bryan, TX, 77807, USA.
- Texas A&M Institute for Neuroscience, College Station, TX, 77840, USA.
| |
Collapse
|
|
22
|
Yu R, Ma C, Li G, Xu J, Feng D, Lan X. Inhibition of Toll-Like Receptor 4 Signaling Pathway Accelerates the Repair of Avascular Necrosis of Femoral Epiphysis through Regulating Macrophage Polarization in Perthes Disease. Tissue Eng Regen Med 2023; 20:489-501. [PMID: 37041432 PMCID: PMC10219917 DOI: 10.1007/s13770-023-00529-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/18/2023] [Accepted: 02/13/2023] [Indexed: 04/13/2023] Open
Abstract
BACKGROUND Legg-Calvé-Perthes disease (LCPD) is still a refractory disease in children's orthopedics. With the introduction of the concept of "osteoimmunology", the immune-inflammatory mechanisms between bone and immune system have become a research focus of LCPD. However, few studies have reported on the pathological role of inflammation-related receptors such as toll-like receptors (TLRs) as well as immune cells such as macrophages in LCPD. This study was for investigating the mechanism of TLR4 signaling pathway on the direction of macrophage polarization and the repair of avascular necrosis of femoral epiphysis in LCPD. METHODS With GSE57614 and GSE74089, differentially expressed genes were screened. Through enrichment analysis and protein-protein interaction network, the functions of TLR4 were explored. Furthermore, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), hematoxylin & eosin (H&E) staining, micro-CT, tartrate-resistant acid phosphatase (TRAP) dyeing and western blotting were performed for determining the influences of TAK-242 (a TLR4 inhibitor) on the repair of avascular necrosis of femoral epiphysis in rat models. RESULTS Totally 40 co-expression genes were screened as well as enriched in TLR4 signaling pathway. Immunohistochemistry and ELISA analyses certified that TLR4 facilitated macrophage polarization toward the M1 phenotype and prevented macrophage polarization toward the M2 phenotype. Besides, the results of H&E and TRAP staining, micro-CT, and western blotting showed that TAK-242 can inhibit osteoclastogenesis and promote osteogenesis. CONCLUSION Inhibition of TLR4 signaling pathway accelerated the repair of avascular necrosis of femoral epiphysis by regulating macrophage polarization in LCPD.
Collapse
Affiliation(s)
- Ronghui Yu
- Department of Orthopedics, First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Cong Ma
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Guoyong Li
- Department of Orthopedics, First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Jianyun Xu
- Department of Orthopedics, First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Dan Feng
- Department of General Surgery, Jiangxi Provincial Children's Hospital, Nanchang, 330046, Jiangxi, China
| | - Xia Lan
- Department of Orthopedics, First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
| |
Collapse
|
|
23
|
Baudo G, Flinn H, Holcomb M, Tiwari A, Soriano S, Taraballi F, Godin B, Zinger A, Villapol S. Sex-dependent improvement in traumatic brain injury outcomes after liposomal delivery of dexamethasone in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.16.541045. [PMID: 37292856 PMCID: PMC10245763 DOI: 10.1101/2023.05.16.541045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Traumatic Brain Injury (TBI) can have long-lasting physical, emotional, and cognitive consequences due to the neurodegeneration caused by its robust inflammatory response. Despite advances in rehabilitation care, effective neuroprotective treatments for TBI patients are lacking. Furthermore, current drug delivery methods for TBI treatment are inefficient in targeting inflamed brain areas. To address this issue, we have developed a liposomal nanocarrier (Lipo) encapsulating dexamethasone (Dex), an agonist for the glucocorticoid receptor utilized to alleviate inflammation and swelling in various conditions. In vitro studies show that Lipo-Dex were well tolerated in human and murine neural cells. Lipo-Dex showed significant suppression of inflammatory cytokines, IL-6 and TNF-α, release after induction of neural inflammation with lipopolysaccharide. Further, the Lipo-Dex were administered to young adult male and female C57BL/6 mice immediately after a controlled cortical impact injury. Our findings demonstrate that Lipo-Dex can selectively target the injured brain, thereby reducing lesion volume, cell death, astrogliosis, the release of proinflammatory cytokines, and microglial activation compared to Lipo-treated mice in a sex-dependent manner, showing a major impact only in male mice. This highlights the importance of considering sex as a crucial variable in developing and evaluating new nano-therapies for brain injury. These results suggest that Lipo-Dex administration may effectively treat acute TBI.
Collapse
Affiliation(s)
- Gherardo Baudo
- Center for Musculoskeletal Regeneration Houston Methodist Academic Institute Department of Orthopedics and Sports Medicine Houston Methodist Hospital Houston TX, USA
| | - Hannah Flinn
- Department of Neurosurgery and Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA
| | - Morgan Holcomb
- Department of Neurosurgery and Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA
| | - Anjana Tiwari
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Sirena Soriano
- Department of Neurosurgery and Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA
| | - Francesca Taraballi
- Center for Musculoskeletal Regeneration Houston Methodist Academic Institute Department of Orthopedics and Sports Medicine Houston Methodist Hospital Houston TX, USA
| | - Biana Godin
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Assaf Zinger
- Laboratory for Bioinspired Nano Engineering and Translational Therapeutics, Department of Chemical Engineering, Technion−Israel Institute of Technology, Haifa, Israel
| | - Sonia Villapol
- Department of Neurosurgery and Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA
| |
Collapse
|
|
24
|
Olivieri F, Marchegiani F, Matacchione G, Giuliani A, Ramini D, Fazioli F, Sabbatinelli J, Bonafè M. Sex/gender-related differences in inflammaging. Mech Ageing Dev 2023; 211:111792. [PMID: 36806605 DOI: 10.1016/j.mad.2023.111792] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/12/2023] [Accepted: 02/15/2023] [Indexed: 02/19/2023]
Abstract
Geroscience puts mechanisms of aging as a driver of the most common age-related diseases and dysfunctions. Under this perspective, addressing the basic mechanisms of aging will produce a better understanding than addressing each disease pathophysiology individually. Worldwide, despite greater functional impairment, life expectancy is higher in women than in men. Gender differences in the prevalence of multimorbidity lead mandatory to the understanding of the mechanisms underlying gender-related differences in multimorbidity patterns and disability-free life expectancy. Extensive literature suggested that inflammaging is at the crossroad of aging and age-related diseases. In this review, we highlight the main evidence on sex/gender differences in the mechanisms that foster inflammaging, i.e. the age-dependent triggering of innate immunity, modifications of adaptive immunity, and accrual of senescent cells, underpinning some biomarkers of inflammaging that show sex-related differences. In the framework of the "gender medicine perspective", we will also discuss how sex/gender differences in inflammaging can affect sex differences in COVID-19 severe outcomes.
Collapse
Affiliation(s)
- Fabiola Olivieri
- Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy; Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy
| | | | - Giulia Matacchione
- Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy
| | - Angelica Giuliani
- Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy
| | - Deborah Ramini
- Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy
| | - Francesca Fazioli
- Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy
| | - Jacopo Sabbatinelli
- Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy; Laboratory Medicine Unit, Azienda Ospedaliero Universitaria delle Marche, Ancona, Italy.
| | - Massimiliano Bonafè
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| |
Collapse
|
|
25
|
Shields CA, Wang X, Cornelius DC. Sex differences in cardiovascular response to sepsis. Am J Physiol Cell Physiol 2023; 324:C458-C466. [PMID: 36571442 PMCID: PMC9902216 DOI: 10.1152/ajpcell.00134.2022] [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: 03/29/2022] [Revised: 12/20/2022] [Accepted: 12/20/2022] [Indexed: 12/27/2022]
Abstract
Recently, there has been increased recognition of the importance of sex as a biological factor affecting disease and health. Many preclinical studies have suggested that males may experience a less favorable outcome in response to sepsis than females. The underlying mechanisms for these differences are still largely unknown but are thought to be related to the beneficial effects of estrogen. Furthermore, the immunosuppressive role of testosterone is also thought to contribute to the sex-dependent differences that are present in clinical sepsis. There are still significant knowledge gaps in this field. This mini-review will provide a brief overview of sex-dependent variables in relation to sepsis and the cardiovascular system. Preclinical animal models for sepsis research will also be discussed. The intent of this mini-review is to inspire interest for future considerations of sex-related variables in sepsis that should be addressed to increase our understanding of the underlying mechanisms in sepsis-induced cardiovascular dysfunction for the identification of therapeutic targets and improved sepsis management and treatment.
