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Gaggioli MR, Jones AG, Panagi I, Washington EJ, Loney RE, Muench JH, Foster MW, Brennan RG, Thurston TLM, Ko DC. A single amino acid in the Salmonella effector SarA/SteE triggers supraphysiological activation of STAT3 for anti-inflammatory gene expression. Cell Rep 2025; 44:115530. [PMID: 40188438 PMCID: PMC12014907 DOI: 10.1016/j.celrep.2025.115530] [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: 02/20/2024] [Revised: 02/25/2025] [Accepted: 03/17/2025] [Indexed: 04/08/2025] Open
Abstract
Salmonella causes ∼1 million cases of gastroenteritis annually in the United States. Critical to virulence are secreted effectors that reprogram host functions. We previously discovered the effector SarA facilitates phosphorylation of STAT3, inducing expression of the anti-inflammatory cytokine interleukin-10 (IL-10). This STAT3 activation requires a region of homology with the host cytokine receptor gp130. Here, we demonstrate that a single amino acid difference is critical for the anti-inflammatory bias of SarA-STAT3 signaling. An isoleucine at pY+1 of the YxxQ motif in SarA (which binds the STAT3 SH2 domain) causes increased STAT3 recruitment and phosphorylation, biasing toward anti-inflammatory targets. This isoleucine renders SarA a better substrate for tyrosine phosphorylation by GSK-3. GSK-3 is canonically a serine/threonine kinase that nonetheless undergoes tyrosine autophosphorylation at a motif with isoleucine at the pY+1 position. Our results provide a molecular basis for how a Salmonella effector achieves supraphysiological levels of STAT3 activation to control host genes.
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Affiliation(s)
- Margaret R Gaggioli
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Angela G Jones
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Ioanna Panagi
- Department of Infectious Disease, Centre for Bacterial Resistance Biology, Imperial College London, London, UK
| | - Erica J Washington
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA; Department of Biochemistry, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Rachel E Loney
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | | | - Matthew W Foster
- Duke Proteomics and Metabolomics Core Facility, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Richard G Brennan
- Department of Biochemistry, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Teresa L M Thurston
- Department of Infectious Disease, Centre for Bacterial Resistance Biology, Imperial College London, London, UK
| | - Dennis C Ko
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA; Division of Infectious Diseases, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA.
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2
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Suur BE, Karadimou G, Willems CJJM, Bergman O, Lengquist M, Kronqvist M, Baumgartner R, Malin S, Gisterå A, Hansson GK, Mälarstig A, Hedin U, Ketelhuth DFJ, Matic L. PCSK6 ablation in blood circulating cells increases atherosclerotic burden, but improves plaque stability by activating Th17-smooth muscle cell modulatory axis. Vascul Pharmacol 2025; 159:107490. [PMID: 40097084 DOI: 10.1016/j.vph.2025.107490] [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: 12/28/2024] [Revised: 03/02/2025] [Accepted: 03/14/2025] [Indexed: 03/19/2025]
Abstract
BACKGROUND Proprotein convertase subtilisins/kexins (PCSKs) have been implicated in cancers and cardiovascular disease. We have shown that PCSK6 is a key protease regulating smooth muscle cell (SMC)-mediated vascular remodeling, but also that it can be expressed by T cells and macrophages in atherosclerotic plaques. Whether PCSK6 regulates innate and adaptive immune responses in the context of vascular inflammation is still unknown. METHODS In this study, detailed immunophenotyping of constitutive Pcsk6-/- mice was performed. Bone marrow transplantation into high-cholesterol diet fed Ldlr-/- mice was used to investigate PCSK6-mediated immune effects in atherogenesis and plaque stability. RESULTS Compared to controls, Pcsk6-/- mice showed higher plasma levels of the chemoattractants CCL2 and CCCL3, and Th17 cytokines IL-17 A and IL-17F. Pcsk6 ablation led to increased naïve and effector-memory CD4+ and CD8+ cell numbers in the spleen, and increased release of IL-17 A, IFN-γ and IL-10 as well as proliferation by spleenocytes in vitro. Lack of Pcsk6 also affected innate immunity as macrophages from Pcsk6-/- mice secreted more cytokines, including TNF-α, CCL2, IL-6 and IL-10 upon LPS stimulation in vitro, and were more prone to oxLDL uptake. In line with a pro-inflammatory phenotype, Pcsk6-/-➔Ldlr-/- transplanted mice presented a higher atherosclerotic plaque burden compared to Ldlr-/- receiving control bone marrow. Although larger, Pcsk6-/-➔Ldlr-/- plaques showed increased stability features, including collagen deposition and SMC presence coinciding with significantly increased local levels of the fibrogenic cytokine IL-17. CONCLUSIONS Global Pcsk6 ablation leads to the activation of both adaptive and innate immune systems. Interestingly, Pcsk6-/- ablation in bone marrow of hyperlipidemic mice revealed its dual role in atherogenesis, activating a Th17-SMC modulatory axis that promotes plaque stability, despite increased atherosclerotic burden.
