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Naidovski N, Chong SKT, Liu F, Riordan SM, Wehrhahn MC, Yuwono C, Zhang L. Human macrophage response to the emerging enteric pathogen Aeromonas veronii: Inflammation, apoptosis, and downregulation of histones. Virulence 2025; 16:2440554. [PMID: 39663607 PMCID: PMC11702953 DOI: 10.1080/21505594.2024.2440554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 11/11/2024] [Accepted: 12/04/2024] [Indexed: 12/13/2024] Open
Abstract
This study investigated the pathogenic mechanisms of Aeromonas veronii in macrophages. THP-1 derived macrophages were used as a human macrophage model and were treated with A. veronii strain AS1 isolated from intestinal biopsies of an IBD patient, or Escherichia coli strain K-12. RNA was extracted and subjected to RNA sequencing and comparative transcriptomic analyses. Protein levels of IL-8, IL-1β, IL-18, and TNFα were measured using ELISA, and apoptosis was assessed using caspase 3/7 assays. Both A. veronii AS1 and E. coli K-12 significantly upregulated the expression of many genes involving inflammation. At the protein level, A. veronii AS1 induced significantly higher levels of IL-8, TNFα, mature IL-18 and IL-1β than E. coli K-12, and led to greater elevation of caspase 3/7 activities. Both A. veronii AS1 and E. coli K-12 upregulated the expression of CASP5, but not other caspase genes. A. veronii AS1 significantly downregulated the expression of 20 genes encoding histone proteins that E. coli K-12 did not. The more profound pathogenic effects of A. veronii in inducing inflammation and apoptosis in macrophages than E. coli K-12 are consistent with its role as a human enteric pathogen. The upregulated expression of CASP5 and increased release of IL-1β and IL-18 support the role of CASP5 in activation of non-canonical inflammasome. The downregulation of histone genes by A. veronii suggests a unique impact on host cell gene expression, which may represent a novel virulence strategy. These findings advance the understanding of pathogenic mechanisms of the emerging human enteric pathogen A. veronii.
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Affiliation(s)
- Nicholas Naidovski
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
| | - Sarah K. T. Chong
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
| | - Fang Liu
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
| | - Stephen M. Riordan
- Gastrointestinal and Liver Unit, Prince of Wales Hospital, University of New South Wales, Sydney, Australia
| | - Michael C. Wehrhahn
- Douglass Hanly Moir Pathology, a Sonic Healthcare Practice, Macquarie Park, NSW, Australia
| | - Christopher Yuwono
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
| | - Li Zhang
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
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Cruz-Granados P, Bianco-Bortoletto G, Aran I, Rivero de Jesus V, Lopez-Escamez JA. An ultra-rare missense variant in the KIF1B gene linked to autoinflammatory Menière's disease. NPJ Genom Med 2025; 10:42. [PMID: 40393993 PMCID: PMC12092769 DOI: 10.1038/s41525-025-00503-6] [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] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 05/08/2025] [Indexed: 05/22/2025] Open
Abstract
Menière's disease (MD) is an inner ear disorder characterised by episodes of vertigo, sensorineural hearing loss and tinnitus linked to autoinflammation and/or type 2 immune response. We hypothesise that rare variation in immune response genes could drive the autoinflammatory phenotype in MD. We retrieved differentially expressed genes (DEG) from single-cell RNAseq and epigenomic datasets to search for rare variants in the MD exome (N = 454) and genome (N = 511) sequencing datasets. The variant chr1:10374335 C > T in the KIF1B gene was found in three MD unrelated individuals and was predicted to be likely pathogenic. According to differential transcript usage, transcript ENST00000622724.3 was found in MD samples, but absent in controls. Furthermore, this variant may influence splicing through the generation of exonic enhancers and silencers, potentially changing transcription factor binding at the promoter. These findings support that this KIF1B gene rare variant is associated with the MD autoinflammatory phenotype and may up-regulate its expression in monocytes.
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Affiliation(s)
- Pablo Cruz-Granados
- Meniere Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, University of Sydney, Sydney, New South Wales, Australia
| | - Giselle Bianco-Bortoletto
- Meniere Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, University of Sydney, Sydney, New South Wales, Australia
- Laboratory of Human Molecular Genetics, Center for Molecular Biology and Genetic Engineering - CBMEG, Programa de Pós Graduação em Ciências Médicas, Faculty of Medical Sciences, State University of Campinas - UNICAMP, Sao Paulo, Brazil
| | - Ismael Aran
- Department of Otolaryngology, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain
| | - Victoria Rivero de Jesus
- Hospital de San Joan Despí CSI, Department of Otorhinolaryngology and Otoneurology, Barcelona, Spain
| | - Jose A Lopez-Escamez
- Meniere Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, University of Sydney, Sydney, New South Wales, Australia.
- Otology & Neurotology Group CTS495, Division of Otolaryngology, Department of Surgery, Instituto de Investigación Biosanitaria, ibs.GRANADA, Universidad de Granada, Granada, Spain.
- Sensorineural Pathology Programme, Centro de Investigación Biomédica en Red en Enfermedades Raras, CIBERER, Madrid, Spain.
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Lee SY, Lee GH, Maeng J, Kim SY, Yun HY, Jeong GS, Jeong HG. Anti-Inflammasome Effect of Impressic Acid on Diesel Exhaust Particulate Matter-Induced NLRP1 Inflammasome via the Keap1/p62/Nrf2-Signaling Pathway in Keratinocytes. Antioxidants (Basel) 2025; 14:610. [PMID: 40427491 PMCID: PMC12109400 DOI: 10.3390/antiox14050610] [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] [Subscribe] [Scholar Register] [Received: 04/10/2025] [Revised: 05/15/2025] [Accepted: 05/16/2025] [Indexed: 05/29/2025] Open
Abstract
Diesel exhaust particulate (DEP) is widely recognized to weaken lung function and skin diseases. When the skin, which defends against external factors, is exposed to PM2.5, various chronic inflammatory diseases occur. When keratinocytes recognize harmful signals, they synthesize the NOD-like receptor protein 1 (NLRP1) inflammasome. DEP enhances NF-κB signaling and NLRP1 inflammasome expression through the interaction of TXNIP with NLRP1 in keratinocytes. Although many studies have reported the anti-inflammatory and antioxidant characteristics of Impressic acid (IPA), the umbrella consequences of IPA for PM2.5-influenced inflammasomes and the associated mechanisms remain unknown. Therefore, this study aimed to examine the protective function of IPA against inflammation in human keratinocytes. IPA attenuated the NLRP1 expression, caspase-1, IL-1β actuation, and NF-κB and IκB phosphorylation induction by DEP. IPA upregulated the Nrf2, HO-1, and NQO1 expression through CaMKKβ, AMPK, and GSK3β phosphorylation. Also, IPA led to the elevation of p62 and the degradation of the Keap1 protein. ML385 reversed the suppressive effect of IPA on the NLRP1 inflammasome, which was enhanced by DEP, and NAC counteracted the effect of ML385. These findings indicate that IPA can suppress inflammation induced by PM2.5 by expressing antioxidant enzymes through the Keap1/p62/Nrf2-signaling pathway in human keratinocytes.
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Affiliation(s)
| | | | | | | | | | | | - Hye Gwang Jeong
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea; (S.Y.L.); (G.H.L.); (J.M.); (S.Y.K.); (H.-Y.Y.); (G.-S.J.)
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Saaoud F, Liu L, Xu K, Lu Y, Shao Y, Ben Issa M, Jiang X, Wang X, Liu X, Autieri M, Wu S, Wei J, Yu J, Bouchareb R, Gillespie A, Luo JJ, Martinez L, Vazquez-Padron R, Sun J, Zhao H, Wang H, Pratico D, Yang X. Alzheimer's disease as an auto-innate immune pathology with potential cell trans-differentiation and enhanced trained immunity in 3xTg-AD mouse model. J Alzheimers Dis 2025; 105:550-572. [PMID: 40232249 DOI: 10.1177/13872877251329583] [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: 04/16/2025]
Abstract
BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder characterized by memory impairment. Neuroinflammatory processes, mediated by glial and immune cells, contribute to neuronal damage. Emerging evidence implicates innate immune mechanisms, including trained immunity and cell trans-differentiation, in AD pathogenesis, though their roles remain unclear.ObjectiveTo investigate transcriptomic changes in the 3xTg-AD mouse model, focusing on trained immunity and cell trans-differentiation in disease mechanisms.MethodsRNA-sequencing was performed on brain tissue (cortex plus hippocampus) from 11-month-old female 3xTg-AD and wild-type mice (n = 3/group). Differentially expressed genes (fold change > 1.5, p < 0.05) were identified and followed by bioinformatics and knowledge-based transcriptomic profiling. Public AD datasets were also analyzed.Results3xTg-AD mice exhibited 316 upregulated and 412 downregulated genes. Downregulated genes included those for blood-brain barrier protein, while upregulated genes related to cerebrospinal fluid. Increased expression of proinflammatory markers, as well as genes related to cell differentiation, proliferation, activation, and adhesion. Upregulation of genes associated with cell migration and trans-differentiation suggests a potential role for inflammation and cellular plasticity. Additionally, genes involved in inflammasome pathways, immunometabolism, and trained immunity were upregulated. Mechanistically, these genes were modulated by knockdown of trained immunity promoter SET-7, overexpression of trained immunity inhibitor IL-37, and knockout of inflammasome genes IL-1 receptor, caspase-1, and pattern recognition receptor CD36.ConclusionsThe finding underscore the potential role of trained immunity and cell trans-differentiation in AD, revealing a mechanistic framework in which danger-associated molecular patterns drive innate immune responses, inflammasome activation, and cell plasticity contribute to AD, offering therapeutic targets for neuroinflammation and cellular reprograming.
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Affiliation(s)
- Fatma Saaoud
- Lemole Center for Integrated Lymphatics and Vascular Research, Temple University, Philadelphia, PA, USA
| | - Lu Liu
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Keman Xu
- Lemole Center for Integrated Lymphatics and Vascular Research, Temple University, Philadelphia, PA, USA
| | - Yifan Lu
- Lemole Center for Integrated Lymphatics and Vascular Research, Temple University, Philadelphia, PA, USA
| | - Ying Shao
- Lemole Center for Integrated Lymphatics and Vascular Research, Temple University, Philadelphia, PA, USA
| | - Mohammed Ben Issa
- Lemole Center for Integrated Lymphatics and Vascular Research, Temple University, Philadelphia, PA, USA
| | - Xiaohua Jiang
- Lemole Center for Integrated Lymphatics and Vascular Research, Temple University, Philadelphia, PA, USA
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Xianwei Wang
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Xiaolei Liu
- Lemole Center for Integrated Lymphatics and Vascular Research, Temple University, Philadelphia, PA, USA
| | - Michael Autieri
- Lemole Center for Integrated Lymphatics and Vascular Research, Temple University, Philadelphia, PA, USA
| | - Sheng Wu
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Juncheng Wei
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Jun Yu
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Rihab Bouchareb
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Avrum Gillespie
- Section of Nephrology, Hypertension, and Kidney Transplantation, Department of Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Jin Jun Luo
- Department of Neurology, Temple University, Philadelphia, PA, USA
| | - Laisel Martinez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Roberto Vazquez-Padron
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Jianxin Sun
- Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Huaqing Zhao
- Department of Biomedical Education and Data Sciences, Temple University, Philadelphia, PA, USA
| | - Hong Wang
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Domenico Pratico
- Alzheimer's Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Xiaofeng Yang
- Lemole Center for Integrated Lymphatics and Vascular Research, Temple University, Philadelphia, PA, USA
- Lemole Center for Integrated Lymphatics and Vascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
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Khazem F, Zetoune AB. Investigating the role of HMGA2 plasma level as a diagnostic marker in bladder urothelial carcinoma patients. J Cancer Res Clin Oncol 2025; 151:134. [PMID: 40204943 PMCID: PMC11982150 DOI: 10.1007/s00432-025-06192-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Accepted: 04/01/2025] [Indexed: 04/11/2025]
Abstract
BACKGROUND Bladder Cancer (BC) is an environmental cancer caused by exposure to a globally widespread carcinogen, which is smoking, and it is characterized by high rates of recurrence and mortality. High Mobility Group A2 (HMGA2) protein is an oncofetal protein that belongs to the HMG family proteins. It is involved in various stages of carcinogenesis and cancer progression. This study investigated the presence and levels of the HMGA2 protein in bladder urothelial carcinoma patients' plasma and in healthy individuals and their association with the clinicopathological features of bladder urothelial carcinoma. METHODS This case-control study included 80 individuals divided into two groups: a healthy group (n = 22) and a patient group with bladder urothelial carcinoma (n = 58). There were 16 patients with Muscle-Invasive Bladder Cancer (MIBC) and 42 patients with Non-Invasive Bladder Cancer (NMIBC) in the patients' cohort according to the European Association of Urology (EAU) classification. HMGA2 plasma levels were measured by Sandwich Enzyme-Linked ImmunoSorbent Assay (ELISA). The statistical analysis was performed using IBM SPSS statistics (version 25) software. The t-test and the Mann-Whitney test were used. RESULTS Plasma HMGA2 protein levels were higher in the BC group than in the healthy group (P < 0.001), they also were higher in MIBC (pT2-pT3) than in NMIBC (pTa-pT1) (P < 0.001). HMGA2 plasma levels were higher in high grade BC patients than in low grade BC patients (P = 0.049). CONCLUSIONS This study confirmed that the plasma HMGA2 protein level was higher in bladder cancer patients than in healthy individuals and that its elevated plasma levels were correlated with advanced stage and grade of BC; thus, the plasma HMGA2 protein level represents a potential non-invasive marker that could be included in bladder cancer diagnosis approach.
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Affiliation(s)
- Farah Khazem
- Department of Biochemistry and Microbiology, Faculty of Pharmacy, Damascus University, Damascus, Syria.
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Nakaya T. Release of FUS into the extracellular space is regulated by its amino-terminal prion-like domain. FEBS Lett 2025; 599:1046-1054. [PMID: 39737526 DOI: 10.1002/1873-3468.15086] [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: 08/22/2024] [Revised: 11/20/2024] [Accepted: 11/21/2024] [Indexed: 01/01/2025]
Abstract
Fused in sarcoma (FUS) is a causative factor of amyotrophic lateral sclerosis (ALS) and is believed to propagate pathologically by transmission from cell to cell. However, the mechanism underlying FUS release from cells, which is a critical step for the propagation system, remains poorly understood. This study conducted an analysis of the release of human and mouse FUS from neurons, revealing that human FUS is significantly released into the media compared to its mouse counterpart. Further study using chimeric FUS proteins identified the amino-terminal region of human FUS as essential for its release. These findings indicate that human FUS is released directly from neurons and underscore the novel functional role of its amino-terminal region in this process.