Collapse
Affiliation(s)
- Corbin A Shields
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi
| | - Xi Wang
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| | - Denise C Cornelius
- Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi
| |
Collapse
|
|
26
|
Anesi N, Miquel CH, Laffont S, Guéry JC. The Influence of Sex Hormones and X Chromosome in Immune Responses. Curr Top Microbiol Immunol 2023; 441:21-59. [PMID: 37695424 DOI: 10.1007/978-3-031-35139-6_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] [Indexed: 09/12/2023]
Abstract
Males and females differ in their susceptibility to develop autoimmunity and allergy but also in their capacity to cope with infections and cancers. Cellular targets and molecular pathways underlying sexual dimorphism in immunity have started to emerge and appeared multifactorial. It became increasingly clear that sex-linked biological factors have important impact on the development, tissue maintenance and effector function acquisition of distinct immune cell populations, thereby regulating multiple layers of innate or adaptive immunity through distinct mechanisms. This review discusses the recent development in our understanding of the cell-intrinsic actions of biological factors linked to sex, sex hormones and sex chromosome complement, on immune cells, which may account for the sex differences in susceptibility to autoimmune diseases and allergies, and the sex-biased responses in natural immunity and cancer.
Collapse
Affiliation(s)
- Nina Anesi
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITY), Université de Toulouse, INSERM, CNRS, UPS, 31300, Toulouse, France
| | - Charles-Henry Miquel
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITY), Université de Toulouse, INSERM, CNRS, UPS, 31300, Toulouse, France
| | - Sophie Laffont
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITY), Université de Toulouse, INSERM, CNRS, UPS, 31300, Toulouse, France
| | - Jean-Charles Guéry
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITY), Université de Toulouse, INSERM, CNRS, UPS, 31300, Toulouse, France.
- INSERM UMR1291, Centre Hospitalier Universitaire Purpan, Place du Dr. Baylac, 31024, Toulouse Cedex 3, France.
| |
Collapse
|
|
27
|
Zhang Y, Ma L, Dong S, Ding Q, Wang S, Wu Q, Ni P, Zhang H, Chen Y, Wu J, Wang X. TLR4 inhibition suppresses growth in oestrogen-induced prolactinoma models. Endocr Relat Cancer 2022; 29:703-716. [PMID: 36219868 DOI: 10.1530/erc-22-0168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 10/11/2022] [Indexed: 11/06/2022]
Abstract
Prolactinomas have harmful effects on human health. Bromocriptine is the only commercially available drug in China, but about 25% of prolactinoma patients do not respond to it in clinic, its pathogenesis remains unknown. Thus, its pathogenesis needs to be determined to develop new therapeutic methods for prolactinomas. The expression of ERβ, TLR4, and prolactin (PRL) in the pituitary gland of C57BL/6 mice and human prolactinoma specimen was examined by immunofluorescence or immunohistochemistry. The role of TLR4 in prolactinoma was determined using estradiol-induced models of C57BL/6 wild-type and TLR4-/- mice. MMQ cells were treated with estradiol, fulvestrant, and lipopolysaccharide (LPS) or transfected with TLR4 siRNA to study the expression of ERβ, TLR4, and PRL in these cells. Furthermore, the interaction between ERβ and TLR4 was investigated by immunoprecipitation analysis. The expression of PRL and TLR4 was co-located and increased in the pituitary gland of mice and human prolactinoma specimen compared to that in the control specimen. Meanwhile, TLR4 knockout or treatment with the TLR4 inhibitor TAK242 not only significantly inhibited tumor overgrowth but also decreased the expression of PRL in estradiol-treated mice through p38 MAPK pathway regulation. However, MMQ treated with estradiol and LPS enhanced PRL expression than treated with estradiol or LPS alone. Finally, ERβ or TLR4 inhibition prevented the estradiol-induced PRL increase by regulating the TLR4/p38 MAPK pathway in vitro. Estradiol promoted prolactinoma development by activating the TLR4/p38 MAPK pathway through ERβ, and TLR4 is a potential therapeutic target for prolactinoma treatment.
Collapse
Affiliation(s)
- Yu Zhang
- Department of Pharmacy, Tongren hospital affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, China
- Department of Pharmacy, Pulmonary Hospital of Wuhan, Wuhan, China
- Faculty of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Li Ma
- Department of Pharmacy, Tongren hospital affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, China
| | - Shuguang Dong
- Department of Cardiology, Tongren Hospital affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, China
| | - Qiaoyan Ding
- Department of Pharmacy, Pulmonary Hospital of Wuhan, Wuhan, China
| | - Shuman Wang
- Department of Pharmacy, Hubei Provincial Hospital of Integrated Traditional Chinese and Western Medicine
| | - Qi Wu
- Department of Pharmacy, Tongren hospital affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, China
| | - Ping Ni
- Faculty of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China
| | - Hong Zhang
- Department of Pharmacy, Tongren hospital affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, China
| | - Yonggang Chen
- Department of Pharmacy, Tongren hospital affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, China
| | - Jinhu Wu
- Department of Pharmacy, Tongren hospital affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, China
| | - Xiong Wang
- Department of Pharmacy, Tongren hospital affiliated to Wuhan University (The Third Hospital of Wuhan), Wuhan, China
| |
Collapse
|
|
28
|
Xu L, Huang G, Cong Y, Yu Y, Li Y. Sex-related Differences in Inflammatory Bowel Diseases: The Potential Role of Sex Hormones. Inflamm Bowel Dis 2022; 28:1766-1775. [PMID: 35486387 DOI: 10.1093/ibd/izac094] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease (IBD), characterized by chronic inflammation of the gastrointestinal tract, is a global health care problem. Compelling evidence shows sex differences regarding the prevalence, pathophysiology, clinical presentation, and treatment outcome of IBD. Sex hormones, including estrogen, progesterone, and androgen, have been proposed to have a role in the pathogenesis of sexual dimorphism in IBD. Clinical and experimental data support the modulatory effects of sex hormones on various clinical characteristics of the disease, including intestinal barrier dysfunction and mucosal immune activation. Additionally, the potential role of sex hormones in the modulation of gut microbiota is attracting increasing attention. Here, we discuss the sex dimorphic disease profile and address the potential mechanisms involved in the sex-specific pathogenesis of IBD. Improved understanding of these sex differences in the clinic could improve the knowledge of patients with IBD with heterogeneous disease profiles.
Collapse
Affiliation(s)
- Leiqi Xu
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
| | - Gang Huang
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA
| | - Yanbo Yu
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
| | - Yanqing Li
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
| |
Collapse
|
|
29
|
Kumar N, Vyas A, Agnihotri SK, Chattopadhyay N, Sachdev M. Small secretory proteins of immune cells can modulate gynecological cancers. Semin Cancer Biol 2022; 86:513-531. [PMID: 35150864 DOI: 10.1016/j.semcancer.2022.02.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/04/2022] [Accepted: 02/05/2022] [Indexed: 01/27/2023]
Abstract
Small secretory proteins of immune cells are mostly Cytokines, which include chemokines, interleukins, interferons, lymphokines and tumor necrosis factors but not hormones or growth factors. These secretory proteins are the molecular messengers and primarily involved in autocrine, paracrine and endocrine signaling as immunomodulating agents. Hence, these proteins actually regulate the cells of immune system to communicate with one another to produce a synchronized, robust, still self-regulated response to a specific antigen. Chemokines are smaller secreted proteins that control overall immune cell movement and location; these chemokines are divided into 4 subgroups, namely, CXC, CC, CX3C and C according to the position of 4 conserved cysteine residues. Complete characterization of cytokines and chemokines can exploit their vast signaling networks to develop cancer treatments. These secretory proteins like IL-6, IL-10, IL-12, TNFα, CCL2, CXCL4 & CXCL8 are predominantly expressed in most of the gynecological cancers, which directly stimulate immune effector cells and stromal cells at the tumor site and augment tumor cell recognition by cytotoxic T-cells. Hence; these secretory proteins are the major regulators, which can actually modulate all kinds of gynecological cancers. Furthermore, advancements in adoptive T-cell treatment have relied on the use of multiple cytokines/chemokines to establish a highly regulated environment for anti-tumor T cell growth. A number of in vitro studies as well as animal models and clinical subjects have also shown that cytokines/chemokines have broad antitumor activity, which has been translated into a number of cancer therapy approaches. This review will focus on the foremost cytokines & chemokines involved in the majority of the gynecological malignancies and discuss their basic biology as well as clinical applications.
Collapse
Affiliation(s)
- Niranjan Kumar
- Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201 002, India
| | - Akanksha Vyas
- Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201 002, India
| | | | - Naibedya Chattopadhyay
- Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201 002, India.
| | - Monika Sachdev
- Division of Endocrinology, CSIR- Central Drug Research Institute, Lucknow, 226 031, India; Academy of Scientific and Innovative Research (AcSIR), Sector 19, Kamla Nehru Nagar, Ghaziabad, 201 002, India.
| |
Collapse
|
|
30
|
Grant-Orser A, Johannson KA. Let's talk about sex in interstitial lung disease. THE LANCET. RHEUMATOLOGY 2022; 4:e648-e650. [PMID: 38265955 DOI: 10.1016/s2665-9913(22)00253-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 08/15/2022] [Indexed: 01/26/2024]
Affiliation(s)
- Amanda Grant-Orser
- Department of Medicine, University of Calgary, Calgary T3M 1M4, AB, Canada
| | - Kerri A Johannson
- Department of Medicine, University of Calgary, Calgary T3M 1M4, AB, Canada; Department of Community Health Sciences, University of Calgary, Calgary T3M 1M4, AB, Canada; Snyder Institute for Chronic Diseases, University of Calgary, Calgary T3M 1M4, AB, Canada.
| |
Collapse
|
|
31
|
Jensen SB, Latysheva N, Hindberg K, Ueland T. Plasma lipopolysaccharide-binding protein is a biomarker for future venous thromboembolism: Results from discovery and validation studies. J Intern Med 2022; 292:523-535. [PMID: 35426199 PMCID: PMC9539954 DOI: 10.1111/joim.13502] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
BACKGROUND Effect-size underestimation impedes biomarker identification. Long follow-up time in prospective studies attenuates effect-size estimates for transient biomarkers, while disease category-specific biomarkers are affected by merging of categories. Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE). OBJECTIVES (i) To re-analyze untargeted proteomic data to identify biomarker candidates for future VTE that differ between DVT and PE and are attenuated by extended time between sampling and VTE. (ii) To perform targeted candidate validation. PATIENTS/METHODS A VTE case-control discovery study and a nested case-control validation study were derived from the general population surveyed in 1994-95. Plasma was obtained at study enrollment, and VTE events were registered until 2007. Untargeted proteomic data were re-analyzed for candidate discovery. Lipopolysaccharide-binding protein (LBP) was validated by enzyme-linked immunosorbent assay. RESULTS Elevated LBP was discovered as a candidate DVT biomarker in women with less than 3 years between blood sampling and DVT. In the validation study, the odds ratio (OR) for DVT was 2.03 (95% confidence intervals [CI]: 1.53-2.74) per standard deviation (SD) increase in LBP for women with less than 3 years between blood sampling and DVT. Adjustment for age, body mass index, and C-reactive protein attenuated the OR to 1.79 (95% CI: 1.25-2.62) per SD. In the validation study, we observed an OR for VTE of 0.47 (95% CI: 0.28-0.77) for men in the 25th to 50th percentiles when compared to the lowest quartile. CONCLUSIONS We discovered and validated increased LBP as a predictive biomarker for DVT in women. We found an increased VTE risk for men in the lowest quartile of LBP.
Collapse
Affiliation(s)
- Søren Beck Jensen
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Nadezhda Latysheva
- K. G. Jebsen Thrombosis Research and Expertise Center, Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Kristian Hindberg
- K. G. Jebsen Thrombosis Research and Expertise Center, Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Thor Ueland
- Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.,K. G. Jebsen Thrombosis Research and Expertise Center, Department of Clinical Medicine, UiT-The Arctic University of Norway, Tromsø, Norway
| |
Collapse
|
|
32
|
Schafer JM, Xiao T, Kwon H, Collier K, Chang Y, Abdel-Hafiz H, Bolyard C, Chung D, Yang Y, Sundi D, Ma Q, Theodorescu D, Li X, Li Z. Sex-biased adaptive immune regulation in cancer development and therapy. iScience 2022; 25:104717. [PMID: 35880048 PMCID: PMC9307950 DOI: 10.1016/j.isci.2022.104717] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The cancer research field is finally starting to unravel the mystery behind why males have a higher incidence and mortality rate than females for nearly all cancer types of the non-reproductive systems. Here, we explain how sex - specifically sex chromosomes and sex hormones - drives differential adaptive immunity across immune-related disease states including cancer, and why males are consequently more predisposed to tumor development. We highlight emerging data on the roles of cell-intrinsic androgen receptors in driving CD8+ T cell dysfunction or exhaustion in the tumor microenvironment and summarize ongoing clinical efforts to determine the impact of androgen blockade on cancer immunotherapy. Finally, we outline a framework for future research in cancer biology and immuno-oncology, underscoring the importance of a holistic research approach to understanding the mechanisms of sex dimorphisms in cancer, so sex will be considered as an imperative factor for guiding treatment decisions in the future.
Collapse
Affiliation(s)
- Johanna M. Schafer
- Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
| | - Tong Xiao
- Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
| | - Hyunwoo Kwon
- Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
- Medical Scientist Training Program, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Katharine Collier
- Division of Medical Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
| | - Yuzhou Chang
- Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
- Department of Biomedical Informatics, the Ohio State University, Columbus, OH 43210, USA
| | - Hany Abdel-Hafiz
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Medicine and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Chelsea Bolyard
- Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
| | - Dongjun Chung
- Department of Biomedical Informatics, the Ohio State University, Columbus, OH 43210, USA
| | - Yuanquan Yang
- Division of Medical Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
| | - Debasish Sundi
- Department of Urology, the Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Qin Ma
- Department of Biomedical Informatics, the Ohio State University, Columbus, OH 43210, USA
| | - Dan Theodorescu
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Xue Li
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Medicine and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Zihai Li
- Pelotonia Institute for Immuno-Oncology, the Ohio State University Comprehensive Cancer Center – the James, Columbus, OH 43210, USA
| |
Collapse
|
|
33
|
Gholiof M, Adamson-De Luca E, Wessels JM. The female reproductive tract microbiotas, inflammation, and gynecological conditions. FRONTIERS IN REPRODUCTIVE HEALTH 2022; 4:963752. [PMID: 36303679 PMCID: PMC9580710 DOI: 10.3389/frph.2022.963752] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/18/2022] [Indexed: 11/23/2022] Open
Abstract
The intricate interactions between the host cells, bacteria, and immune components that reside in the female reproductive tract (FRT) are essential in maintaining reproductive tract homeostasis. Much of our current knowledge surrounding the FRT microbiota relates to the vaginal microbiota, where ‘health’ has long been associated with low bacterial diversity and Lactobacillus dominance. This concept has recently been challenged as women can have a diverse vaginal microbial composition in the absence of symptomatic disease. The structures of the upper FRT (the endocervix, uterus, Fallopian tubes, and ovaries) have distinct, lower biomass microbiotas than the vagina; however, the existence of permanent microbiotas at these sites is disputed. During homeostasis, a balance exists between the FRT bacteria and the immune system that maintains immune quiescence. Alterations in the bacteria, immune system, or local environment may result in perturbances to the FRT microbiota, defined as dysbiosis. The inflammatory signature of a perturbed or “dysbiotic” FRT microbiota is characterized by elevated concentrations of pro-inflammatory cytokines in cervical and vaginal fluid. It appears that vaginal homeostasis can be disrupted by two different mechanisms: first, a shift toward increased bacterial diversity can trigger vaginal inflammation, and second, local immunity is altered in some manner, which disrupts the microbiota in response to an environmental change. FRT dysbiosis can have negative effects on reproductive health. This review will examine the increasing evidence for the involvement of the FRT microbiotas and inflammation in gynecologic conditions such as endometriosis, infertility, and endometrial and ovarian cancer; however, the precise mechanisms by which bacteria are involved in these conditions remains speculative at present. While only in their infancy, the use of antibiotics and probiotics to therapeutically alter the FRT microbiota is being studied and is discussed herein. Our current understanding of the intimate relationship between immunity and the FRT microbiota is in its early days, and more research is needed to deepen our mechanistic understanding of this relationship and to assess how our present knowledge can be harnessed to assist in diagnosis and treatment of gynecologic conditions.