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Affiliation(s)
- Tadashi Nakaya
- School of Pharmacy at Fukuoka, International University of Health and Welfare, Fukuoka, Japan
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Liang YB, Luo RX, Lu Z, Mao Y, Song PP, Li QW, Peng ZQ, Zhang YS. VX-765 attenuates secondary damage and β-amyloid accumulation in ipsilateral thalamus after experimental stroke in rats. Exp Neurol 2025; 385:115097. [PMID: 39647574 DOI: 10.1016/j.expneurol.2024.115097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 11/16/2024] [Accepted: 12/04/2024] [Indexed: 12/10/2024]
Abstract
Focal cortical infarction can result both in the accumulation of Aβ in as well as further secondary damage and inflammation within the ipsilateral thalamus. VX-765 is a potent and selective small-molecule capable of inhibiting caspase-1, which has been shown to exhibit active neuroprotection properties in multiple disease. However, the neuroprotection efficacy of VX-765 as a means of attenuating secondary damage after MCAO remains uncertain. As such, we sought to determine the ability of VX-765 to alter thalamic Aβ accumulation, secondary damage, and sensory deficits in rats of focal cortical infarction. A rat model of distal branch of middle cerebral artery occlusion (dMCAO) was used to evaluate the effects of the VX-765 on the secondary damage and β-amyloid accumulation in ipsilateral thalamus after dMCAO in rats. The activation of astrocyte and microglia, loss of neuron, and damage to sensory function were detected weekly till 4 weeks after modeling. VX-765 was injected intraperitoneally delayed after 7 days injury and the status of secondary damage, inflammation and β-amyloid accumulation in ipsilateral thalamus after dMCAO were examined.Our results revealed that VX-765 markedly reduce sensory deficits in these rats, suppressing secondary damage through reductions in APP and accumulations of Aβ with an accompanying reduction in both neuronal loss, astrocyte and microglia activation. VX-765 markedly inhibited NLRP3 and caspase-1, and downregulation of ASC, GSDMD, IL-1β, and IL-18 in the ipsilateral thalamus after MCAO. Our results further suggested that VX-765 may regulate secondary damage via control inflammation and suppressing the production of pro-inflammatory factors such as iNOS, TNF-α, IL-6 and COX2 that are produced downstream NF-κB signaling. Taken together, VX-765 is well-suited to attenuate secondary damage and accumulations of Aβ, improving recovery from sensory deficits and cognitive deficits after MCAO, at least in part via suppressing pyroptosis and inflammation.
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Affiliation(s)
- Yu-Bin Liang
- Department of 2nd Bain Science Center and Stroke Center, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China; Department of Neurology and Stroke Center, The First Affiliated Hospital with Jinan University, Guangzhou, China; Geriatric Medicine Institute of Panyu District, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China
| | - Ri-Xin Luo
- Department of 2nd Bain Science Center and Stroke Center, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China; Geriatric Medicine Institute of Panyu District, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhen Lu
- Postgraduate Cultivation Base of Guangzhou University of Chinese Medicine, Panyu Central Hospital, Guangzhou, China
| | - Ying Mao
- Zunyi Medical University, Zhuhai Campus, Zhuhai, Guangdong 519,041, China
| | - Ping-Ping Song
- Department of Neurology and Stroke Center, The First Affiliated Hospital with Jinan University, Guangzhou, China
| | - Qiao-Wei Li
- Department of 2nd Bain Science Center and Stroke Center, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China; Geriatric Medicine Institute of Panyu District, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhi-Qiang Peng
- Department of 2nd Bain Science Center and Stroke Center, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China; Geriatric Medicine Institute of Panyu District, The Affiliated Panyu Central Hospital, Guangzhou Medical University, Guangzhou, China; Postgraduate Cultivation Base of Guangzhou University of Chinese Medicine, Panyu Central Hospital, Guangzhou, China.
| | - Yu-Sheng Zhang
- Department of Neurology and Stroke Center, The First Affiliated Hospital with Jinan University, Guangzhou, China.
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Lesiak A, Wodz K, Ceryn J, Sobolewska-Sztychny D, Bednarski I, Piekarski J, Pabianek M, Nejc D, Dróżdż I, Narbutt J, Noweta M, Ciążyńska M. New insight into the role of the pathway NLRP1 and NLRP3 inflammasomes and IL-33 in ultraviolet-induced cutaneous carcinogenesis. Front Med (Lausanne) 2025; 11:1483208. [PMID: 39839625 PMCID: PMC11747519 DOI: 10.3389/fmed.2024.1483208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 12/17/2024] [Indexed: 01/23/2025] Open
Abstract
Introduction Inflammasomes NLRP1 (NLR family pyrin domain containing 1) and NLRP3 are pivotal regulators of the innate immune response, activated by a spectrum of endogenous and exogenous stressors, including ultraviolet radiation (UVR). The precise molecular mechanisms underlying the activation of these inflammasomes remain unclear. Furthermore, the involvement of interleukin-33 (IL-33) in UVR-induced skin carcinogenesis is not well defined. Purpose The objective of this study is to evaluate the expression of interleukin genes (IL-33, IL-18, IL-1β) following the activation and silencing of NLRP1 and NLRP3 at various wavelengths and doses of UV radiation, and to correlate these expressions with pertinent tumor markers (e.g., Gli1, Gli2, FOXO3A, SerpinA1, SerpinA3, and EphB2). Methods and materials Cultures of keratinocyte cell lines were exposed to varying doses of UV radiation using specific lamps. To inhibit the expression of NLRP1 and NLRP3 genes, cells were transfected with targeted siRNAs. Gene expression of inflammasome components and effector proteins was quantified using Real-time PCR and ELISA. Results There was a marked upregulation in the expression levels of cytokine genes IL-18, IL-1β, and IL-33 upon exposure to UVB and UVA radiation, compared to non-irradiated keratinocytes. Silencing NLRP1 or NLRP3 via RNA interference in primary human keratinocytes resulted in a significant reduction of cytokine gene expression. Additionally, a notable increase in tumor marker gene expression was observed in cells with functional NLRP1 and NLRP3 following UV radiation, whereas silencing these inflammasome genes altered the expression profiles of these markers. Conclusion This study provides a pioneering comprehensive assessment of the roles of NLRP1, NLRP3, and IL-33 in the pathogenesis of UV-induced cutaneous carcinogenesis. Our findings substantiate the role of IL-33 as a critical early danger signal elicited in response to inflammatory UV radiation, presumably regulated by inflammasomes.
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Affiliation(s)
- Aleksandra Lesiak
- Department of Dermatology, Paediatric Dermatology and Oncology, Medical University of Łódź, Łódź, Poland
- Laboratory of Autoinflammatory, Genetic and Rare Skin Disorders Medical University of Łódź, Łódź, Poland
| | - Karolina Wodz
- Laboratory of Molecular Biology, Vet-Lab Brudzew, Brudzew, Poland
| | - Justyna Ceryn
- Department of Dermatology, Paediatric Dermatology and Oncology, Medical University of Łódź, Łódź, Poland
| | - Dorota Sobolewska-Sztychny
- Department of Dermatology, Paediatric Dermatology and Oncology, Medical University of Łódź, Łódź, Poland
- Laboratory of Autoinflammatory, Genetic and Rare Skin Disorders Medical University of Łódź, Łódź, Poland
| | - Igor Bednarski
- Department of Neurology, Medical University of Lodz, Łódź, Poland
| | - Janusz Piekarski
- Department of Surgical Oncology, Central Teaching Hospital of the Medical University of Lodz, Łódź, Poland
| | - Marta Pabianek
- Chemotherapy Sub-Department and One-Day Chemotherapy Department, Specialist Oncological Hospital NU-MED sp. z o. o., Tomaszów Mazowiecki, Poland
| | - Dariusz Nejc
- Department of Surgical Oncology, Central Teaching Hospital of the Medical University of Lodz, Łódź, Poland
| | - Izabela Dróżdż
- Department of Clinical Genetics, Medical University of Lodz, Łódź, Poland
| | - Joanna Narbutt
- Department of Dermatology, Paediatric Dermatology and Oncology, Medical University of Łódź, Łódź, Poland
| | - Marcin Noweta
- Department of Dermatology, Paediatric Dermatology and Oncology, Medical University of Łódź, Łódź, Poland
| | - Magdalena Ciążyńska
- Department of Dermatology, Paediatric Dermatology and Oncology, Medical University of Łódź, Łódź, Poland
- Chemotherapy Sub-Department and One-Day Chemotherapy Department, Specialist Oncological Hospital NU-MED sp. z o. o., Tomaszów Mazowiecki, Poland
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Xie J, Idris A, Feng R. The complex interplay between encephalomyocarditis virus and the host defence system. Virulence 2024; 15:2383559. [PMID: 39066684 PMCID: PMC11285270 DOI: 10.1080/21505594.2024.2383559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 07/13/2024] [Accepted: 07/18/2024] [Indexed: 07/30/2024] Open
Abstract
A variety of animals can be infected by encephalomyocarditis virus (EMCV). EMCV is the established causative agent of myocarditis and encephalitis in some animals. EMCV causes high fatality in suckling and weaning piglets, making pigs the most susceptible domestic animal species. Importantly, EMCV has zoonotic potential to infect the human population. The ability of the pathogen to avoid and undermine the initial defence mechanism of the host contributes to its virulence and pathogenicity. A large body of literature highlights the intricate strategies employed by EMCV to escape the innate immune machinery to suit its "pathogenic needs." Here, we also provide examples on how EMCV interacts with certain host proteins to dampen the infection process. Hence, this concise review aims to summarize these findings in a compendium of decades of research on this exciting yet underappreciated topic.
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Affiliation(s)
- Jingying Xie
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China
- College of Life Science and Engineering, Northwest Minzu University, Lanzhou, China
| | - Adi Idris
- Centre for Immunology and Infection Control, School of Biomedical Sciences, Queensland University of Technology, QLD, Australia
- Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia
| | - Ruofei Feng
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China
- Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University, Lanzhou, China
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Taru V, Szabo G, Mehal W, Reiberger T. Inflammasomes in chronic liver disease: Hepatic injury, fibrosis progression and systemic inflammation. J Hepatol 2024; 81:895-910. [PMID: 38908436 PMCID: PMC11881887 DOI: 10.1016/j.jhep.2024.06.016] [Citation(s) in RCA: 37] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 05/23/2024] [Accepted: 06/17/2024] [Indexed: 06/24/2024]
Abstract
Chronic liver disease leads to hepatocellular injury that triggers a pro-inflammatory state in several parenchymal and non-parenchymal hepatic cell types, ultimately resulting in liver fibrosis, cirrhosis, portal hypertension and liver failure. Thus, an improved understanding of inflammasomes - as key molecular drivers of liver injury - may result in the development of novel diagnostic or prognostic biomarkers and effective therapeutics. In liver disease, innate immune cells respond to hepatic insults by activating cell-intrinsic inflammasomes via toll-like receptors and NF-κB, and by releasing pro-inflammatory cytokines (such as IL-1β, IL-18, TNF-α and IL-6). Subsequently, cells of the adaptive immune system are recruited to fuel hepatic inflammation and hepatic parenchymal cells may undergo gasdermin D-mediated programmed cell death, termed pyroptosis. With liver disease progression, there is a shift towards a type 2 inflammatory response, which promotes tissue repair but also fibrogenesis. Inflammasome activation may also occur at extrahepatic sites, such as the white adipose tissue in MASH (metabolic dysfunction-associated steatohepatitis). In end-stage liver disease, flares of inflammation (e.g., in severe alcohol-related hepatitis) that spark on a dysfunctional immune system, contribute to inflammasome-mediated liver injury and potentially result in organ dysfunction/failure, as seen in ACLF (acute-on-chronic liver failure). This review provides an overview of current concepts regarding inflammasome activation in liver disease progression, with a focus on related biomarkers and therapeutic approaches that are being developed for patients with liver disease.
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Affiliation(s)
- Vlad Taru
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Iuliu Hatieganu University of Medicine and Pharmacy, 4(th) Dept. of Internal Medicine, Cluj-Napoca, Romania
| | - Gyongyi Szabo
- Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
| | - Wajahat Mehal
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA; West Haven Veterans Medical Center, West Haven, CT, USA.
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Center for Molecular Medicine (CeMM) of the Austrian Academy of Science, Vienna, Austria
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11
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Takenouchi T, Masujin K, Ikeda R, Haraguchi S, Suzuki S, Uenishi H, Onda E, Kokuho T. Establishment and characterization of an immortalized red river hog blood-derived macrophage cell line. Front Immunol 2024; 15:1465952. [PMID: 39324137 PMCID: PMC11422137 DOI: 10.3389/fimmu.2024.1465952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 08/26/2024] [Indexed: 09/27/2024] Open
Abstract
Red river hogs (RRHs) (Potamochoerus porcus), a wild species of Suidae living in Africa with a major distribution in the Guinean and Congolian forests, are natural reservoirs of African swine fever virus (ASFV) and typically are asymptomatic. Since blood and tissue macrophages of suid animals are target cell lineages of ASFV, RRH-derived macrophages are expected to play an important role in suppressing disease development in infected individuals. In the present study, we successfully isolated RRH-derived blood macrophages using co-culture techniques of RRH blood cells with porcine kidney-derived feeder cells and immortalized them by transferring SV40 large T antigen and porcine telomerase reverse transcriptase genes. The newly established macrophage cell line of the RRH-derived blood cell origin (RZJ/IBM) exhibited an Iba1-, CD172a-, and CD203a-positive typical macrophage-like phenotype and up-regulated the phosphorylation of nuclear factor-κB p65 subunit and p38 mitogen-activated protein kinase in response to the bacterial cell wall components, lipopolysaccharide (LPS) and muramyl dipeptide. In addition, RZJ/IBM cells produced the precursor form of interleukin (IL)-1β and IL-18 upon a stimulation with LPS, leading to the conversion of IL-18, but not IL-1β, into the mature form. Time-lapse live cell imaging with pHrodo dye-conjugated Escherichia coli BioParticles demonstrated the phagocytotic activity of RZJ/IBM cells. It is important to note that RZJ/IBM cells are clearly susceptible to ASFV infection and support viral replication in vitro. Therefore, the RZJ/IBM cell line provides a unique model for investigating the pathogenesis of ASFV.