Collapse
Affiliation(s)
- Mahsa Gholiof
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada
| | - Emma Adamson-De Luca
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada
- AIMA Laboratories Inc., Hamilton, ON, Canada
| | - Jocelyn M. Wessels
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada
- AIMA Laboratories Inc., Hamilton, ON, Canada
- *Correspondence: Jocelyn M. Wessels
| |
Collapse
|
|
34
|
Balan I, Aurelian L, Williams KS, Campbell B, Meeker RB, Morrow AL. Inhibition of human macrophage activation via pregnane neurosteroid interactions with toll-like receptors: Sex differences and structural requirements. Front Immunol 2022; 13:940095. [PMID: 35967446 PMCID: PMC9373802 DOI: 10.3389/fimmu.2022.940095] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/07/2022] [Indexed: 11/13/2022] Open
Abstract
We recently discovered that (3α,5α)3-hydroxypregnan-20-one (allopregnanolone) inhibits pro-inflammatory toll-like receptor (TLR) activation and cytokine/chemokine production in mouse macrophage RAW264.7 cells. The present studies evaluate neurosteroid actions upon TLR activation in human macrophages from male and female healthy donors. Buffy coat leukocytes were obtained from donors at the New York Blood Center (http://nybloodcenter.org/), and peripheral blood mononuclear cells were isolated and cultured to achieve macrophage differentiation. TLR4 and TLR7 were activated by lipopolysaccharide (LPS) or imiquimod in the presence/absence of allopregnanolone or related neurosteroids and pro-inflammatory markers were detected by ELISA or western blotting. Cultured human monocyte-derived-macrophages exhibited typical morphology, a mixed immune profile of both inflammatory and anti-inflammatory markers, with no sex difference at baseline. Allopregnanolone inhibited TLR4 activation in male and female donors, preventing LPS-induced elevations of TNF-α, MCP-1, pCREB and pSTAT1. In contrast, 3α,5α-THDOC and SGE-516 inhibited the TLR4 pathway activation in female, but not male donors. Allopregnanolone completely inhibited TLR7 activation by imiquimod, blocking IL-1-β, IL-6, pSTAT1 and pIRF7 elevations in females only. 3α,5α-THDOC and SGE-516 partially inhibited TLR7 activation, only in female donors. The results indicate that allopregnanolone inhibits TLR4 and TLR7 activation in cultured human macrophages resulting in diminished cytokine/chemokine production. Allopregnanolone inhibition of TLR4 activation was found in males and females, but inhibition of TLR7 signals exhibited specificity for female donors. 3α,5α-THDOC and SGE-516 inhibited TLR4 and TLR7 pathways only in females. These studies demonstrate anti-inflammatory effects of allopregnanolone in human macrophages for the first time and suggest that inhibition of pro-inflammatory cytokines/chemokines may contribute to its therapeutic actions.
Collapse
Affiliation(s)
- Irina Balan
- Department of Psychiatry, Department of Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, United States
| | - Laure Aurelian
- Stanford University School of Medicine, Stanford, CA, United States
| | - Kimberly S. Williams
- Department of Neurology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, United States
| | - Brian Campbell
- Translational Sciences, Sage Therapeutics Inc., Cambridge, MA, United States
| | - Rick B. Meeker
- Department of Neurology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, United States
| | - A. Leslie Morrow
- Department of Psychiatry, Department of Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, United States
- *Correspondence: A. Leslie Morrow,
| |
Collapse
|
|
35
|
Wu H, Zeng L, Ou J, Wang T, Chen Y, Nandakumar KS. Estrogen Acts Through Estrogen Receptor-β to Promote Mannan-Induced Psoriasis-Like Skin Inflammation. Front Immunol 2022; 13:818173. [PMID: 35663991 PMCID: PMC9160234 DOI: 10.3389/fimmu.2022.818173] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 04/21/2022] [Indexed: 11/13/2022] Open
Abstract
Sex-bias is more obvious in several autoimmune disorders, but not in psoriasis. However, estrogen levels fluctuate during puberty, menstrual cycle, pregnancy, and menopause, which are related to variations in psoriasis symptoms observed in female patients. Estrogen has disease promoting or ameliorating functions based on the type of immune responses and tissues involved. To investigate the effects of estrogen on psoriasis, at first, we developed an innate immunity dependent mannan-induced psoriasis model, which showed a clear female preponderance in disease severity in several mouse strains. Next, we investigated the effects of endogenous and exogenous estrogen using ovariectomy and sham operated mice. 17-β-estradiol (E2) alone promoted the skin inflammation and it also significantly enhanced mannan-induced skin inflammation. We also observed a prominent estrogen receptor-β (ER-β) expression in the skin samples, especially on keratinocytes. Subsequently, we confirmed the effects of E2 on psoriasis using ER-β antagonist (PHTPP) and agonist (DPN). In addition, estrogen was found to affect the expression of certain genes (vgll3 and cebpb), microRNAs (miR146a and miR21), and immune cells (DCs and γδ T cells) as well as chemokines (CCL5 and CXCL10) and cytokines (TNF-α, IL-6, IL-22, IL-23, and IL-17 family), which promoted the skin inflammation. Thus, we demonstrate a pathogenic role for 17-β-estradiol in promoting skin inflammation, which should be considered while designing new treatment strategies for psoriasis patients.
Collapse
Affiliation(s)
- Huimei Wu
- Southern Medical University - Karolinska Institute United Medical Inflammation Center, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Longhui Zeng
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jiaxin Ou
- Southern Medical University - Karolinska Institute United Medical Inflammation Center, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Tingting Wang
- Southern Medical University - Karolinska Institute United Medical Inflammation Center, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Yong Chen
- Department of Rheumatology and Immunology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Kutty Selva Nandakumar
- Southern Medical University - Karolinska Institute United Medical Inflammation Center, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
36
|
You DJ, Lee HY, Taylor-Just AJ, Bonner JC. Synergistic induction of IL-6 production in human bronchial epithelial cells in vitro by nickel nanoparticles and lipopolysaccharide is mediated by STAT3 and C/EBPβ. Toxicol In Vitro 2022; 83:105394. [PMID: 35623502 DOI: 10.1016/j.tiv.2022.105394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 05/03/2022] [Accepted: 05/19/2022] [Indexed: 11/24/2022]
Abstract
We previously reported that delivery of nickel nanoparticles (NiNPs) and bacterial lipopolysaccharide (LPS) into the lungs of mice synergistically increased IL-6 production and inflammation, and male mice were more susceptible than female mice. The primary goal of this study was to utilize an in vitro human lung epithelial cell model (BEAS-2B) to investigate the intracellular signaling mechanisms that mediate IL-6 production by LPS and NiNPs. We also investigated the effect of sex hormones on NiNP and LPS-induced IL-6 production in vitro. LPS and NiNPs synergistically induced IL-6 mRNA and protein in BEAS-2B cells. TPCA-1, a dual inhibitor of IKK-2 and STAT3, blocked the synergistic increase in IL-6 caused by LPS and NiNPs, abolished STAT3 activation, and reduced C/EBPβ. Conversely, SC144, an inhibitor of the gp130 component of the IL-6 receptor, enhanced IL-6 production induced by LPS and NiNPs. Treatment of BEAS-2B cells with sex hormones (17β-estradiol, progesterone, or testosterone) or the anti-oxidant NAC, had no effect on IL-6 induction by LPS and NiNPs. These data suggest that LPS and NiNPs induce IL-6 via STAT3 and C/EBPβ in BEAS-2B cells. While BEAS-2B cells are a suitable model to study mechanisms of IL-6 production, they do not appear to be suitable for studying the effect of sex hormones.
Collapse
Affiliation(s)
- Dorothy J You
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC 27606, United States of America
| | - Ho Young Lee
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC 27606, United States of America
| | - Alexia J Taylor-Just
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC 27606, United States of America
| | - James C Bonner
- Toxicology Program, Department of Biological Sciences, North Carolina State University, Raleigh, NC 27606, United States of America.
| |
Collapse
|
|
37
|
Immune Cell Contributors to the Female Sex Bias in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis. Curr Top Behav Neurosci 2022; 62:333-373. [PMID: 35467295 DOI: 10.1007/7854_2022_324] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Multiple sclerosis (MS) is a chronic, autoimmune, demyelinating disease of the central nervous system (CNS) that leads to axonal damage and accumulation of disability. Relapsing-remitting MS (RR-MS) is the most frequent presentation of MS and this form of MS is three times more prevalent in females than in males. This female bias in MS is apparent only after puberty, suggesting a role for sex hormones in this regulation; however, very little is known of the biological mechanisms that underpin the sex difference in MS onset. Experimental autoimmune encephalomyelitis (EAE) is an animal model of RR-MS that presents more severely in females in certain mouse strains and thus has been useful to study sex differences in CNS autoimmunity. Here, we overview the immunopathogenesis of MS and EAE and how immune mechanisms in these diseases differ between a male and female. We further describe how females exhibit more robust myelin-specific T helper (Th) 1 immunity in MS and EAE and how this sex bias in Th cells is conveyed by sex hormone effects on the T cells, antigen presenting cells, regulatory T cells, and innate lymphoid cell populations.
Collapse
|
|
38
|
Wu M, Cong Y, Wang K, Yu H, Zhang X, Ma M, Duan Z, Pei X. Bisphenol A impairs macrophages through inhibiting autophagy via AMPK/mTOR signaling pathway and inducing apoptosis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 234:113395. [PMID: 35298966 DOI: 10.1016/j.ecoenv.2022.113395] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 03/03/2022] [Accepted: 03/05/2022] [Indexed: 06/14/2023]
Abstract
Bisphenol A (BPA) is a widespread endocrine disruptor that induces the impairment of immune cells, but the mechanism remains unknown. Macrophages are one of the most important immune cells in innate and adaptive immunity. In this study, we aimed to probe the effects of BPA on the damage of RAW264.7 cells and its mechanisms of action, especially focusing on the relationship between autophagy and apoptosis. Cells were pretreated with 10 mg/L LPS, or added autophagy activator RAPA, autophagy inhibitor 3-MA or Bcl-2 inhibitor ABT-737, then treated with BPA (0, 10, 100 and 200 μmol/L) for 12 h. Results have shown that BPA decreased the cell viability and disrupted secretory function by promoting pro-inflammatory cytokines TNF-α and IL-6 and reducing anti-inflammatory cytokines IL-10 TGF-β, as well as phagocytic ability. Moreover, autophagy was inhibited by BPA through decreasing p-AMPK/AMPK and increasing p-mTOR/mTOR, and further down-regulating autophagy proteins ATG6, LC3II/I ratio, and up-regulating autophagy flux protein p62. Additionally, BPA significantly increased Bax/Bcl-2 ratio, Caspase-3 expression and apoptosis rate. We found that RAPA ameliorated the cell viability, Bax/Bcl-2 ratio, and macrophage function damage induced by BPA. Intriguingly, ABT-737 might promote ATG6 expression. In summary, our study demonstrated that the effects of BPA on macrophages seemed to be mediated by inhibiting AMPK/mTOR-dependent autophagy and inducing apoptosis via endogenous mitochondrial pathway. Both Bcl-2 and ATG6 were involved in the regulation of apoptosis and autophagy by BPA. These findings provide a broader perspective for understanding the interaction between autophagy and apoptosis in BPA-induced immune cell injury.
Collapse
Affiliation(s)
- Mingfei Wu
- Shenyang Medical College, Shenyang 110034, China.
| | - Yan Cong
- Shenyang Medical College, Shenyang 110034, China.
| | - Kailu Wang
- Shenyang Medical College, Shenyang 110034, China.
| | - Haiyang Yu
- Shenyang Medical College, Shenyang 110034, China.
| | - Xuan Zhang
- Shenyang Medical College, Shenyang 110034, China.
| | - Mingyue Ma
- Shenyang Medical College, Shenyang 110034, China.
| | - Zhiwen Duan
- Shenyang Medical College, Shenyang 110034, China.
| | - Xiucong Pei
- Shenyang Medical College, Shenyang 110034, China.
| |
Collapse
|
|
39
|
Chronic exposure to nonylphenol induces oxidative stress and liver damage in male zebrafish (Danio rerio): Mechanistic insight into cellular energy sensors, lipid accumulation and immune modulation. Chem Biol Interact 2022; 351:109762. [PMID: 34843692 DOI: 10.1016/j.cbi.2021.109762] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/06/2021] [Accepted: 11/25/2021] [Indexed: 02/07/2023]
Abstract
Nonylphenol (NP), an environmentally persistent and toxic endocrine-disrupting chemical with estrogenic properties, has severe implications on humans and wildlife. Accumulating evidence demonstrates the toxic response of NP on the developmental process, nervous system, and reproductive parameters. Although NP exposure has been implicated in chronic liver injury, the underlying events associated with hepatic pathophysiology remain less investigated. Using male zebrafish (Danio rerio) as the model, the present study investigates the impact of environmentally relevant concentrations of NP (50 and 100 μg/L, 21 days) on hepatic redox homeostasis vis-à-vis cellular energy sensors, inflammatory response, and cell death involving a mechanistic insight into estrogen receptor (ER) modulation. Our results demonstrate that congruent with significant alteration in transcript abundance of antioxidant enzymes (SOD1, SOD2, Catalase, GPx1a, GSTα1), chronic exposure to NP promotes ROS synthesis, more specifically superoxide anions and H2O2 levels, and lipid peroxidation potentially through elevated NOX4 expression. Importantly, NP perturbation of markers associated with fatty acid biosynthesis (srebf1/fasn) and cellular energy-sensing network (sirt1/ampkα/pgc1α) indicates dysregulated energy homeostasis, metabolic disruption, and macrovesicular steatosis, albeit with differential sensitivity at the dose level tested. Besides, elevated p38-MAPK phosphorylation (activation) together with loss of ER homeostasis at both mRNA (esr1, esr2a, esr2b) and protein (ERα, ERβ) levels suggest that NP modulation of ER abundance may have a significant influence on hepatic events. Elevated expression of inflammatory markers (TLR4, p-NF-κB, TNF-α, IL-6, IL-1β, and NOS2) and pro-apoptotic and necrotic regulators, e.g., Bax, caspase- 8, -9 and cleaved PARP1 (50 kDa), indicate chronic inflammation and hepatotoxicity in NP-exposed males. Collectively, elevated oxidative stress, metabolic dysregulation and immune modulation may lead to chronic liver injury in organisms exposed to metabolic disrupting chemicals.