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Affiliation(s)
- Takato Takenouchi
- Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Japan
| | - Kentaro Masujin
- Division of Transboundary Animal Disease Research, National Institute of Animal Health, National Agriculture and Food Research Organization, Kodaira, Japan
| | - Rina Ikeda
- Kyusyu Research Station, National Institute of Animal Health, National Agriculture and Food Research Organization, Kagoshima, Japan
| | - Seiki Haraguchi
- Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Japan
| | - Shunichi Suzuki
- Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Japan
| | - Hirohide Uenishi
- Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Japan
| | - Eiji Onda
- Yokohama Zoological Gardens, ZOORASIA, Yokohama, Japan
| | - Takehiro Kokuho
- Division of Transboundary Animal Disease Research, National Institute of Animal Health, National Agriculture and Food Research Organization, Kodaira, Japan
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12
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Biadun M, Sochacka M, Kalka M, Chorazewska A, Karelus R, Krowarsch D, Opalinski L, Zakrzewska M. Uncovering key steps in FGF12 cellular release reveals a common mechanism for unconventional FGF protein secretion. Cell Mol Life Sci 2024; 81:356. [PMID: 39158730 PMCID: PMC11335280 DOI: 10.1007/s00018-024-05396-9] [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: 06/11/2024] [Revised: 08/03/2024] [Accepted: 08/04/2024] [Indexed: 08/20/2024]
Abstract
FGF12 belongs to a subfamily of FGF proteins called FGF homologous factors (FHFs), which until recently were thought to be non-signaling intracellular proteins. Our recent studies have shown that although they lack a conventional signal peptide for secretion, they can reach the extracellular space, especially under stress conditions. Here, we unraveled that the long "a" isoform of FGF12 is secreted in a pathway involving the A1 subunit of Na(+)/K(+) ATPase (ATP1A1), Tec kinase and lipids such as phosphatidylinositol and phosphatidylserine. Further, we showed that the short "b" isoform of FGF12, which binds ATP1A1 and phosphatidylserine less efficiently, is not secreted from cells. We also indicated regions in the FGF12a protein sequence that are crucial for its secretion, including N-terminal fragment and specific residues, and proposed that liquid-liquid phase separation may be important in this process. Our results strongly suggest that the mechanism of this process is very similar for all unconventionally secreted FGF proteins.
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Affiliation(s)
- Martyna Biadun
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw, 50-383, Poland
| | - Martyna Sochacka
- Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw, 50-383, Poland
| | - Marta Kalka
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw, 50-383, Poland
| | - Aleksandra Chorazewska
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw, 50-383, Poland
| | - Radoslaw Karelus
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw, 50-383, Poland
| | - Daniel Krowarsch
- Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw, 50-383, Poland
| | - Lukasz Opalinski
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw, 50-383, Poland
| | - Malgorzata Zakrzewska
- Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, Wroclaw, 50-383, Poland.
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13
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Xu H, Qin K, Hao K, Yuan Z, Sun L. Pufferfish gasdermin Ea is a significant player in the defense against bacterial pathogens. MARINE LIFE SCIENCE & TECHNOLOGY 2024; 6:462-474. [PMID: 39219679 PMCID: PMC11358365 DOI: 10.1007/s42995-024-00237-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 05/31/2024] [Indexed: 09/04/2024]
Abstract
Gasdermins (GSDMs) are proteins cleaved by caspase (CASP) to trigger pyroptosis. In teleosts, pyroptosis is mediated by gasdermin E (GSDME). The Pufferfish, Takifugu rubripes, possesses two GSDME orthologs: named TrGSDMEa and TrGSDMEb. TrGSDMEa is cleaved by CASP3/7 to liberate the N-terminal (NT) domain that can trigger pyroptosis in mammalian cells. However, the biological function of TrGSDMEa in pufferfish is unknown, and TrGSDMEb is poorly studied. We found that TrGSDMEb was cleaved by CASP1/3/6/7/8, but the resulting NT domain, despite its similarity to TrGSDMEa-NT domain in sequence and structure, failed to induce pyroptosis. TrGSDMEa and TrGSDMEb exhibited similar expression patterns in pufferfish under normal physiological conditions but were up- and downregulated, respectively, in expression during Vibrio harveyi and Edwardsiella tarda infection. Bacterial infection induced the activation of TrGSDMEa and CASP3/7 in pufferfish cells, resulting in pyroptosis accompanied with IL-1β production and maturation. Inhibition of TrGSDMEa-mediated pyroptosis via TrCASP3/7 reduced the death of pufferfish cells and augmented bacterial dissemination in fish tissues. Structure-oriented mutagenesis identified 16 conserved residues in teleost GSDMEa that were required for the pore formation or auto-inhibition of GSDMEa. This study illustrates the role of GSDMEa-mediated pyroptosis in teleost defense against bacterial pathogens and provides new insights into the structure-based function of vertebrate GSDME. Supplementary Information The online version contains supplementary material available at 10.1007/s42995-024-00237-x.
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Affiliation(s)
- Hang Xu
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, CAS Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071 China
- Laboratory for Marine Biology and Biotechnology, Laoshan Laboratory, Qingdao, 266237 China
- School of Marine Science, University of Chinese Academy of Sciences, Qingdao, 266400 China
| | - Kunpeng Qin
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, CAS Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071 China
- Laboratory for Marine Biology and Biotechnology, Laoshan Laboratory, Qingdao, 266237 China
- School of Marine Science, University of Chinese Academy of Sciences, Qingdao, 266400 China
| | - Kangwei Hao
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, CAS Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071 China
- Laboratory for Marine Biology and Biotechnology, Laoshan Laboratory, Qingdao, 266237 China
- School of Marine Science, University of Chinese Academy of Sciences, Qingdao, 266400 China
| | - Zihao Yuan
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, CAS Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071 China
- Laboratory for Marine Biology and Biotechnology, Laoshan Laboratory, Qingdao, 266237 China
- School of Marine Science, University of Chinese Academy of Sciences, Qingdao, 266400 China
| | - Li Sun
- CAS and Shandong Province Key Laboratory of Experimental Marine Biology, Institute of Oceanology, CAS Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, 266071 China
- Laboratory for Marine Biology and Biotechnology, Laoshan Laboratory, Qingdao, 266237 China
- School of Marine Science, University of Chinese Academy of Sciences, Qingdao, 266400 China
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Abstract
Inflammasomes are supramolecular complexes that form in the cytosol in response to pathogen-associated and damage-associated stimuli, as well as other danger signals that perturb cellular homoeostasis, resulting in host defence responses in the form of cytokine release and programmed cell death (pyroptosis). Inflammasome activity is closely associated with numerous human disorders, including rare genetic syndromes of autoinflammation, cardiovascular diseases, neurodegeneration and cancer. In recent years, a range of inflammasome components and their functions have been discovered, contributing to our knowledge of the overall machinery. Here, we review the latest advances in inflammasome biology from the perspective of structural and mechanistic studies. We focus on the most well-studied components of the canonical inflammasome - NAIP-NLRC4, NLRP3, NLRP1, CARD8 and caspase-1 - as well as caspase-4, caspase-5 and caspase-11 of the noncanonical inflammasome, and the inflammasome effectors GSDMD and NINJ1. These structural studies reveal important insights into how inflammasomes are assembled and regulated, and how they elicit the release of IL-1 family cytokines and induce membrane rupture in pyroptosis.
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Affiliation(s)
- Jianing Fu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Kate Schroder
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia
| | - Hao Wu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
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15
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Hegde A, Ghosh S, Ananthan ASHP, Kataria S, Dutta A, Prabhu S, Khedkar SU, Dutta A, Jamora C. Extracellular Caspase-1 induces hair stem cell migration in wounded and inflamed skin conditions. J Cell Biol 2024; 223:e202306028. [PMID: 38587472 PMCID: PMC11001599 DOI: 10.1083/jcb.202306028] [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: 06/07/2023] [Revised: 12/18/2023] [Accepted: 03/25/2024] [Indexed: 04/09/2024] Open
Abstract
The wound-healing process is a paradigm of the directed migration of various pools of stem cells from their niche to the site of injury where they replenish damaged cells. Two decades have elapsed since the observation that wounding activates multipotent hair follicle stem cells to infiltrate the epidermis, but the cues that coax these cells out of their niche remain unknown. Here, we report that Caspase-1, a protein classically known as an integral component of the cytosolic inflammasome, is secreted upon wounding and has a non-canonical role in the extracellular milieu. Through its caspase activation recruitment domain (CARD), Caspase-1 is sufficient to initiate the migration of hair follicle stem cells into the epidermis. Uncovering this novel function of Caspase-1 also facilitates a deeper understanding of the mechanistic basis of the epithelial hyperplasia found to accompany numerous inflammatory skin diseases.
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Affiliation(s)
- Akshay Hegde
- IFOM-inStem Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
- School of Chemical and Biotechnology (SCBT), Shanmugha Arts, Science, Technology and Research Academy (SASTRA), Deemed to be University, Thanjavur, India
| | - Subhasri Ghosh
- IFOM-inStem Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
| | - Akhil SHP Ananthan
- IFOM-inStem Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
| | - Sunny Kataria
- IFOM-inStem Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
| | - Abhik Dutta
- IFOM-inStem Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
- School of Chemical and Biotechnology (SCBT), Shanmugha Arts, Science, Technology and Research Academy (SASTRA), Deemed to be University, Thanjavur, India
| | - Srilekha Prabhu
- IFOM-inStem Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
| | - Sneha Uday Khedkar
- IFOM-inStem Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
| | - Anupam Dutta
- IFOM-inStem Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
| | - Colin Jamora
- IFOM-inStem Joint Research Laboratory, Centre for Inflammation and Tissue Homeostasis, Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
- FIRC Institute of Molecular Oncology, Milan, Italy
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16
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Fan SY, Zhao ZC, Liu XL, Peng YG, Zhu HM, Yan SF, Liu YJ, Xie Q, Jiang Y, Zeng SZ. Metformin Mitigates Sepsis-Induced Acute Lung Injury and Inflammation in Young Mice by Suppressing the S100A8/A9-NLRP3-IL-1β Signaling Pathway. J Inflamm Res 2024; 17:3785-3799. [PMID: 38895139 PMCID: PMC11182881 DOI: 10.2147/jir.s460413] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Background Globally, the subsequent complications that accompany sepsis result in remarkable morbidity and mortality rates. The lung is among the vulnerable organs that incur the sepsis-linked inflammatory storm and frequently culminates into ARDS/ALI. The metformin-prescribed anti-diabetic drug has been revealed with anti-inflammatory effects in sepsis, but the underlying mechanisms remain unclear. This study aimed to ascertain metformin's effects and functions in a young mouse model of sepsis-induced ALI. Methods Mice were randomly divided into 4 groups: sham, sham+ Met, CLP, and CLP+ Met. CLP was established as the sepsis-induced ALI model accompanied by intraperitoneal metformin treatment. At day 7, the survival state of mice was noted, including survival rate, weight, and M-CASS. Lung histological pathology and injury scores were determined by hematoxylin-eosin staining. The pulmonary coefficient was used to evaluate pulmonary edema. Furthermore, IL-1β, CCL3, CXCL11, S100A8, S100A9 and NLRP3 expression in tissues collected from lungs were determined by qPCR, IL-1β, IL-18, TNF-α by ELISA, caspase-1, ASC, NLRP3, P65, p-P65, GSDMD-F, GSDMD-N, IL-1β and S100A8/A9 by Western blot. Results The data affirmed that metformin enhanced the survival rate, lessened lung tissue injury, and diminished the expression of inflammatory factors in young mice with sepsis induced by CLP. In contrast to sham mice, the CLP mice were affirmed to manifest ALI-linked pathologies following CLP-induced sepsis. The expressions of pro-inflammatory factors, for instance, IL-1β, IL-18, TNF-α, CXCL11, S100A8, and S100A9 are markedly enhanced by CLP, while metformin abolished this adverse effect. Western blot analyses indicated that metformin inhibited the sepsis-induced activation of GSDMD and the upregulation of S100A8/A9, NLRP3, and ASC. Conclusion Metformin could improve the survival rate, lessen lung tissue injury, and minimize the expression of inflammatory factors in young mice with sepsis induced by CLP. Metformin reduced sepsis-induced ALI via inhibiting the NF-κB signaling pathway and inhibiting pyroptosis by the S100A8/A9-NLRP3-IL-1β pathway.
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Affiliation(s)
- Shi-Yuan Fan
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People’s Hospital), Changsha, Hunan, 410005, People’s Republic of China
| | - Zi-Chi Zhao
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People’s Hospital), Changsha, Hunan, 410005, People’s Republic of China
| | - Xing-Lv Liu
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People’s Hospital), Changsha, Hunan, 410005, People’s Republic of China
| | - Ying-Gang Peng
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People’s Hospital), Changsha, Hunan, 410005, People’s Republic of China
| | - Hui-Min Zhu
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People’s Hospital), Changsha, Hunan, 410005, People’s Republic of China
| | - Shi-Fan Yan
- Department of Emergency, Institute of Emergency Medicine, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, People’s Republic of China
| | - Yan-Juan Liu
- Department of Emergency, Institute of Emergency Medicine, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, People’s Republic of China
| | - Qin Xie
- Department of Emergency, Institute of Emergency Medicine, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, People’s Republic of China
| | - Yu Jiang
- Department of Emergency, Institute of Emergency Medicine, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan, 410005, People’s Republic of China
| | - Sai-Zhen Zeng
- The First Affiliated Hospital of Hunan Normal University (Hunan Provincial People’s Hospital), Changsha, Hunan, 410005, People’s Republic of China
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Liang W, Wei R, Zhu X, Li J, Lin A, Chen J, Wu W, Jie Q. Downregulation of HMGB1 carried by macrophage-derived extracellular vesicles delays atherosclerotic plaque formation through Caspase-11-dependent macrophage pyroptosis. Mol Med 2024; 30:38. [PMID: 38493291 PMCID: PMC10943908 DOI: 10.1186/s10020-023-00753-z] [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: 04/02/2023] [Accepted: 11/02/2023] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Macrophage-derived extracellular vesicle (macrophage-EV) is highly studied for its regulatory role in atherosclerosis (AS). Our current study tried to elucidate the possible role of macrophage-EV loaded with small interfering RNA against high-mobility group box 1 (siHMGB1) affecting atherosclerotic plaque formation. METHODS In silico analysis was performed to find critical factors in mouse atherosclerotic plaque formation. EVs secreted by RAW 264.7 cells were collected by ultracentrifugation and characterized, followed by the preparation of macrophage-EV-loaded siHMGB1 (macrophage-EV/siHMGB1). ApoE-/- mice were used to construct an AS mouse model by a high-fat diet, followed by injection of macrophage-EV/siHMGB1 to assess the in vivo effect of macrophage-EV/siHMGB1 on AS mice. RAW264.7 cells were subjected to ox-LDL, LPS or macrophage-EV/siHMGB1 for analyzing the in vitro effect of macrophage-EV/siHMGB1 on macrophage pyrophosis and inflammation. RESULTS In silico analysis found that HMGB1 was closely related to the development of AS. Macrophage-EV/siHMGB could inhibit the release of HMGB1 from macrophages to outside cells, and the reduced HMGB1 release could inhibit foam cell formation. Besides, macrophage-EV/siHMGB also inhibited the LPS-induced Caspase-11 activation, thus inhibiting macrophage pyroptosis and preventing atherosclerotic plaque formation. CONCLUSION Our results proved that macrophage-EV/siHMGB could inhibit foam cell formation and suppress macrophage pyroptosis, finally preventing atherosclerotic plaque formation in AS mice.
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Affiliation(s)
- Weijie Liang
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China
| | - Ruibin Wei
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China
| | - Xingxing Zhu
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China
| | - Jinliang Li
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China
| | - Aiwen Lin
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China
| | - Jun Chen
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China
| | - Wen Wu
- Department of Endocrinology, Guangdong Geriatrics Institute, Guangdong Academy of Medical Sciences, Guangdong Provincial People's Hospital, No. 106, Zhongshan Second Road, Yuexiu District, Guangzhou, 510080, Guangdong Province, People's Republic of China.
| | - Qiang Jie
- Department of Cardiology, Panyu Central Hospital, Cardiovascular Institute of Panyu District, No. 8, Fuyu East Road, Qiaonan Street, Panyu District, Guangzhou, 511400, Guangdong Province, People's Republic of China.
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Zhao Z, Zhang Y, Luo B. The role of pyroptosis in viral infection. Arch Virol 2024; 169:69. [PMID: 38456965 DOI: 10.1007/s00705-024-05978-9] [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: 09/07/2023] [Accepted: 12/17/2023] [Indexed: 03/09/2024]
Abstract
Pyroptosis, also known as inflammatory necrosis, is a form of programmed cell death, which is an important natural immune response. Pyroptosis plays a major role in combating pathogenic infections. The mechanism of pyroptosis is distinct from other forms of cell death and is characterized by its dependence on inflammatory caspases (mainly caspases 1, 4, 5, and 11). Activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammatory vesicles is involved in caspase-1 activation and cleavage, which in turn triggers cleavage and multimerization of multiple gasdermin family members, including gasdermin-D (GSDMD). This further leads to cell perforation and cellular distension, causing cell membrane rupture, resulting in a massive efflux of cell contents, which triggers inflammatory reactions. In recent years, detailed study of viral diseases, has demonstrated that pyroptosis is closely associated with the development of viral diseases. This article focuses on the mechanism of pyroptosis and the connection between pyroptosis and viral infection.
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Affiliation(s)
- Zhen Zhao
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Yan Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
- Department of Clinical Laboratory, Zibo Central Hospital, Zibo, 255036, China.
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
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19
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Huang L, Kim JH, You L, Park SH, Zhang J, Shin CY, Sutopo NC, Byun HW, Omaliss K, Masphal K, Son J, Kim GR, Lee BH, Kim JH, Lee J, Cho JY. Anti-oxidative, anti-apoptotic, and anti-inflammatory activities of Connarus semidecandrus Jack ethanol extract in UVB-irradiated human keratinocytes. JOURNAL OF ETHNOPHARMACOLOGY 2024; 321:117574. [PMID: 38097025 DOI: 10.1016/j.jep.2023.117574] [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: 08/07/2023] [Revised: 12/07/2023] [Accepted: 12/08/2023] [Indexed: 12/19/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Connarus semidecandrus Jack (Family: connaraceae) is a medicinal plant known for its wide distribution throughout Southeast Asia. Renowned for its diverse therapeutic properties, it has been traditionally used for treating fever, skin irritation, and colic. AIM OF THE STUDY Numerous individuals suffer from skin issues, including wrinkles, hyperpigmentation, and inflammation, due to environmental factors. Although many drugs are available to treat skin problems, chemical drugs have many shortcomings and side effects. Therefore, natural products are attractive potential medicines for alleviating skin troubles. We recently showed that Connarus semidecandrus Jack ethanol extract (Cs-EE) has anti-alopecia potential. This paper aims to explore the potential skin-protective effects and underlying molecular mechanisms of Connarus semidecandrus Jack in UVB-induced human keratinocytes (HaCaT). MATERIALS AND METHODS Before utilization, Cs-EE was dissolved in dimethyl sulfoxide (DMSO) and was preserved at a temperature of -20 °C. The phytochemical constituents of Cs-EE were detected by gas chromatography-mass spectrometry analysis (GC-MS). Sequentially, HaCaT cells were exposed to varying concentrations of Cs-EE prior to ultraviolet B (UVB) irradiation. Evaluations of cellular responses in HaCaT cells, including assessments of cell viability, deoxyribonucleic acid (DNA) damage, and gene and protein expressions, were carried out. To explore the specific signaling pathway involved, we conducted a luciferase assay in addition to validating these pathways using Western blot analysis. RESULTS Nitric oxide (NO) and intracellular reactive oxygen species were decreased. Melanin production through the activation of melanocytes by α-melanocyte-stimulating hormone (MSH) was also inhibited by Cs-EE. Furthermore, the mRNA expression levels of key factors such as cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), MMP-1, MMP-3, and MMP-9 exhibited a remarkable decrease. In addition, the phosphorylation of TAK1 within the signaling cascade exhibited a decline, and the activities of the transcription factor AP-1 were decreased according to a luciferase reporter assay. CONCLUSIONS Taken together, these findings suggest that the anti-inflammatory, anti-aging, and anti-apoptotic effects of Cs-EE indicate the compound's potential usefulness as a natural component in pharmaceutical and cosmetic products.
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Affiliation(s)
- Lei Huang
- Department of Biocosmetics, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Ji Hye Kim
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Long You
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Sang Hee Park
- Department of Biocosmetics, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Jianmei Zhang
- Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Chae Yun Shin
- Department of Biocosmetics, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | | | - Hye-Woo Byun
- Biodiversity Research and Cooperation Division, National Institute of Biological Resources, Incheon, 22689, Republic of Korea.
| | - Keo Omaliss
- Forestry Administration, Ministry of Agriculture Forestry and Fisheries, #40 Norodom Blvd, Daun Penh, Phnom Penh, 12205, Cambodia.
| | - Kry Masphal
- Forestry Administration, Ministry of Agriculture Forestry and Fisheries, #40 Norodom Blvd, Daun Penh, Phnom Penh, 12205, Cambodia.
| | - Jino Son
- Biological and Genetic Resources Assessment Division, National Institute of Biological Resources, Incheon, 22689, Republic of Korea.
| | - Ga Ryun Kim
- Biological and Genetic Resources Assessment Division, National Institute of Biological Resources, Incheon, 22689, Republic of Korea.
| | - Byoung-Hee Lee
- Biological and Genetic Resources Assessment Division, National Institute of Biological Resources, Incheon, 22689, Republic of Korea.
| | - Jong-Hoon Kim
- Department of Veterinary Physiology College of Medicine, Chonbuk National University, Iksan, 54596, Republic of Korea.
| | - Jongsung Lee
- Department of Biocosmetics, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Jae Youl Cho
- Department of Biocosmetics, Sungkyunkwan University, Suwon, 16419, Republic of Korea; Department of Integrative Biotechnology and Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon, 16419, Republic of Korea.
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Xin Y, Li X, Ping K, Xiang Y, Li M, Li X, Yang H, Dong J. Pesticide avermectin-induced hepatotoxicity and growth inhibition in carp: Ameliorative capacity and potential mechanisms of quercetin as a dietary additive. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2024; 268:106859. [PMID: 38342007 DOI: 10.1016/j.aquatox.2024.106859] [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: 08/27/2023] [Revised: 02/02/2024] [Accepted: 02/03/2024] [Indexed: 02/13/2024]
Abstract
Flavonoid quercetin (QUE) has biological activities of anti-oxidation, anti-inflammation and anti-apoptosis, however, its protective effects against avermectin (AVM) induced liver toxicity in carp remains unclear. The objective of this research is to explore the biologically potent effects of QUE in AVM-induced hepatotoxicity in carp and its underlying mechanism. Therefore, we established a liver injury model in carp induced by AVM to evaluate QUE against AVM induced liver toxicity in carp. In this investigation, AVM dosage was determined as 2.404 μg/L for both groups, and an experimentation of 30 days duration was carried out. Various methods including hematoxylin and eosin (H&E) staining, biochemical kits, real-time quantitative PCR (qRT-PCR), western blotting, TUNEL, reactive oxygen species (ROS) staining, immunofluorescence (Hoseinifar, et al.,), and oil red O staining were used in this study. Results showed that the growth inhibition of carp was relieved in the QUE treatment group comparing to the AVM group. In the QUE treatment group, there was a significant decrease in the levels of ALT and AST in carp liver tissue. Additionally, the histopathological damage and lipid accumulation were alleviated compared to the AVM group. Moreover, QUE prevented AVM induced decrease in the activities of antioxidant enzymes of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), glutathione (GSH), catalase (CAT) and the accumulation of reactive oxygen species (ROS), but reduced accumulation of malondialdehyde (MDA). In addition, the mRNA levels of liver pro-inflammatory factors of tumor necrosis factor-α (TNF-α), interleukin-1β (iL-1β), interleukin-6 (iL-6), interleukin-10 (iL-10) and the protein levels of NOD-like receptor protein 3 (NLRP3) inflammasome were significantly down-regulated in the QUE treatment group in comparison to the AVM group. We also found that QUE could affect the expression of Bcl2-associated x (Bax), B-cell lymphoma-2 (Bcl-2), cleaved-cysteinyl aspartate specific proteinase (CCaspase3) key apoptotic proteins and TUNEL-labeled apoptotic hepatocytes by regulating SIRT1/FOXO3a signal pathway. In summary, QUE alleviated the growth inhibition, liver oxidative damage, lipid accumulation, inflammatory response, and apoptosis of carp induced by AVM. QUE is a potential protective agent against liver injury induced by AVM in carp.
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Affiliation(s)
- Yue Xin
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Xueqing Li
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Kaixin Ping
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Yannan Xiang
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Mengxin Li
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Xing Li
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Haitao Yang
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China
| | - Jingquan Dong
- Jiangsu Key Laboratory of Marine Bioresources and Environment, Co-Innovation Center of Jiangsu Marine Bio-industry Technology, Jiangsu Marine Pharmaceutical Resources Development Engineering Research Center, Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, School of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China.
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Schroeder HT, De Lemos Muller CH, Heck TG, Krause M, Homem de Bittencourt PI. Heat shock response during the resolution of inflammation and its progressive suppression in chronic-degenerative inflammatory diseases. Cell Stress Chaperones 2024; 29:116-142. [PMID: 38244765 PMCID: PMC10939074 DOI: 10.1016/j.cstres.2024.01.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 01/22/2024] Open
Abstract
The heat shock response (HSR) is a crucial biochemical pathway that orchestrates the resolution of inflammation, primarily under proteotoxic stress conditions. This process hinges on the upregulation of heat shock proteins (HSPs) and other chaperones, notably the 70 kDa family of heat shock proteins, under the command of the heat shock transcription factor-1. However, in the context of chronic degenerative disorders characterized by persistent low-grade inflammation (such as insulin resistance, obesity, type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular diseases) a gradual suppression of the HSR does occur. This work delves into the mechanisms behind this phenomenon. It explores how the Western diet and sedentary lifestyle, culminating in the endoplasmic reticulum stress within adipose tissue cells, trigger a cascade of events. This cascade includes the unfolded protein response and activation of the NOD-like receptor pyrin domain-containing protein-3 inflammasome, leading to the emergence of the senescence-associated secretory phenotype and the propagation of inflammation throughout the body. Notably, the activation of the NOD-like receptor pyrin domain-containing protein-3 inflammasome not only fuels inflammation but also sabotages the HSR by degrading human antigen R, a crucial mRNA-binding protein responsible for maintaining heat shock transcription factor-1 mRNA expression and stability on heat shock gene promoters. This paper underscores the imperative need to comprehend how chronic inflammation stifles the HSR and the clinical significance of evaluating the HSR using cost-effective and accessible tools. Such understanding is pivotal in the development of innovative strategies aimed at the prevention and treatment of these chronic inflammatory ailments, which continue to take a heavy toll on global health and well-being.
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Affiliation(s)
- Helena Trevisan Schroeder
- Laboratory of Cellular Physiology (FisCel), Department of Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil
| | - Carlos Henrique De Lemos Muller
- Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX), Department of Physiology, ICBS, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil
| | - Thiago Gomes Heck
- Post Graduate Program in Integral Health Care (PPGAIS-UNIJUÍ/UNICRUZ/URI), Regional University of Northwestern Rio Grande Do Sul State (UNIJUI) and Post Graduate Program in Mathematical and Computational Modeling (PPGMMC), UNIJUI, Ijuí, Rio Grande do Sul, Brazil
| | - Mauricio Krause
- Laboratory of Inflammation, Metabolism and Exercise Research (LAPIMEX), Department of Physiology, ICBS, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil
| | - Paulo Ivo Homem de Bittencourt
- Laboratory of Cellular Physiology (FisCel), Department of Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.
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22
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Balci CN, Acar N. NLRP3 inflammasome pathway, the hidden balance in pregnancy: A comprehensive review. J Reprod Immunol 2024; 161:104173. [PMID: 38043434 DOI: 10.1016/j.jri.2023.104173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 11/01/2023] [Accepted: 11/26/2023] [Indexed: 12/05/2023]
Abstract
The balance of the inflammatory response is indispensable during pregnancy. Inflammasomes are the cytosolic supramolecular protein complexes activated by pattern recognition receptors. These receptors recognize the pathogen and damage/danger-associated molecular patterns. NLRP3 inflammasome complex consists mainly of NLRP3 (leucine-rich repeat-containing and pyrin domain-containing protein 3), a cytosolic sensor molecule, ASC (apoptosis-associated speck-like protein containing a CARD) protein and a cysteine protease pro-caspase-1 as an effector molecule. This complex has a role in producing inflammatory cytokines, interleukin 1 beta and interleukin 18, and inflammasome-dependent programmed cell death pathway pyroptosis. In this review, we focused on and summarised the NLRP3 inflammasome and its roles in normal and pathological pregnancies. The NLRP3 inflammasome pathway influences endometrial receptivity and embryo invasion by inducing epithelial-mesenchymal transition. Abnormal inflammasome activation in the endometrium may adversely affect endometrial receptivity. In addition, NLRP3 inflammasome pathway overactivation may mediate the abnormal inflammatory response at the maternal-fetal interface and be associated with pregnancy complications, such as recurrent implantation failure, pregnancy loss, pre-term birth and pre-eclampsia. Therefore, targeting the NLRP3 inflammasome pathway could develop a new therapeutic approach to prevent the aforementioned pregnancy pathologies.
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Affiliation(s)
- Cemre Nur Balci
- Department of Histology and Embryology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Nuray Acar
- Department of Histology and Embryology, Faculty of Medicine, Akdeniz University, Antalya, Turkey.