Collapse
|
|
40
|
Zhao Y, Zhu Y, Chen X, Lin H, Qin N, Zhou Z, Liu H, Hao Y, Zhou C, Liu X, Jin L, Sheng J, Huang H. Circulating Innate Lymphoid Cells Exhibit Distinctive Distribution During Normal Pregnancy. Reprod Sci 2022; 29:1124-1135. [PMID: 34988918 PMCID: PMC8907087 DOI: 10.1007/s43032-021-00834-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 12/14/2021] [Indexed: 12/25/2022]
Abstract
Over the past decades, the investigation of innate lymphoid cells (ILCs) has revealed their significance in successful pregnancy. Sex hormones, such as estradiol and progesterone, show specific changes during pregnancy and modulate both adaptive and innate immune systems. ILC subset distribution in peripheral blood of pregnant women and its potential association with sex hormone levels have not been well revealed. Peripheral blood was obtained from healthy non-pregnant, early-pregnant, and late-pregnant women. Radioimmunoassay was performed to measure plasma estradiol and progesterone levels. The levels of type 1 ILCs (ILC1s), type 2 ILCs (ILC2s), type 3 ILCs (ILC3s), and total ILCs as well as estrogen and progesterone receptors of ILC2s in peripheral blood were analyzed using flow cytometry. The proportion of total ILCs and distribution of ILC subsets in peripheral blood changed dynamically during pregnancy. Compared to non-pregnant women, late-pregnant women displayed significantly higher proportion of circulating ILCs, among which ILC2s accounted for the majority in late-pregnant women while a smaller part in others, and ILC3s displayed the opposite. Plasma estradiol and progesterone levels elevated while pregnancy proceeded and the expression of their receptors in ILC2s increased consisted with the proportion of circulating ILC2s. Our work first observed the existence of progesterone receptors in human circulating ILC2s and revealed the distribution pattern of circulating ILC subsets and their interrelation with plasma sex hormone levels during pregnancy. Our results suggested that the estradiol and progesterone levels might partly influence the distribution of circulating ILC subsets and implied the interplay between circulating ILCs and pregnancy.
Collapse
Affiliation(s)
- Yiran Zhao
- The International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Yajie Zhu
- The International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Xi Chen
- The International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Hui Lin
- The International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Ningxin Qin
- The International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Zhiyang Zhou
- The International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Han Liu
- The International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Yanhui Hao
- The International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Chengliang Zhou
- The International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
| | - Xinmei Liu
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
- Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200010, China
| | - Li Jin
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China
- Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200010, China
| | - Jianzhong Sheng
- Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Zhejiang, 310058, China
| | - Hefeng Huang
- The International Peace Maternity & Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
- Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China.
- Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200010, China.
| |
Collapse
|
|
41
|
Del Rio-Pertuz G, Benjanuwattra J, Nawaa SE, Lahoti A, Shurmur S. Low-Dose Oral Contraceptives and Spontaneous Coronary Artery Dissection With Heavy Clot Burden in a Nonpregnant Woman. J Investig Med High Impact Case Rep 2022; 10:23247096221104466. [PMID: 35712846 PMCID: PMC9210072 DOI: 10.1177/23247096221104466] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Spontaneous coronary artery dissection (SCAD) is an infrequent cause of acute coronary syndrome (ACS) caused by a nontraumatic tear in the coronary artery wall. The true incidence is thought to be underestimated owing to its diagnostic difficulty as coronary angiography is insensitive in assessing the arterial wall structure, thereby warranting additional diagnostic modalities such as intravascular ultrasound. We report a case of a young woman who had been taking oral contraceptives, and presented with acute non-ST segment elevation myocardial infarction due to SCAD with superimposed thrombosis.
Collapse
Affiliation(s)
- Gaspar Del Rio-Pertuz
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Juthipong Benjanuwattra
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Saif El Nawaa
- Division of Cardiology, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Ankush Lahoti
- Division of Cardiology, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Scott Shurmur
- Division of Cardiology, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| |
Collapse
|
|
42
|
Depression and obesity among females, are sex specificities considered? Arch Womens Ment Health 2021; 24:851-866. [PMID: 33880649 DOI: 10.1007/s00737-021-01123-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 03/21/2021] [Indexed: 12/13/2022]
Abstract
This study aimed to systematically review the relationship of obesity-depression in the female sex. We carried out a systematic search (PubMed, MEDLINE, Embase) to quantify the articles (controlled trials and randomized controlled trials) regarding obesity and depression on a female population or a mixed sample. Successively, we established whether the sex specificities were studied by the authors and if they reported on collecting data regarding factors that may contribute to the evolution of obesity and depression and that could be responsible for the greater susceptibility of females to those conditions. After applying the inclusion and exclusion criteria, we found a total of 20 articles with a female sample and 54 articles with a mixed sample. More than half of all articles (51.35%, n = 38) evaluated the relationship between depression and obesity, but only 20 (27.03%) evaluated this relationship among females; still, 80% of those (n = 16) presented supporting results. However, few articles considered confounding factors related to female hormones (12.16%, n = 9) and none of the articles focused on factors responsible for the binomial obesity-depression in the female sex. The resulting articles also supported that depression (and related impairments) influencing obesity (and related impairments) is a two-way road. This systematic review supports the concurrency of obesity-depression in females but also shows how sex specificities are ultimately under-investigated. Female sex specificity is not being actively considered when studying the binomial obesity-depression, even within a female sample. Future studies should focus on trying to understand how the female sex and normal hormonal variations influence these conditions.
Collapse
|
|
43
|
Wu YS, Chen CR, Yeh YT, Lin HH, Peng YH, Lin YL. 7,7″-Dimethoxyagastisflavone Inhibits Proinflammatory Cytokine Release and Inflammatory Cell Recruitment through Modulating ERα Signaling. Biomedicines 2021; 9:biomedicines9121778. [PMID: 34944595 PMCID: PMC8698781 DOI: 10.3390/biomedicines9121778] [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: 10/06/2021] [Revised: 11/15/2021] [Accepted: 11/24/2021] [Indexed: 11/16/2022] Open
Abstract
Acute systemic inflammatory diseases, including sepsis, usually result in cytokine disorder and multiple-organ failure. 7,7″-Dimethoxyagastisflavone (DMGF), a biflavonoid isolated from the needles of Taxus x media var. Hicksii, has previously been evaluated for its antiproliferative and antineoplastic effects in cancer cells. In this study, the effects of DMGF on the cytokine production and cell migration of inflammatory macrophages were investigated. The inhibition of cytokine and chemokine production by DMGF in LPS-treated macrophages was analyzed by a multiplex cytokine assay. Then, the integrin molecules used for cell adhesion and regulators of actin polymerization were observed by RT-PCR and recorded using confocal imaging. The DMGF interaction with estrogen receptor α (ERα) was modeled structurally by molecular docking and validated by an ERα reporter assay. DMGF inhibited TNF-α, IL-1β, and IL-6 production in LPS-induced macrophages. DMGF also inhibited inflammatory macrophage migration by downregulating the gene and protein expression of adhesion molecules (LFA-1 and VLA4) and regulators of actin assembly (Cdc42-Rac1 pathway). DMGF might interact with the ligand-binding domain of ERα and downregulate its transcriptional activity. These results indicated that DMGF effectively inhibited the production of proinflammatory cytokines and the recruitment of inflammatory cells through downregulating ERα signaling.
Collapse
|
|
44
|
Yang Q, Zhang H, Wei T, Lin A, Sun Y, Luo P, Zhang J. Single-Cell RNA Sequencing Reveals the Heterogeneity of Tumor-Associated Macrophage in Non-Small Cell Lung Cancer and Differences Between Sexes. Front Immunol 2021; 12:756722. [PMID: 34804043 PMCID: PMC8602907 DOI: 10.3389/fimmu.2021.756722] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/21/2021] [Indexed: 12/25/2022] Open
Abstract
Non-Small Cell Lung Cancer (NSCLC) is a disease with high morbidity and mortality, which has sex-related differences in prognosis and immunotherapy efficacy. However, the difference in the mechanisms remains unclear. Macrophages, characterized by high plasticity and heterogeneity, act as one of the key cells that exert anti-tumor effects in the tumor microenvironment (TME) and play a complicated role in the process of tumor progression. To elucidate the subtype composition and functional heterogeneity of tumor-associated macrophages (TAMs) in NSCLC and further compare the sex-mediated differences, we conducted a single-cell level analysis in early-stage smoking NSCLC patients, combined with ssGSEA analysis, pseudotime ordering, and SCENIC analysis. We found two universally presented immune-suppressive TAMs with different functional and metabolic characteristics in the TME of NSCLC. Specifically, CCL18+ macrophages exerted immune-suppressive effects by inhibiting the production of inflammatory factors and manifested high levels of fatty acid oxidative phosphorylation metabolism. Conversely, the main metabolism pathway for SPP1+ macrophage was glycolysis which contributed to tumor metastasis by promoting angiogenesis and matrix remodeling. In terms of the differentially expressed genes, the complement gene C1QC and the matrix remodeling relevant genes FN1 and SPP1 were differentially expressed in the TAMs between sexes, of which the male upregulated SPP1 showed the potential as an ideal target for adjuvant immunotherapy and improving the efficacy of immunotherapy. According to the early-stage TCGA-NSCLC cohort, high expression of the above three genes in immune cells were associated with poor prognosis and acted as independent prognostic factors. Moreover, through verification at the transcription factor, transcriptome, and protein levels, we found that TAMs from women showed stronger immunogenicity with higher interferon-producing and antigen-presenting ability, while men-derived TAMs upregulated the PPARs and matrix remodeling related pathways, thus were more inclined to be immunosuppressive. Deconstruction of the TAMs at the single-cell level deepens our understanding of the mechanism for tumor occurrence and progress, which could be helpful to achieve the precise sex-specific tumor treatment sooner.
Collapse
Affiliation(s)
- Qi Yang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Hongman Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Ting Wei
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yueqin Sun
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
45
|
Arnold ML, Saijo K. Estrogen Receptor β as a Candidate Regulator of Sex Differences in the Maternal Immune Activation Model of ASD. Front Mol Neurosci 2021; 14:717411. [PMID: 34531723 PMCID: PMC8438209 DOI: 10.3389/fnmol.2021.717411] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 08/09/2021] [Indexed: 12/25/2022] Open
Abstract
Interestingly, more males are diagnosed with autism spectrum disorder (ASD) than females, yet the mechanism behind this difference is unclear. Genes on the sex chromosomes and differential regulation by sex steroid hormones and their receptors are both candidate mechanisms to explain this sex-dependent phenotype. Nuclear receptors (NRs) are a large family of transcription factors, including sex hormone receptors, that mediate ligand-dependent transcription and may play key roles in sex-specific regulation of immunity and brain development. Infection during pregnancy is known to increase the probability of developing ASD in humans, and a mouse model of maternal immune activation (MIA), which is induced by injecting innate immune stimulants into pregnant wild-type mice, is commonly used to study ASD. Since this model successfully recaptures the behavioral phenotypes and male bias observed in ASD, we will discuss the potential role of sex steroid hormones and their receptors, especially focusing on estrogen receptor (ER)β, in MIA and how this signaling may modulate transcription and subsequent inflammation in myeloid-lineage cells to contribute to the etiology of this neurodevelopmental disorder.
Collapse
Affiliation(s)
- Madeline L Arnold
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, United States
| | - Kaoru Saijo
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, United States.,Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, United States
| |
Collapse
|
|
46
|
Batty MJ, Chabrier G, Sheridan A, Gage MC. Metabolic Hormones Modulate Macrophage Inflammatory Responses. Cancers (Basel) 2021; 13:cancers13184661. [PMID: 34572888 PMCID: PMC8467249 DOI: 10.3390/cancers13184661] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/31/2021] [Accepted: 09/13/2021] [Indexed: 12/17/2022] Open
Abstract
Simple Summary Macrophages are a type of immune cell which play an important role in the development of cancer. Obesity increases the risk of cancer and obesity also causes disruption to the normal levels of hormones that are produced to coordinate metabolism. Recent research now shows that these metabolic hormones also play important roles in macrophage immune responses and so through macrophages, disrupted metabolic hormone levels may promote cancer. This review article aims to highlight and summarise these recent findings so that the scientific community may better understand how important this new area of research is, and how these findings can be capitalised on for future scientific studies. Abstract Macrophages are phagocytotic leukocytes that play an important role in the innate immune response and have established roles in metabolic diseases and cancer progression. Increased adiposity in obese individuals leads to dysregulation of many hormones including those whose functions are to coordinate metabolism. Recent evidence suggests additional roles of these metabolic hormones in modulating macrophage inflammatory responses. In this review, we highlight key metabolic hormones and summarise their influence on the inflammatory response of macrophages and consider how, in turn, these hormones may influence the development of different cancer types through the modulation of macrophage functions.
Collapse
|
|
47
|
Nasser SA, Afify EA, Kobeissy F, Hamam B, Eid AH, El-Mas MM. Inflammatory Basis of Atherosclerosis: Modulation by Sex Hormones. Curr Pharm Des 2021; 27:2099-2111. [PMID: 33480335 DOI: 10.2174/1381612827666210122142811] [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] [Received: 10/26/2020] [Accepted: 12/17/2020] [Indexed: 11/22/2022]
Abstract
Atherosclerosis-related cardiovascular diseases (CVDs) are the leading cause of death globally. Several lines of evidence are supportive of the contributory role of vascular inflammation in atherosclerosis. Diverse immune cell types, including monocytes/macrophages, T-cells and neutrophils, as well as specialized proresolving lipid mediators, have been successfully characterized as key players in vascular inflammation. The increased prevalence of atherosclerotic CVD in men in comparison to age-matched premenopausal women and the abolition of sex differences in prevalence during menopause strongly suggest a pivotal role of sex hormones in the development of CVD. Indeed, many animal and human studies conclusively implicate sex hormones as a crucial component in driving the immune response. This is further corroborated by the effective identification of sex hormone receptors in vascular endothelial cells, vascular smooth muscle cells and immune cells. Collectively, these findings suggest a cellular communication between sex hormones and vascular or immune cells underlying the vascular inflammation in atherosclerosis. The aim of this review is to provide an overview of vascular inflammation as a causal cue underlying atherosclerotic CVDs within the context of the modulatory effects of sex hormones. Moreover, the cellular and molecular signaling pathways underlying the sex hormones- immune system interactions as potential culprits for vascular inflammation are highlighted with detailed and critical discussion. Finally, the review concludes by speculations on the potential sex-related efficacy of currently available immunotherapies in mitigating vascular inflammation. Conceivably, a deeper understanding of the immunoregulatory influence of sex hormones on vascular inflammation-mediated atherosclerosis permits sex-based management of atherosclerosis-related CVDs.