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23
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Hánělová K, Raudenská M, Masařík M, Balvan J. Protein cargo in extracellular vesicles as the key mediator in the progression of cancer. Cell Commun Signal 2024; 22:25. [PMID: 38200509 PMCID: PMC10777590 DOI: 10.1186/s12964-023-01408-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 11/24/2023] [Indexed: 01/12/2024] Open
Abstract
Exosomes are small vesicles of endosomal origin that are released by almost all cell types, even those that are pathologically altered. Exosomes widely participate in cell-to-cell communication via transferring cargo, including nucleic acids, proteins, and other metabolites, into recipient cells. Tumour-derived exosomes (TDEs) participate in many important molecular pathways and affect various hallmarks of cancer, including fibroblasts activation, modification of the tumour microenvironment (TME), modulation of immune responses, angiogenesis promotion, setting the pre-metastatic niche, enhancing metastatic potential, and affecting therapy sensitivity and resistance. The unique exosome biogenesis, composition, nontoxicity, and ability to target specific tumour cells bring up their use as promising drug carriers and cancer biomarkers. In this review, we focus on the role of exosomes, with an emphasis on their protein cargo, in the key mechanisms promoting cancer progression. We also briefly summarise the mechanism of exosome biogenesis, its structure, protein composition, and potential as a signalling hub in both normal and pathological conditions. Video Abstract.
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Affiliation(s)
- Klára Hánělová
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
| | - Martina Raudenská
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
| | - Michal Masařík
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, Vestec, CZ-252 50, Czech Republic
| | - Jan Balvan
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic.
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24
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Chamanara S, Hozouri V, Irandoost E. Inhibition of NLRP3 inflammasome-A potential mechanistic therapeutic for treatment of polycystic ovary syndrome? J Biochem Mol Toxicol 2024; 38:e23592. [PMID: 38054794 DOI: 10.1002/jbt.23592] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 11/05/2023] [Accepted: 11/20/2023] [Indexed: 12/07/2023]
Abstract
This review article explores the relationship between the NOD-like receptor protein 3 (NLRP3) inflammasome and the risk of developing polycystic ovary syndrome (PCOS). The NLRP3 inflammasome, a fundamental element of the innate immune system, plays a crucial role in the production of proinflammatory mediators and pyroptosis, a type inflammatory cell death. We conducted a thorough search on scientific databases to gather relevant information on this topic, utilizing relevant keywords. The reviewed studies indicated a correlation between PCOS and a higher incidence of granulosa cell (GC) death and the presence of ovarian tissue fibrosis. NLRP3 inflammasome stimulation and subsequent pyroptosis in GCs play a significant role in the pathophysiology of PCOS. Active NLRP3 inflammasome is involved in the production of inflammatory mediators like interleukin-1β (IL-1β) and IL-18, contributing to the development of PCOS, particularly in overweight patients. Therefore, inhibiting NLRP3 activation and pyroptosis could potentially offer novel therapeutic strategies for PCOS. Some limited studies have explored the use of agents with antioxidant and anti-inflammatory properties, as well as gene therapy approaches, to target the NLRP3 and pyroptosis signaling pathways. This study overview the understanding of the relationship between NLRP3 inflammasome activation, pyroptosis, and PCOS. It highlights the potential of targeting the NLRP3 inflammasome as an approach for treating PCOS. Nonetheless, further research and clinical trials are imperative to validate these results and explore the effectiveness of NLRP3 inflammasome inhibition in the management of PCOS.
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Affiliation(s)
- Solmaz Chamanara
- Department of Gynecology and Obstetrics, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Vahid Hozouri
- Internal Medicine Department, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Elnaz Irandoost
- Department of Gynecology and Obstetrics, Tehran University of Medical Sciences, Tehran, Iran
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25
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Badr G, El-Hossary FM, Lasheen FEDM, Negm NZ, Khalaf M, Salah M, Sayed LH, Abdel-Maksoud MA, Elminshawy A. Cold atmospheric plasma induces the curing mechanism of diabetic wounds by regulating the oxidative stress mediators iNOS and NO, the pyroptotic mediators NLRP-3, Caspase-1 and IL-1β and the angiogenesis mediators VEGF and Ang-1. Biomed Pharmacother 2023; 169:115934. [PMID: 38000357 DOI: 10.1016/j.biopha.2023.115934] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/12/2023] [Accepted: 11/21/2023] [Indexed: 11/26/2023] Open
Abstract
It has been demonstrated that cold atmospheric plasma (CAP) accelerates the wound healing process, however the underlying molecular pathways behind this effect remain unclear. Thus, the goal of the proposed investigation is to elucidate the therapeutic advantages of CAP on angiogenesis, pyroptotic, oxidative stress, and inflammatory mediators during the wound-healing mechanisms associated with diabetes. Intraperitoneal administration of streptozotocin (STZ, 60 mg/Kg) of body weight was used to induce type-1 diabetes. Seventy-five male mice were randomized into 3 groups: the control non-diabetic group, the diabetic group that was not treated, and the diabetic group that was treated with CAP. The key mediators of pyroptosis and its impact on the slow healing process of diabetic wounds were examined using histological investigations employing H&E staining, immunohistochemistry, ELISA, and Western blotting analysis. Angiogenesis proteins (VEGF, Ang-1, and HO-1) showed a significant decline in expression concentrations in the diabetic wounds, indicating that diabetic animals' wounds were less likely to heal. Furthermore, compared to the controls, the major mediators of pyroptosis (NLRP-3, IL-1β, and caspase-1), oxidative stress (iNOS and NO), and inflammation (TNF-α and IL-6) have higher expression levels in the diabetic wounds. These factors substantially impede the healing mechanism of diabetic wounds. Interestingly, our results disclosed the therapeutic impacts of CAP treatment in the healing process of diabetic wounds via significantly regulating the expression levels of angiogenesis, pyroptosis, oxidative stress and pro-inflammatory mediators. Our findings demonstrated the curative likelihood of CAP and the underlying mechanisms for enhancing the healing process of diabetic wounds.
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Affiliation(s)
- Gamal Badr
- Zoology Department, Faculty of Science, Assiut University, 71516 Assiut, Egypt.
| | - Fayez M El-Hossary
- Physics Department, Faculty of Science, Sohag University, 82524 Sohag, Egypt
| | | | - Niemat Z Negm
- Physics Department, Faculty of Science, Sohag University, 82524 Sohag, Egypt
| | - Mohamed Khalaf
- Physics Department, Faculty of Science, Sohag University, 82524 Sohag, Egypt
| | - Mohamed Salah
- Botany and Microbiology Department, Faculty of Science, Assiut University, 71516 Assiut, Egypt; Institut Cochin, Université de Paris, INSERM, CNRS, 75014 Paris, France
| | - Leila H Sayed
- Zoology Department, Faculty of Science, Assiut University, 71516 Assiut, Egypt
| | - Mostafa A Abdel-Maksoud
- Botany and Microbiology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Ahmed Elminshawy
- Deptartment of Cardiothoracic Surgery, Faculty of Medicine, Assiut University, Assiut, Egypt
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Ghait M, Duduskar SN, Rooney M, Häfner N, Reng L, Göhrig B, Reuken PA, Bloos F, Bauer M, Sponholz C, Bruns T, Rubio I. The non-canonical inflammasome activators Caspase-4 and Caspase-5 are differentially regulated during immunosuppression-associated organ damage. Front Immunol 2023; 14:1239474. [PMID: 38106412 PMCID: PMC10722270 DOI: 10.3389/fimmu.2023.1239474] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 11/16/2023] [Indexed: 12/19/2023] Open
Abstract
The non-canonical inflammasome, which includes caspase-11 in mice and caspase-4 and caspase-5 in humans, is upregulated during inflammatory processes and activated in response to bacterial infections to carry out pyroptosis. Inadequate activity of the inflammasome has been associated with states of immunosuppression and immunopathological organ damage. However, the regulation of the receptors caspase-4 and caspase-5 during severe states of immunosuppression is largely not understood. We report that CASP4 and CASP5 are differentially regulated during acute-on-chronic liver failure and sepsis-associated immunosuppression, suggesting non-redundant functions in the inflammasome response to infection. While CASP5 remained upregulated and cleaved p20-GSDMD could be detected in sera from critically ill patients, CASP4 was downregulated in critically ill patients who exhibited features of immunosuppression and organ failure. Mechanistically, downregulation of CASP4 correlated with decreased gasdermin D levels and impaired interferon signaling, as reflected by decreased activity of the CASP4 transcriptional activators IRF1 and IRF2. Caspase-4 gene and protein expression inversely correlated with markers of organ dysfunction, including MELD and SOFA scores, and with GSDMD activity, illustrating the association of CASP4 levels with disease severity. Our results document the selective downregulation of the non-canonical inflammasome activator caspase-4 in the context of sepsis-associated immunosuppression and organ damage and provide new insights for the development of biomarkers or novel immunomodulatory therapies for the treatment of severe infections.
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Affiliation(s)
- Mohamed Ghait
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Shivalee N Duduskar
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Michael Rooney
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
| | - Norman Häfner
- Department of Gynecology, Jena University Hospital, Jena, Germany
| | - Laura Reng
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Bianca Göhrig
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Philipp A Reuken
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
| | - Frank Bloos
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Michael Bauer
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Christoph Sponholz
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Tony Bruns
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ignacio Rubio
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany
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Slaufova M, Karakaya T, Di Filippo M, Hennig P, Beer HD. The gasdermins: a pore-forming protein family expressed in the epidermis. Front Immunol 2023; 14:1254150. [PMID: 37771587 PMCID: PMC10523161 DOI: 10.3389/fimmu.2023.1254150] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/24/2023] [Indexed: 09/30/2023] Open
Abstract
Gasdermins comprise a family of pore-forming proteins, which play critical roles in (auto)inflammatory diseases and cancer. They are expressed as self-inhibited precursor proteins consisting of an aminoterminal cytotoxic effector domain (NT-GSDM) and a carboxyterminal inhibitor domain (GSDM-CT) separated by an unstructured linker region. Proteolytic processing in the linker region liberates NT-GSDM, which translocates to membranes, forms oligomers, and induces membrane permeabilization, which can disturb the cellular equilibrium that can lead to cell death. Gasdermin activation and pore formation are associated with inflammation, particularly when induced by the inflammatory protease caspase-1 upon inflammasome activation. These gasdermin pores allow the release of the pro-inflammatory cytokines interleukin(IL)-1β and IL-18 and induce a lytic type of cell death, termed pyroptosis that supports inflammation, immunity, and tissue repair. However, even at the cellular level, the consequences of gasdermin activation are diverse and range from induction of programmed cell death - pyroptosis or apoptosis - to poorly characterized protective mechanisms. The specific effects of gasdermin activation can vary between species, cell types, the membrane that is being permeabilized (plasma membrane, mitochondrial membrane, etc.), and the overall biological state of the local tissue/cells. In epithelia, gasdermins seem to play crucial roles. Keratinocytes represent the main cell type of the epidermis, which is the outermost skin layer with an essential barrier function. Compared to other tissues, keratinocytes express all members of the gasdermin family, in part in a differentiation-specific manner. That raises questions regarding the specific roles of individual GSDM family members in the skin, the mechanisms and consequences of their activation, and the potential crosstalk between them. In this review, we summarize the current knowledge about gasdermins with a focus on keratinocytes and the skin and discuss the possible roles of the different family members in immunity and disease.
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Affiliation(s)
- Marta Slaufova
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Tugay Karakaya
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Michela Di Filippo
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Paulina Hennig
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Hans-Dietmar Beer
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
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28
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Broz P. Unconventional protein secretion by gasdermin pores. Semin Immunol 2023; 69:101811. [PMID: 37473560 DOI: 10.1016/j.smim.2023.101811] [Citation(s) in RCA: 10] [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: 04/27/2023] [Revised: 07/14/2023] [Accepted: 07/14/2023] [Indexed: 07/22/2023]
Abstract
Unconventional protein secretion (UPS) allows the release of specific leaderless proteins independently of the classical endoplasmic reticulum (ER)-Golgi secretory pathway. While it remains one of the least understood mechanisms in cell biology, UPS plays an essential role in immunity as it controls the release of the IL-1 family of cytokines, which coordinate host defense and inflammatory responses. The unconventional secretion of IL-1β and IL-18, the two most prominent members of the IL-1 family, is initiated by inflammasome complexes - cytosolic signaling platforms that are assembled in response to infectious or noxious stimuli. Inflammasomes activate inflammatory caspases that proteolytically mature IL-1β/- 18, but also induce pyroptosis, a lytic form of cell death. Pyroptosis is caused by gasdermin-D (GSDMD), a member of the gasdermin protein family, which is activated by caspase cleavage and forms large β-barrel plasma membrane pores. This pore-forming activity is shared with other family members that are activated during infection or upon treatment with chemotherapy drugs. While the induction of cell death was assumed to be the main function of gasdermin pores, accumulating evidence suggests that they have also non-lytic functions, such as in the release of cytokines and alarmins, or in regulating ion fluxes. This has raised the possibility that gasdermin pores are one of the main mediators of UPS. Here, I summarize and discuss new insights into gasdermin activation and pore formation, how gasdermin pores achieve selective cargo release, and how gasdermin pore formation and ninjurin-1-driven plasma membrane rupture are executed and regulated.
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Affiliation(s)
- Petr Broz
- Department of Immunobiology, University of Lausanne, Switzerland.
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29
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Chai Q, Lei Z, Liu CH. Pyroptosis modulation by bacterial effector proteins. Semin Immunol 2023; 69:101804. [PMID: 37406548 DOI: 10.1016/j.smim.2023.101804] [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: 03/21/2023] [Revised: 06/28/2023] [Accepted: 06/29/2023] [Indexed: 07/07/2023]
Abstract
Pyroptosis is a proinflammatory form of programmed cell death featured with membrane pore formation that causes cellular swelling and allows the release of intracellular inflammatory mediators. This cell death process is elicited by the activation of the pore-forming proteins named gasdermins, and is intricately orchestrated by diverse regulatory factors in mammalian hosts to exert a prompt immune response against infections. However, growing evidence suggests that bacterial pathogens have evolved to regulate host pyroptosis for evading immune clearance and establishing progressive infection. In this review, we highlight current understandings of the functional role and regulatory network of pyroptosis in host antibacterial immunity. Thereafter, we further discuss the latest advances elucidating the mechanisms by which bacterial pathogens modulate pyroptosis through adopting their effector proteins to drive infections. A better understanding of regulatory mechanisms underlying pyroptosis at the interface of host-bacterial interactions will shed new light on the pathogenesis of infectious diseases and contribute to the development of promising therapeutic strategies against bacterial pathogens.
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Affiliation(s)
- Qiyao Chai
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
| | - Zehui Lei
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 101408, China
| | - Cui Hua Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Savaid Medical School, University of Chinese Academy of Sciences, Beijing 101408, China.
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30
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Jiang B, Zhou Y, Liu Y, He S, Liao B, Peng T, Yao L, Qi L. Research Progress on the Role and Mechanism of IL-37 in Liver Diseases. Semin Liver Dis 2023; 43:336-350. [PMID: 37582401 PMCID: PMC10620037 DOI: 10.1055/a-2153-8836] [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] [Indexed: 08/17/2023]
Abstract
Cytokines are important components of the immune system that can predict or influence the development of liver diseases. IL-37, a new member of the IL-1 cytokine family, exerts potent anti-inflammatory and immunosuppressive effects inside and outside cells. IL-37 expression differs before and after liver lesions, suggesting that it is associated with liver disease; however, its mechanism of action remains unclear. This article mainly reviews the biological characteristics of IL-37, which inhibits hepatitis, liver injury, and liver fibrosis by inhibiting inflammation, and inhibits the development of hepatocellular carcinoma (HCC) by regulating the immune microenvironment. Based on additional evidence, combining IL-37 with liver disease markers for diagnosis and treatment can achieve more significant effects, suggesting that IL-37 can be developed into a powerful tool for the clinical adjuvant treatment of liver diseases, especially HCC.
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Affiliation(s)
- Baoyi Jiang
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Yulin Zhou
- Department of Clinical Laboratory, Shunde New Rongqi Hospital, Foshan, China
| | - Yanting Liu
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Siqi He
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Baojian Liao
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Tieli Peng
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Leyi Yao
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Ling Qi
- Institute of Digestive Disease, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
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31
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Fang Y, Tang Y, Huang B. Pyroptosis: A road to next-generation cancer immunotherapy. Semin Immunol 2023; 68:101782. [PMID: 37302166 DOI: 10.1016/j.smim.2023.101782] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/13/2023] [Accepted: 06/05/2023] [Indexed: 06/13/2023]
Abstract
The goal of cancer immunotherapy is to clear tumor cells by activating antitumor immunity, especially by mobilizing tumor-reactive CD8+T cells. Pyroptosis, programmed lytic cell death mediated by gasdermin (GSDM), results in the release of cellular antigens, damage-associated molecular patterns (DAMPs) and cytokines. Therefore, pyroptotic tumor cell-derived tumor antigens and DAMPs not only reverse immunosuppression of the tumor microenvironment (TME) but also enhance tumor antigen presentation by dendritic cells, leading to robust antitumor immunity. Exploring nanoparticles and other approaches to spatiotemporally control tumor pyroptosis by regulating gasdermin expression and activation is promising for next-generation immunotherapy.
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Affiliation(s)
- Yiliang Fang
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, PR China
| | - Yaxing Tang
- Department of Anaesthesiology, the Second Affiliated Hospital of Chongqing Medical University, 400010, Chongqing, PR China
| | - Bo Huang
- Department of Immunology and National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing 100005, PR China.
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32
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Niu J, Meng G. Roles and Mechanisms of NLRP3 in Influenza Viral Infection. Viruses 2023; 15:1339. [PMID: 37376638 DOI: 10.3390/v15061339] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Pathogenic viral infection represents a major challenge to human health. Due to the vast mucosal surface of respiratory tract exposed to the environment, host defense against influenza viruses has perpetually been a considerable challenge. Inflammasomes serve as vital components of the host innate immune system and play a crucial role in responding to viral infections. To cope with influenza viral infection, the host employs inflammasomes and symbiotic microbiota to confer effective protection at the mucosal surface in the lungs. This review article aims to summarize the current findings on the function of NACHT, LRR and PYD domains-containing protein 3 (NLRP3) in host response to influenza viral infection involving various mechanisms including the gut-lung crosstalk.
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Affiliation(s)
- Junling Niu
- The Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology & Immunology, University of Chinese Academy of Sciences, 320 Yueyang Road, Life Science Research Building B-205, Shanghai 200031, China
| | - Guangxun Meng
- The Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology & Immunology, University of Chinese Academy of Sciences, 320 Yueyang Road, Life Science Research Building B-205, Shanghai 200031, China
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33
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Yazdanpanah N, Rezaei A, Ziaee V, Rezaei N. Study of NLRP3 Single Nucleotide Polymorphisms in Juvenile Systemic Lupus Erythematosus (JSLE). Immunol Invest 2023:1-18. [PMID: 37262326 DOI: 10.1080/08820139.2023.2215280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Juvenile systemic lupus erythematosus (JSLE) is a multifaceted multifactorial disorder with an unclear etiopathogenesis. Environmental factors, genetic factors, and dysregulated and defective immune system responses are known to have a role in JSLE etiopathogenesis. NLRP3 inflammasome, as an important contributor to immune-mediated inflammatory responses, is assumed to be involved in JSLE etiopathogenesis. To determine whether the NLRP3 genetic variants are altered in patients with JSLE. Fifty-three patients diagnosed with JSLE and 56 healthy sex-matched controls were studied. NLRP3 (C/G rs10754558, C/T rs3806265, C/T rs4612666, A/C rs35829419) gene polymorphisms were evaluated using a TaqMan single-nucleotide polymorphism assay. C allele at position rs3806265 was detected in higher frequencies in patients than in the control group (37.74% vs 23.21%, P-value = .028). At the genotype level at the same position, CT has a significantly higher frequency in patients than the healthy subjects (75.47% vs 46.43%, P-value = .003). The NLRP3 rs3806265 CT genotype was detected at a higher frequency in patients with JSLE than in the healthy control group.
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Affiliation(s)
- Niloufar Yazdanpanah
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Students' Scientific Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Arezou Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Ziaee
- Children's Medical Center, Pediatrics Center of Excellence, Tehran, Iran
- Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran
- Pediatric Rheumatology Research Group, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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34
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Saaoud F, Martinez L, Lu Y, Xu K, Shao Y, Zhuo JL, Gillespie A, Wang H, Tabbara M, Salama A, Yang X, Vazquez-Padron RI. Chronic Kidney Disease Transdifferentiates Veins into a Specialized Immune-Endocrine Organ with Increased MYCN-AP1 Signaling. Cells 2023; 12:1482. [PMID: 37296603 PMCID: PMC10252601 DOI: 10.3390/cells12111482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/27/2023] [Accepted: 05/17/2023] [Indexed: 06/12/2023] Open
Abstract
Most patients with end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) choose hemodialysis as their treatment of choice. Thus, upper-extremity veins provide a functioning arteriovenous access to reduce dependence on central venous catheters. However, it is unknown whether CKD reprograms the transcriptome of veins and primes them for arteriovenous fistula (AVF) failure. To examine this, we performed transcriptomic analyses of bulk RNA sequencing data of veins isolated from 48 CKD patients and 20 non-CKD controls and made the following findings: (1) CKD converts veins into immune organs by upregulating 13 cytokine and chemokine genes, and over 50 canonical and noncanonical secretome genes; (2) CKD increases innate immune responses by upregulating 12 innate immune response genes and 18 cell membrane protein genes for increased intercellular communication, such as CX3CR1 chemokine signaling; (3) CKD upregulates five endoplasmic reticulum protein-coding genes and three mitochondrial genes, impairing mitochondrial bioenergetics and inducing immunometabolic reprogramming; (4) CKD reprograms fibrogenic processes in veins by upregulating 20 fibroblast genes and 6 fibrogenic factors, priming the vein for AVF failure; (5) CKD reprograms numerous cell death and survival programs; (6) CKD reprograms protein kinase signal transduction pathways and upregulates SRPK3 and CHKB; and (7) CKD reprograms vein transcriptomes and upregulates MYCN, AP1, and 11 other transcription factors for embryonic organ development, positive regulation of developmental growth, and muscle structure development in veins. These results provide novel insights on the roles of veins as immune endocrine organs and the effect of CKD in upregulating secretomes and driving immune and vascular cell differentiation.
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Affiliation(s)
- Fatma Saaoud
- Center for Cardiovascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Laisel Martinez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Yifan Lu
- Center for Cardiovascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Keman Xu
- Center for Cardiovascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Ying Shao
- Center for Cardiovascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Jia L Zhuo
- Tulane Hypertension and Renal Center of Excellence, Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Avrum Gillespie
- Section of Nephrology, Hypertension and Kidney Transplantation, Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Hong Wang
- Center for Metabolic Disease Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Marwan Tabbara
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Alghidak Salama
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Xiaofeng Yang
- Center for Cardiovascular Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
- Section of Nephrology, Hypertension and Kidney Transplantation, Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
| | - Roberto I. Vazquez-Padron
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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35
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Ke Q, Greenawalt AN, Manukonda V, Ji X, Tisch RM. The regulation of self-tolerance and the role of inflammasome molecules. Front Immunol 2023; 14:1154552. [PMID: 37081890 PMCID: PMC10110889 DOI: 10.3389/fimmu.2023.1154552] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 03/17/2023] [Indexed: 04/07/2023] Open
Abstract
Inflammasome molecules make up a family of receptors that typically function to initiate a proinflammatory response upon infection by microbial pathogens. Dysregulation of inflammasome activity has been linked to unwanted chronic inflammation, which has also been implicated in certain autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and related animal models. Classical inflammasome activation-dependent events have intrinsic and extrinsic effects on both innate and adaptive immune effectors, as well as resident cells in the target tissue, which all can contribute to an autoimmune response. Recently, inflammasome molecules have also been found to regulate the differentiation and function of immune effector cells independent of classical inflammasome-activated inflammation. These alternative functions for inflammasome molecules shape the nature of the adaptive immune response, that in turn can either promote or suppress the progression of autoimmunity. In this review we will summarize the roles of inflammasome molecules in regulating self-tolerance and the development of autoimmunity.
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Affiliation(s)
- Qi Ke
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Ashley Nicole Greenawalt
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Veera Manukonda
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Xingqi Ji
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Roland Michael Tisch
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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36
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TXNIP shuttling - a key molecular link in regulating inflammation and mitochondrial dysfunction in freeze tolerant wood frogs. Gene 2023; 857:147184. [PMID: 36627089 DOI: 10.1016/j.gene.2023.147184] [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: 08/19/2022] [Revised: 11/27/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023]
Abstract
Amphibians such as the wood frogs,Rana sylvatica, are a primary example of a freeze-tolerant vertebrate that undergoes whole body freezing. Multiple adaptations including sequestering 65-70% of total body water as extracellular/extra organ ice and producing massive amounts of glucose as a cryoprotectant support this. Interestingly, the high glucose levels induced in response to freezing can amplify oxidative stress's effects (reactive oxygen species, ROS) and induce inflammation and mitochondrial dysfunction. Since both freezing and dehydration stress (independent of freezing) can render wood frogs hyperglycemic, this study focussed on these two stresses to elucidate the role of a scaffold protein thioredoxin interacting protein (TXNIP), which localizes in multiple compartments inside the cell under hyperglycemic conditions and mediate diverse stress responses. The results from this study suggest a stress-specific response of TXNIP in inducing the cell-damaging pathway of inflammasome activation via its cytoplasmic localization during freezing. Interestingly, mitochondrial localization of TXNIP did not leads to increase in its binding to thioredoxin 2 (TRX-2) and activating the dysfunction of this organelle by releasing a mitochondrial protein cytochrome c (Cyt c) in cytoplasm under both freezing and dehydration stresses. Post-translational modifications of TXNIP hinted on changes in the regulating proteins involved in the inflammasome and mitochondrial dysfunction pathways, whereas sequential differences (cytosine residues) of amphibian TXNIP (compared to mammalian) assessed via 3D-modeling attributed to its weak binding to TRX-2. Overall, this study summarizes differential role of proteins activated under freeze and dehydration induced hyperglycemic response in freeze tolerant wood frogs.
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Devi S, Indramohan M, Jäger E, Carriere J, Chu LH, de Almeida L, Greaves DR, Stehlik C, Dorfleutner A. CARD-only proteins regulate in vivo inflammasome responses and ameliorate gout. Cell Rep 2023; 42:112265. [PMID: 36930645 PMCID: PMC10151391 DOI: 10.1016/j.celrep.2023.112265] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 01/10/2023] [Accepted: 02/28/2023] [Indexed: 03/18/2023] Open
Abstract
Inflammatory responses are crucial for controlling infections and initiating tissue repair. However, excessive and uncontrolled inflammation causes inflammatory disease. Processing and release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 depend on caspase-1 activation within inflammasomes. Assembly of inflammasomes is initiated upon activation of cytosolic pattern recognition receptors (PRRs), followed by sequential polymerization of pyrin domain (PYD)-containing and caspase recruitment domain (CARD)-containing proteins mediated by homotypic PYD and CARD interactions. Small PYD- or CARD-only proteins (POPs and COPs, respectively) evolved in higher primates to target these crucial interactions to limit inflammation. Here, we show the ability of COPs to regulate inflammasome activation by modulating homotypic CARD-CARD interactions in vitro and in vivo. CARD16, CARD17, and CARD18 displace crucial CARD interactions between caspase-1 proteins through competitive binding and ameliorate uric acid crystal-mediated NLRP3 inflammasome activation and inflammatory disease. COPs therefore represent an important family of inflammasome regulators and ameliorate inflammatory disease.
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Affiliation(s)
- Savita Devi
- Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Mohanalaxmi Indramohan
- Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Elisabeth Jäger
- Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jessica Carriere
- Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Lan H Chu
- Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Lucia de Almeida
- Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - David R Greaves
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
| | - Christian Stehlik
- Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; The Kao Autoimmunity Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
| | - Andrea Dorfleutner
- Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA; The Kao Autoimmunity Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
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38
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Chao YY, Puhach A, Frieser D, Arunkumar M, Lehner L, Seeholzer T, Garcia-Lopez A, van der Wal M, Fibi-Smetana S, Dietschmann A, Sommermann T, Ćiković T, Taher L, Gresnigt MS, Vastert SJ, van Wijk F, Panagiotou G, Krappmann D, Groß O, Zielinski CE. Human T H17 cells engage gasdermin E pores to release IL-1α on NLRP3 inflammasome activation. Nat Immunol 2023; 24:295-308. [PMID: 36604548 PMCID: PMC9892007 DOI: 10.1038/s41590-022-01386-w] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 11/04/2022] [Indexed: 01/07/2023]
Abstract
It has been shown that innate immune responses can adopt adaptive properties such as memory. Whether T cells utilize innate immune signaling pathways to diversify their repertoire of effector functions is unknown. Gasdermin E (GSDME) is a membrane pore-forming molecule that has been shown to execute pyroptotic cell death and thus to serve as a potential cancer checkpoint. In the present study, we show that human T cells express GSDME and, surprisingly, that this expression is associated with durable viability and repurposed for the release of the alarmin interleukin (IL)-1α. This property was restricted to a subset of human helper type 17 T cells with specificity for Candida albicans and regulated by a T cell-intrinsic NLRP3 inflammasome, and its engagement of a proteolytic cascade of successive caspase-8, caspase-3 and GSDME cleavage after T cell receptor stimulation and calcium-licensed calpain maturation of the pro-IL-1α form. Our results indicate that GSDME pore formation in T cells is a mechanism of unconventional cytokine release. This finding diversifies our understanding of the functional repertoire and mechanistic equipment of T cells and has implications for antifungal immunity.