Collapse
Affiliation(s)
- Suzanne A Nasser
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, P.O. Box 11-5020, Beirut, Lebanon
| | - Elham A Afify
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, American University of Beirut, P.O. Box 11-0236, Beirut, Lebanon
| | - Bassam Hamam
- Department of Biological and Chemical Sciences, School of Arts and Sciences, Lebanese International University, P.O. Box 146404, Beirut, Lebanon
| | - Ali H Eid
- Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Mahmoud M El-Mas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| |
Collapse
|
|
48
|
Lenert ME, Avona A, Garner KM, Barron LR, Burton MD. Sensory Neurons, Neuroimmunity, and Pain Modulation by Sex Hormones. Endocrinology 2021; 162:bqab109. [PMID: 34049389 PMCID: PMC8237991 DOI: 10.1210/endocr/bqab109] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Indexed: 12/16/2022]
Abstract
The inclusion of women in preclinical pain studies has become more commonplace in the last decade as the National Institutes of Health (NIH) released its "Sex as a Biological Variable" mandate. Presumably, basic researchers have not had a comprehensive understanding about neuroimmune interactions in half of the population and how hormones play a role in this. To date, we have learned that sex hormones contribute to sexual differentiation of the nervous system and sex differences in behavior throughout the lifespan; however, the cycling of sex hormones does not always explain these differences. Here, we highlight recent advances in our understanding of sex differences and how hormones and immune interactions influence sensory neuron activity to contribute to physiology and pain. Neuroimmune mechanisms may be mediated by different cell types in each sex, as the actions of immune cells are sexually dimorphic. Unfortunately, the majority of studies assessing neuronal contributions to immune function have been limited to males, so it is unclear if the mechanisms are similar in females. Finally, pathways that control cellular metabolism, like nuclear receptors, have been shown to play a regulatory role both in pain and inflammation. Overall, communication between the neuroimmune and endocrine systems modulate pain signaling in a sex-dependent manner, but more research is needed to reveal nuances of these mechanisms.
Collapse
Affiliation(s)
- Melissa E Lenert
- Neuroimmunology and Behavior Laboratory, Center for Advanced Pain Studies (CAPS), Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, USA
| | - Amanda Avona
- Neuroimmunology and Behavior Laboratory, Center for Advanced Pain Studies (CAPS), Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, USA
| | - Katherine M Garner
- Neuroimmunology and Behavior Laboratory, Center for Advanced Pain Studies (CAPS), Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, USA
| | - Luz R Barron
- Neuroimmunology and Behavior Laboratory, Center for Advanced Pain Studies (CAPS), Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, USA
| | - Michael D Burton
- Neuroimmunology and Behavior Laboratory, Center for Advanced Pain Studies (CAPS), Department of Neuroscience, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, USA
| |
Collapse
|
|
49
|
Zein JG, McManus JM, Sharifi N, Erzurum SC, Marozkina N, Lahm T, Giddings O, Davis MD, DeBoer MD, Comhair SA, Bazeley P, Kim HJ, Busse W, Calhoun W, Castro M, Chung KF, Fahy JV, Israel E, Jarjour NN, Levy BD, Mauger DT, Moore WC, Ortega VE, Peters M, Bleecker ER, Meyers DA, Zhao Y, Wenzel SE, Gaston B. Benefits of Airway Androgen Receptor Expression in Human Asthma. Am J Respir Crit Care Med 2021; 204:285-293. [PMID: 33779531 DOI: 10.1164/rccm.202009-3720oc] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Rationale: Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways.Objectives: To measure whether AR and its ligands are associated with human asthma outcomes.Methods: We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (FeNO) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey).Measurements and Main Results: In SARP (n = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV1/FVC ratio (R2 = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R2 = 0.056, P = 0.016) and was negatively associated with FeNO (R2 = 0.178, P = 9.8 × 10-6) and NOS2 (nitric oxide synthase gene) expression (R2 = 0.281, P = 1.2 × 10-10). In SARP (n = 1,659), the Cleveland Clinic Health System (n = 32,527), and the NHANES (n = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV1 in both women and men.Conclusions: Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower FeNO in human asthma. The role of androgens should be considered in asthma management.
Collapse
Affiliation(s)
- Joe G Zein
- Lerner Research Institute and.,Respiratory Institute, Cleveland Clinic, Cleveland, Ohio
| | | | | | - Serpil C Erzurum
- Lerner Research Institute and.,Respiratory Institute, Cleveland Clinic, Cleveland, Ohio
| | | | | | | | | | - Mark D DeBoer
- Department of Pediatrics, University of Virginia, Charlottesville, Virginia
| | - Suzy A Comhair
- Lerner Research Institute and.,Respiratory Institute, Cleveland Clinic, Cleveland, Ohio
| | - Peter Bazeley
- Lerner Research Institute and.,Respiratory Institute, Cleveland Clinic, Cleveland, Ohio
| | - Hyun Jo Kim
- Department of Systems Biology and Bioinformatics, Case Western Reserve University, Cleveland, Ohio
| | - William Busse
- Department of Medicine, School of Medicine, University of Wisconsin, Madison, Wisconsin
| | - William Calhoun
- Department of Medicine, University of Texas Medical Branch, University of Texas, Galveston, Texas
| | - Mario Castro
- Division of Pulmonary, Critical Care, and Sleep Medicine, School of Medicine, University of Kansas, Kansas City, Kansas
| | - Kian Fan Chung
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - John V Fahy
- Division of Pulmonary, Critical Care, and Sleep Medicine, School of Medicine, University of Kansas, Kansas City, Kansas.,Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California at San Francisco, San Francisco, California
| | - Elliot Israel
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard University, Boston, Massachusetts
| | - Nizar N Jarjour
- Department of Medicine, School of Medicine, University of Wisconsin, Madison, Wisconsin
| | - Bruce D Levy
- Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard University, Boston, Massachusetts
| | - David T Mauger
- Center for Biostatistics and Epidemiology, School of Medicine, Pennsylvania State University, Hershey, Pennsylvania
| | - Wendy C Moore
- Section on Pulmonary, Critical Care, Allergic, and Immunologic Disease, Department of Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, North Carolina
| | - Victor E Ortega
- Section on Pulmonary, Critical Care, Allergic, and Immunologic Disease, Department of Internal Medicine, School of Medicine, Wake Forest University, Winston-Salem, North Carolina
| | - Michael Peters
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California at San Francisco, San Francisco, California
| | - Eugene R Bleecker
- Division of Genetics, Genomics, and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Arizona; and
| | - Deborah A Meyers
- Division of Genetics, Genomics, and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Arizona; and
| | - Yi Zhao
- Department of Biostatistics and Health Science Data, School of Medicine, Indiana University, Indianapolis, Indiana
| | - Sally E Wenzel
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | |
Collapse
|
|
50
|
Nowak K, Jabłońska E, Ratajczak-Wrona W. NF-κB-An Important Player in Xenoestrogen Signaling in Immune Cells. Cells 2021; 10:1799. [PMID: 34359968 PMCID: PMC8304139 DOI: 10.3390/cells10071799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 02/07/2023] Open
Abstract
The proper functioning of the immune system is critical for an effective defense against pathogenic factors such as bacteria and viruses. All the cellular processes taking place in an organism are strictly regulated by an intracellular network of signaling pathways. In the case of immune cells, the NF-κB pathway is considered the key signaling pathway as it regulates the expression of more than 200 genes. The transcription factor NF-κB is sensitive to exogenous factors, such as xenoestrogens (XEs), which are compounds mimicking the action of endogenous estrogens and are widely distributed in the environment. Moreover, XE-induced modulation of signaling pathways may be crucial for the proper development of the immune system. In this review, we summarize the effects of XEs on the NF-κB signaling pathway. Based on our analysis, we constructed a model of XE-induced signaling in immune cells and found that in most cases XEs activate NF-κB. Our analysis indicated that the indirect impact of XEs on NF-κB in immune cells is related to the modulation of estrogen signaling and other pathways such as MAPK and JAK/STAT. We also summarize the role of these aspects of signaling in the development and further functioning of the immune system in this paper.
Collapse
Affiliation(s)
- Karolina Nowak
- Department of Immunology, Medical University of Bialystok, Waszyngtona 15A, 15-269 Bialystok, Poland; (E.J.); (W.R.-W.)
| | | | | |
Collapse
|