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Affiliation(s)
- Ying-Yin Chao
- Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany.,Center for Translational Cancer Research & Institute of Virology, Technical University of Munich, Munich, Germany
| | - Alisa Puhach
- Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany
| | - David Frieser
- Center for Translational Cancer Research & Institute of Virology, Technical University of Munich, Munich, Germany
| | - Mahima Arunkumar
- Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany
| | - Laurens Lehner
- Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany
| | - Thomas Seeholzer
- Research Unit Cellular Signal Integration, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
| | - Albert Garcia-Lopez
- Department of Systems Biology and Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany
| | - Marlot van der Wal
- Center for Translational Immunology, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands
| | - Silvia Fibi-Smetana
- Institute of Biomedical Informatics, Graz University of Technology, Graz, Austria
| | - Axel Dietschmann
- Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Jena, Germany
| | - Thomas Sommermann
- Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany
| | - Tamara Ćiković
- Institute of Neuropathology, Medical Center & Signalling Research Centres BIOSS and CIBSS & Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Leila Taher
- Institute of Biomedical Informatics, Graz University of Technology, Graz, Austria
| | - Mark S Gresnigt
- Adaptive Pathogenicity Strategies, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute, Jena, Germany
| | - Sebastiaan J Vastert
- Center for Translational Immunology, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands
| | - Femke van Wijk
- Center for Translational Immunology, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands
| | - Gianni Panagiotou
- Department of Systems Biology and Bioinformatics, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany
| | - Daniel Krappmann
- Research Unit Cellular Signal Integration, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany
| | - Olaf Groß
- Institute of Neuropathology, Medical Center & Signalling Research Centres BIOSS and CIBSS & Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Christina E Zielinski
- Department of Infection Immunology, Leibniz Institute for Natural Product Research and Infection Biology, Hans-Knöll-Institute, Jena, Germany. .,Center for Translational Cancer Research & Institute of Virology, Technical University of Munich, Munich, Germany. .,Institute of Microbiology, Faculty of Biological Sciences, Friedrich Schiller University, Jena, Germany. .,German Center for Infection Research, Munich, Germany. .,Department of Cellular Immunoregulation, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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Guan K, Xu J, Gu X, He R, Xie Y, Jing B, Peng X, Yang G. Artificial Infestation of Sarcoptes scabiei (Acari: Sarcoptidae) in Rabbits Exhibits Progressive Pathological Changes, Apoptosis, and Keratinization in the Skin. Int J Mol Sci 2023; 24:ijms24032187. [PMID: 36768507 PMCID: PMC9917239 DOI: 10.3390/ijms24032187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/14/2023] [Accepted: 01/17/2023] [Indexed: 01/24/2023] Open
Abstract
Sarcoptes scabiei (S. scabiei) is an ectoparasite that can infest humans and 150 mammalian host species, primarily causing pruritus, crust, and alopecia. However, neither the pathological process of host skin under S. scabiei infection nor the mechanism of S. scabiei infection in regulating apoptosis and keratinization of host skin has been studied yet. In this study, a total of 56 rabbits were artificially infested with S. scabiei, and the skin samples were collected at seven different time points, including 6 h, 12 h, day 1, day 3, 1 week, 4 weeks, and 8 weeks, whereas a group of eight rabbits served as controls. We measured epidermal thickness by H&E staining, observed the skin ultrastructure by electron microscopy, and detected the degree of skin apoptosis by TUNEL staining. The level of transcription of genes related to apoptosis and keratinization was detected by quantitative real-time PCR (qRT-PCR), and the level of Bcl-2 protein expression was further detected using immunohistochemistry. Our results showed that, with increased infestation time, the epidermal layer of the rabbit skin exhibited significant thickening and keratinization, swollen mitochondria in the epidermal cells, and increased skin apoptosis. The level of caspase-1, 3, 8, 10, 14, and Bcl-2 mRNA expression was increased, whereas the level of keratin 1 and 5 was decreased after S. scabiei infestation. In conclusion, S. scabiei infestation causes thickening of the epidermis, which may be related to apoptosis-induced proliferation and skin keratinization.
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Affiliation(s)
- Ke Guan
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Jing Xu
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
- Correspondence: (J.X.); (G.Y.)
| | - Xiaobin Gu
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Ran He
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Yue Xie
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Bo Jing
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Xuerong Peng
- Department of Chemistry, College of Life and Basic Science, Sichuan Agricultural University, Chengdu 611130, China
| | - Guangyou Yang
- Department of Parasitology, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
- Correspondence: (J.X.); (G.Y.)
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40
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Saaoud F, Liu L, Xu K, Cueto R, Shao Y, Lu Y, Sun Y, Snyder NW, Wu S, Yang L, Zhou Y, Williams DL, Li C, Martinez L, Vazquez-Padron RI, Zhao H, Jiang X, Wang H, Yang X. Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways. JCI Insight 2023; 8:e158183. [PMID: 36394956 PMCID: PMC9870092 DOI: 10.1172/jci.insight.158183] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 11/16/2022] [Indexed: 11/18/2022] Open
Abstract
We determined whether gut microbiota-produced trimethylamine (TMA) is oxidized into trimethylamine N-oxide (TMAO) in nonliver tissues and whether TMAO promotes inflammation via trained immunity (TI). We found that endoplasmic reticulum (ER) stress genes were coupregulated with MitoCarta genes in chronic kidney diseases (CKD); TMAO upregulated 190 genes in human aortic endothelial cells (HAECs); TMAO synthesis enzyme flavin-containing monooxygenase 3 (FMO3) was expressed in human and mouse aortas; TMAO transdifferentiated HAECs into innate immune cells; TMAO phosphorylated 12 kinases in cytosol via its receptor PERK and CREB, and integrated with PERK pathways; and PERK inhibitors suppressed TMAO-induced ICAM-1. TMAO upregulated 3 mitochondrial genes, downregulated inflammation inhibitor DARS2, and induced mitoROS, and mitoTEMPO inhibited TMAO-induced ICAM-1. β-Glucan priming, followed by TMAO restimulation, upregulated TNF-α by inducing metabolic reprogramming, and glycolysis inhibitor suppressed TMAO-induced ICAM-1. Our results have provided potentially novel insights regarding TMAO roles in inducing EC activation and innate immune transdifferentiation and inducing metabolic reprogramming and TI for enhanced vascular inflammation, and they have provided new therapeutic targets for treating cardiovascular diseases (CVD), CKD-promoted CVD, inflammation, transplantation, aging, and cancer.
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Affiliation(s)
| | - Lu Liu
- Metabolic Disease Research and Thrombosis Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Keman Xu
- Centers for Cardiovascular Research and
| | - Ramon Cueto
- Metabolic Disease Research and Thrombosis Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Ying Shao
- Centers for Cardiovascular Research and
| | - Yifan Lu
- Centers for Cardiovascular Research and
| | - Yu Sun
- Centers for Cardiovascular Research and
| | - Nathaniel W. Snyder
- Metabolic Disease Research and Thrombosis Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Sheng Wu
- Metabolic Disease Research and Thrombosis Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Ling Yang
- Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Yan Zhou
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Temple Health, Philadelphia, Pennsylvania, USA
| | - David L. Williams
- Department of Surgery, Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Chuanfu Li
- Department of Surgery, Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA
| | - Laisel Martinez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Roberto I. Vazquez-Padron
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Huaqing Zhao
- Center for Biostatistics and Epidemiology, Department of Biomedical Education and Data Science, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Xiaohua Jiang
- Centers for Cardiovascular Research and
- Metabolic Disease Research and Thrombosis Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Hong Wang
- Metabolic Disease Research and Thrombosis Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
| | - Xiaofeng Yang
- Centers for Cardiovascular Research and
- Metabolic Disease Research and Thrombosis Research, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA
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41
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Li Y, Jiang Q. Uncoupled pyroptosis and IL-1β secretion downstream of inflammasome signaling. Front Immunol 2023; 14:1128358. [PMID: 37090724 PMCID: PMC10117957 DOI: 10.3389/fimmu.2023.1128358] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 03/24/2023] [Indexed: 04/25/2023] Open
Abstract
Inflammasomes are supramolecular platforms that organize in response to various damage-associated molecular patterns and pathogen-associated molecular patterns. Upon activation, inflammasome sensors (with or without the help of ASC) activate caspase-1 and other inflammatory caspases that cleave gasdermin D and pro-IL-1β/pro-IL-18, leading to pyroptosis and mature cytokine secretion. Pyroptosis enables intracellular pathogen niche disruption and intracellular content release at the cost of cell death, inducing pro-inflammatory responses in the neighboring cells. IL-1β is a potent pro-inflammatory regulator for neutrophil recruitment, macrophage activation, and T-cell expansion. Thus, pyroptosis and cytokine secretion are the two main mechanisms that occur downstream of inflammasome signaling; they maintain homeostasis, drive the innate immune response, and shape adaptive immunity. This review aims to discuss the possible mechanisms, timing, consequences, and significance of the two uncoupling preferences downstream of inflammasome signaling. While pyroptosis and cytokine secretion may be usually coupled, pyroptosis-predominant and cytokine-predominant uncoupling are also observed in a stimulus-, cell type-, or context-dependent manner, contributing to the pathogenesis and development of numerous pathological conditions such as cryopyrin-associated periodic syndromes, LPS-induced sepsis, and Salmonella enterica serovar Typhimurium infection. Hyperactive cells consistently release IL-1β without LDH leakage and pyroptotic death, thereby leading to prolonged inflammation, expanding the lifespans of pyroptosis-resistant neutrophils, and hyperactivating stimuli-challenged macrophages, dendritic cells, monocytes, and specific nonimmune cells. Death inflammasome activation also induces GSDMD-mediated pyroptosis with no IL-1β secretion, which may increase lethality in vivo. The sublytic GSDMD pore formation associated with lower expressions of pyroptotic components, GSDMD-mediated extracellular vesicles, or other GSDMD-independent pathways that involve unconventional secretion could contribute to the cytokine-predominant uncoupling; the regulation of caspase-1 dynamics, which may generate various active species with different activities in terms of GSDMD or pro-IL-1β, could lead to pyroptosis-predominant uncoupling. These uncoupling preferences enable precise reactions to different stimuli of different intensities under specific conditions at the single-cell level, promoting cooperative cell and host fate decisions and participating in the pathogen "game". Appropriate decisions in terms of coupling and uncoupling are required to heal tissues and eliminate threats, and further studies exploring the inflammasome tilt toward pyroptosis or cytokine secretion may be helpful.
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Yang M, Li J, Liu Z, Zhang H, Liu J, Liu Y, Zhuang A, Zhou H, Gu P, Fan X. An injectable vitreous substitute with sustained release of metformin for enhanced uveal melanoma immunotherapy. Biomater Sci 2022; 10:7077-7092. [PMID: 36326609 DOI: 10.1039/d2bm01058e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Uveal melanoma (UM) is the most prevalent primary intraocular malignant tumor in adults with a high rate of metastasis. Conventional treatments have limited effects on metastasis and cause permanent ocular tissue defects. Here, a novel strategy based on an injectable vitreous substitute with sustained metformin release ability (IVS-Met) was reported for efficient UM therapy as well as for repairing vitreous deficiency and preserving visual function. IVS-Met showed an excellent long-term anti-tumor effect by direct tumor attack and modulation of the tumor microenvironment (TME). IVS-Met reduced the proportion of pro-tumor M2 tumor-associated macrophages and induced the pro-inflammatory M1 phenotype, thus reversing the immunosuppressive TME and eliciting robust anti-tumor immune responses. Notably, IVS-Met demonstrated high performance in the inhibition of UM metastasis and significantly extended the survival time of mice. In addition, the vitreous substitute achieved facile administration via direct injection and exhibited excellent rheological and optical properties with the key parameters very close to those of the vitreous body to repair vitreous deficiency and preserve visual function. In summary, this strategy has realized effective UM treatment while retaining eyeballs and vision for the first time, revealing great potential for translation to clinical practice.
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Affiliation(s)
- Muyue Yang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Jipeng Li
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Zeyang Liu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Haiyang Zhang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Jin Liu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Yan Liu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Ai Zhuang
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Huifang Zhou
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Ping Gu
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
| | - Xianqun Fan
- Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China. .,Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
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43
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Vasconcelos DP, Águas AP, Barbosa JN. The inflammasome in biomaterial-driven immunomodulation. J Tissue Eng Regen Med 2022; 16:1109-1120. [PMID: 36327091 PMCID: PMC10092308 DOI: 10.1002/term.3361] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 10/07/2022] [Accepted: 10/23/2022] [Indexed: 11/05/2022]
Abstract
Inflammasomes are intracellular structures formed upon the assembly of several proteins that have a considerable size and are very important in innate immune responses being key players in host defense. They are assembled after the perception of pathogens or danger signals. The activation of the inflammasome pathway induces the production of high levels of the pro-inflammatory cytokines Interleukin (IL)-1β and IL-18 through the caspase activation. The procedure for the implantation of a biomaterial causes tissue injury, and the injured cells will secrete danger signals recognized by the inflammasome. There is growing evidence that the inflammasome participates in a number of inflammatory processes, including pathogen clearance, chronic inflammation and tissue repair. Therefore, the control of the inflammasome activity is a promising target in the development of capable approaches to be applied in regenerative medicine. In this review, we revisit current knowledge of the inflammasome in the inflammatory response to biomaterials and point to the yet underexplored potential of the inflammasome in the context of immunomodulation.
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Affiliation(s)
- Daniela P Vasconcelos
- i3S - Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Porto, Portugal.,INEB - Instituto de Engenharia Biomédica, Porto, Portugal
| | - Artur P Águas
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.,UMIB - Unit for Multidisciplinary Biomedical Research of ICBAS - Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Judite N Barbosa
- i3S - Instituto de Inovação e Investigação em Saúde, Universidade do Porto, Porto, Portugal.,INEB - Instituto de Engenharia Biomédica, Porto, Portugal.,ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
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44
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Takenouchi T, Masujin K, Suzuki S, Haraguchi S, Hiramatsu K, Kokuho T, Uenishi H. Establishment and characterization of the immortalized porcine lung-derived mononuclear phagocyte cell line. Front Vet Sci 2022; 9:1058124. [PMID: 36467652 PMCID: PMC9715978 DOI: 10.3389/fvets.2022.1058124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 11/04/2022] [Indexed: 08/27/2023] Open
Abstract
Mononuclear phagocytes (MNP), including monocytes, dendritic cells (DC), and macrophages, play critical roles in innate immunity. MNP are abundant in the lungs and contribute to host defense against airborne agents and pulmonary immune homeostasis. In this study, we isolated porcine lung-derived MNP (PLuM) from primary cultures of parenchymal lung cells and then immortalized them by transferring the SV40 large T antigen gene and porcine telomerase reverse transcriptase gene using lentiviral vectors. The established cell line, immortalized PLuM (IPLuM), expressed DC/macrophage markers; i.e., CD163, CD172a, and major histocompatibility complex class II, whereas they did not express a porcine monocyte-specific marker, CD52. The expression patterns of these cell surface markers indicate that IPLuM originate from the DC/macrophage lineage rather than the monocyte lineage. The bacterial cell wall components muramyl dipeptide and lipopolysaccharide induced the production of the interleukin-1 family of pro-inflammatory cytokines in IPLuM. Phagocytotic activity was also detected by time-lapse fluorescence imaging of live cells when IPLuM were cultured in the presence of pHrodo dye-conjugated E. coli BioParticles. It is worth noting that IPLuM are susceptible to African swine fever virus infection and support the virus' efficient replication in vitro. Taken together, the IPLuM cell line may be a useful model for investigating host-agent interactions in the respiratory microenvironments of the porcine lung.
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Affiliation(s)
- Takato Takenouchi
- Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Japan
| | - Kentaro Masujin
- Division of Transboundary Animal Disease Research, National Institute of Animal Health, National Agriculture and Food Research Organization, Tokyo, Japan
| | - Shunichi Suzuki
- Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Japan
| | - Seiki Haraguchi
- Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Japan
| | - Kanae Hiramatsu
- Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Japan
- Division of Infectious Animal Disease Research, National Institute of Animal Health, National Agriculture and Food Research Organization, Tsukuba, Japan
| | - Takehiro Kokuho
- Division of Transboundary Animal Disease Research, National Institute of Animal Health, National Agriculture and Food Research Organization, Tokyo, Japan
| | - Hirohide Uenishi
- Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Japan
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45
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Zhang X, Xu A, Ran Y, Wei C, Xie F, Wu J. Design, synthesis and biological evaluation of phenyl vinyl sulfone based NLRP3 inflammasome inhibitors. Bioorg Chem 2022; 128:106010. [DOI: 10.1016/j.bioorg.2022.106010] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 05/26/2022] [Accepted: 07/06/2022] [Indexed: 11/02/2022]
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46
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Pan L, Tang WD, Wang K, Fang QF, Liu MR, Wu ZX, Wang Y, Cui SL, Hu G, Hou TJ, Hu WW, Chen Z, Zhang XN. Novel Caspase-1 inhibitor CZL80 improves neurological function in mice after progressive ischemic stroke within a long therapeutic time-window. Acta Pharmacol Sin 2022; 43:2817-2827. [PMID: 35501362 PMCID: PMC9622895 DOI: 10.1038/s41401-022-00913-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 04/16/2022] [Indexed: 11/09/2022]
Abstract
Progressive ischemic stroke (PIS) is featured by progressive neurological dysfunction after ischemia. Ischemia-evoked neuroinflammation is implicated in the progressive brain injury after cerebral ischemia, while Caspase-1, an active component of inflammasome, exaggerates ischemic brain injury. Current Caspase-1 inhibitors are inadequate in safety and druggability. Here, we investigated the efficacy of CZL80, a novel Caspase-1 inhibitor, in mice with PIS. Mice and Caspase-1-/- mice were subjected to photothrombotic (PT)-induced cerebral ischemia. CZL80 (10, 30 mg·kg-1·d-1, i.p.) was administered for one week after PT onset. The transient and the progressive neurological dysfunction (as foot faults in the grid-walking task and forelimb symmetry in the cylinder task) was assessed on Day1 and Day4-7, respectively, after PT onset. Treatment with CZL80 (30 mg/kg) during Day1-7 significantly reduced the progressive, but not the transient neurological dysfunction. Furthermore, we showed that CZL80 administered on Day4-7, when the progressive neurological dysfunction occurred, produced significant beneficial effects against PIS, suggesting an extended therapeutic time-window. CZL80 administration could improve the neurological function even as late as Day43 after PT. In Caspase-1-/- mice with PIS, the beneficial effects of CZL80 were abolished. We found that Caspase-1 was upregulated during Day4-7 after PT and predominantly located in activated microglia, which was coincided with the progressive neurological deficits, and attenuated by CZL80. We showed that CZL80 administration did not reduce the infarct volume, but significantly suppressed microglia activation in the peri-infarct cortex, suggesting the involvement of microglial inflammasome in the pathology of PIS. Taken together, this study demonstrates that Caspase-1 is required for the progressive neurological dysfunction in PIS. CZL80 is a promising drug to promote the neurological recovery in PIS by inhibiting Caspase-1 within a long therapeutic time-window.
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Affiliation(s)
- Ling Pan
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Wei-Dong Tang
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Ke Wang
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Qi-Feng Fang
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Meng-Ru Liu
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Zhan-Xun Wu
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Yi Wang
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Sun-Liang Cui
- Department of Pharmachemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Gang Hu
- Department of Pharmacology, School of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Ting-Jun Hou
- Department of Pharmachemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Wei-Wei Hu
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Zhong Chen
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Xiang-Nan Zhang
- Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
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47
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Di Filippo M, Hennig P, Karakaya T, Slaufova M, Beer HD. NLRP1 in Cutaneous SCCs: An Example of the Complex Roles of Inflammasomes in Cancer Development. Int J Mol Sci 2022; 23:12308. [PMID: 36293159 PMCID: PMC9603439 DOI: 10.3390/ijms232012308] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/28/2022] [Accepted: 10/12/2022] [Indexed: 11/05/2022] Open
Abstract
Protein complexes termed inflammasomes ensure tissue protection from pathogenic and sterile stressors by induction of inflammation. This is mediated by different caspase-1-induced downstream pathways, including activation of the pro-inflammatory cytokines proIL-1β and -18, induction of a lytic type of cell death, and regulation of the release of other pro-inflammatory molecules. Aberrant inflammasome activation underlies the pathology of numerous (auto)inflammatory diseases. Furthermore, inflammasomes support or suppress tumor development in a complex cell-type- and stage-dependent manner. In human keratinocytes and skin, NLRP1 is the central inflammasome sensor activated by cellular perturbation induced, for example, by UVB radiation. UVB represents the main inducer of skin cancer, which is the most common type of malignancy in humans. Recent evidence demonstrates that activation of NLRP1 in human skin supports the development of cutaneous squamous cell carcinomas (cSCCs) by inducing skin inflammation. In contrast, the NLRP1 inflammasome pathway is restrained in established cSCCs, suggesting that, at this stage, the protein complex has a tumor suppressor role. A better understanding of the complex functions of NLRP1 in the development of cSCCs and in general of inflammasomes in cancer might pave the way for novel strategies for cancer prevention and therapy. These strategies might include stage-specific modulation of inflammasome activation or its downstream pathways by mono- or combination therapy.
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Affiliation(s)
- Michela Di Filippo
- Department of Dermatology, University Hospital of Zurich, 8091 Zurich, Switzerland
| | - Paulina Hennig
- Department of Dermatology, University Hospital of Zurich, 8091 Zurich, Switzerland
| | - Tugay Karakaya
- Department of Dermatology, University Hospital of Zurich, 8091 Zurich, Switzerland
| | - Marta Slaufova
- Department of Dermatology, University Hospital of Zurich, 8091 Zurich, Switzerland
| | - Hans-Dietmar Beer
- Department of Dermatology, University Hospital of Zurich, 8091 Zurich, Switzerland
- Faculty of Medicine, University of Zurich, 8032 Zurich, Switzerland
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García-Sancha N, Corchado-Cobos R, Gómez-Vecino A, Jiménez-Navas A, Pérez-Baena MJ, Blanco-Gómez A, Holgado-Madruga M, Mao JH, Cañueto J, Castillo-Lluva S, Mendiburu-Eliçabe M, Pérez-Losada J. Evolutionary Origins of Metabolic Reprogramming in Cancer. Int J Mol Sci 2022; 23:12063. [PMID: 36292921 PMCID: PMC9603151 DOI: 10.3390/ijms232012063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/29/2022] [Accepted: 10/06/2022] [Indexed: 11/23/2022] Open
Abstract
Metabolic changes that facilitate tumor growth are one of the hallmarks of cancer. These changes are not specific to tumors but also take place during the physiological growth of tissues. Indeed, the cellular and tissue mechanisms present in the tumor have their physiological counterpart in the repair of tissue lesions and wound healing. These molecular mechanisms have been acquired during metazoan evolution, first to eliminate the infection of the tissue injury, then to enter an effective regenerative phase. Cancer itself could be considered a phenomenon of antagonistic pleiotropy of the genes involved in effective tissue repair. Cancer and tissue repair are complex traits that share many intermediate phenotypes at the molecular, cellular, and tissue levels, and all of these are integrated within a Systems Biology structure. Complex traits are influenced by a multitude of common genes, each with a weak effect. This polygenic component of complex traits is mainly unknown and so makes up part of the missing heritability. Here, we try to integrate these different perspectives from the point of view of the metabolic changes observed in cancer.
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Affiliation(s)
- Natalia García-Sancha
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Roberto Corchado-Cobos
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Aurora Gómez-Vecino
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Alejandro Jiménez-Navas
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Manuel Jesús Pérez-Baena
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Adrián Blanco-Gómez
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Marina Holgado-Madruga
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, 37007 Salamanca, Spain
- Instituto de Neurociencias de Castilla y León (INCyL), 37007 Salamanca, Spain
| | - Jian-Hua Mao
- Lawrence Berkeley National Laboratory, Biological Systems and Engineering Division, Berkeley, CA 94720, USA
- Berkeley Biomedical Data Science Center, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
| | - Javier Cañueto
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
- Departamento de Dermatología, Hospital Universitario de Salamanca, Paseo de San Vicente 58-182, 37007 Salamanca, Spain
| | - Sonia Castillo-Lluva
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain
| | - Marina Mendiburu-Eliçabe
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
| | - Jesús Pérez-Losada
- Instituto de Biología Molecular y Celular del Cáncer (IBMCC-CIC), Universidad de Salamanca/CSIC, 37007 Salamanca, Spain
- Instituto de Investigación Biosanitaria de Salamanca (IBSAL), 37007 Salamanca, Spain
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de Almeida L, Devi S, Indramohan M, Huang QQ, Ratsimandresy RA, Pope RM, Dorfleutner A, Stehlik C. POP1 inhibits MSU-induced inflammasome activation and ameliorates gout. Front Immunol 2022; 13:912069. [PMID: 36225929 PMCID: PMC9550078 DOI: 10.3389/fimmu.2022.912069] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 09/06/2022] [Indexed: 01/13/2023] Open
Abstract
Canonical inflammasomes are innate immune protein scaffolds that enable the activation of inflammatory caspase-1, and subsequently the processing and release of interleukin (IL)-1β, IL-18, and danger signals, as well as the induction of pyroptotic cell death. Inflammasome assembly and activation occurs in response to sensing of infectious, sterile and self-derived molecular patterns by cytosolic pattern recognition receptors, including the Nod-like receptor NLRP3. While these responses are essential for host defense, excessive and uncontrolled NLRP3 inflammasome responses cause and contribute to a wide spectrum of inflammatory diseases, including gout. A key step in NLRP3 inflammasome assembly is the sequentially nucleated polymerization of Pyrin domain (PYD)- and caspase recruitment domain (CARD)-containing inflammasome components. NLRP3 triggers polymerization of the adaptor protein ASC through PYD-PYD interactions, but ASC polymerization then proceeds in a self-perpetuating manner and represents a point of no return, which culminates in the activation of caspase-1 by induced proximity. In humans, small PYD-only proteins (POPs) lacking an effector domain regulate this key process through competitive binding, but limited information exists on their physiological role during health and disease. Here we demonstrate that POP1 expression in macrophages is sufficient to dampen MSU crystal-mediated inflammatory responses in animal models of gout. Whether MSU crystals are administered into a subcutaneous airpouch or into the ankle joint, the presence of POP1 significantly reduces neutrophil infiltration. Also, airpouch exudates have much reduced IL-1β and ASC, which are typical pro-inflammatory indicators that can also be detected in synovial fluids of gout patients. Exogenous expression of POP1 in mouse and human macrophages also blocks MSU crystal-induced NLRP3 inflammasome assembly, resulting in reduced IL-1β and IL-18 secretion. Conversely, reduced POP1 expression in human macrophages enhances IL-1β secretion. We further determined that the mechanism for the POP1-mediated inhibition of NLRP3 inflammasome activation is through its interference with the crucial NLRP3 and ASC interaction within the inflammasome complex. Strikingly, administration of an engineered cell permeable version of POP1 was able to ameliorate MSU crystal-mediated inflammation in vivo, as measured by neutrophil infiltration. Overall, we demonstrate that POP1 may play a crucial role in regulating inflammatory responses in gout.
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Affiliation(s)
- Lucia de Almeida
- 1Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Savita Devi
- 2Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA, United States
| | - Mohanalaxmi Indramohan
- 2Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA, United States
| | - Qi-Quan Huang
- 1Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Rojo A. Ratsimandresy
- 2Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA, United States
| | - Richard M. Pope
- 1Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Andrea Dorfleutner
- 2Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA, United States,3Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, United States,4The Kao Autoimmunity Institute, Cedars Sinai Medical Center, Los Angeles, CA, United States,*Correspondence: Andrea Dorfleutner, ; Christian Stehlik,
| | - Christian Stehlik
- 2Department of Academic Pathology, Cedars Sinai Medical Center, Los Angeles, CA, United States,3Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, United States,4The Kao Autoimmunity Institute, Cedars Sinai Medical Center, Los Angeles, CA, United States,5Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, United States,*Correspondence: Andrea Dorfleutner, ; Christian Stehlik,
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50
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Anes E, Pires D, Mandal M, Azevedo-Pereira JM. Spatial localization of cathepsins: Implications in immune activation and resolution during infections. Front Immunol 2022; 13:955407. [PMID: 35990632 PMCID: PMC9382241 DOI: 10.3389/fimmu.2022.955407] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 07/14/2022] [Indexed: 11/17/2022] Open
Abstract
Cathepsins were first described, as endolysosomal proteolytic enzymes in reference to the organelles where they degrade the bulk of endogenous and exogenous substrates in a slightly acidic environment. These substrates include pathogens internalized via endocytosis and/or marked for destruction by autophagy. However, the role of cathepsins during infection far exceeds that of direct digestion of the pathogen. Cathepsins have been extensively investigated in the context of tumour associated immune cells and chronic inflammation. Several cathepsin-dependent immune responses develop in the endocytic pathway while others take place in the cytosol, the nucleus, or in the extracellular space. In this review we highlight the spatial localization of cathepsins and their implications in immune activation and resolution pathways during infection.
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