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Affiliation(s)
- Bianca E Suur
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Glykeria Karadimou
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden
| | - Colin J J M Willems
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden
| | - Otto Bergman
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden; Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden
| | - Mariette Lengquist
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden
| | - Malin Kronqvist
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden
| | - Roland Baumgartner
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden
| | - Stephen Malin
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden
| | - Anton Gisterå
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden
| | - Göran K Hansson
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden
| | - Anders Mälarstig
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden
| | - Ulf Hedin
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden
| | - Daniel F J Ketelhuth
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Sweden; Department of Molecular Medicine, University of Southern Denmark, Denmark
| | - Ljubica Matic
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Sweden.
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3
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Nayak I, Biondo R, Stewart WC, Fulton RJ, Möker N, Zhang C, Khakoo SI, Das J. Modeling the response to interleukin-21 to inform natural killer cell immunotherapy. Immunol Cell Biol 2025; 103:192-212. [PMID: 39865344 PMCID: PMC11792776 DOI: 10.1111/imcb.12848] [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: 11/04/2024] [Revised: 11/15/2024] [Accepted: 12/15/2024] [Indexed: 01/28/2025]
Abstract
Natural killer (NK) cells are emerging agents for cancer therapy. Several different cytokines are used to generate NK cells for adoptive immunotherapy including interleukin (IL)-2, IL-12, IL-15 and IL-18 in solution, and membrane-bound IL-21. These cytokines drive NK cell activation through the integration of signal transducers and activators of transcription (STAT) and nuclear factor-kappa B (NF-κB) pathways, which overlap and synergize, making it challenging to predict optimal cytokine combinations for both proliferation and cytotoxicity. We integrated functional assays for NK cells cultured in a variety of cytokine combinations with mathematical modeling using feature selection and mechanistic regression models. Our regression model successfully predicts NK cell proliferation for different cytokine combinations and indicates synergy of activated STATs and NF-κB transcription factors between priming and post-priming phases. The use of IL-21 in solution in the priming of NK cell culture resulted in an improved NK cell proliferation, without compromising cytotoxicity potential or interferon gamma secretion against hepatocellular carcinoma cell lines. Our work provides an integrative framework for interrogating NK cell proliferation and activation for cancer immunotherapy.
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Affiliation(s)
- Indrani Nayak
- Steve and Cindy Rasmussen Institute for Genomic MedicineAbigail Wexner Research Institute, Nationwide Children's HospitalColumbusOHUSA
| | - Rosalba Biondo
- School of Clinical and Experimental SciencesUniversity of SouthamptonSouthamptonUK
| | | | - Rebecca J Fulton
- School of Clinical and Experimental SciencesUniversity of SouthamptonSouthamptonUK
| | - Nina Möker
- Miltenyi Biotec B.V. & Co. KGBergisch GladbachGermany
| | | | - Salim I Khakoo
- School of Clinical and Experimental SciencesUniversity of SouthamptonSouthamptonUK
| | - Jayajit Das
- Steve and Cindy Rasmussen Institute for Genomic MedicineAbigail Wexner Research Institute, Nationwide Children's HospitalColumbusOHUSA
- Biomedical Sciences Graduate ProgramThe Ohio State UniversityColumbusOHUSA
- Department of PediatricsThe Ohio State UniversityColumbusOHUSA
- Pelotonia Institute for Immuno‐OncologyThe Ohio State UniversityColumbusOHUSA
- The Biophysics Graduate ProgramThe Ohio State UniversityColumbusOHUSA
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Grunwell JR, Huang M, Stephenson ST, Tidwell M, Ripple MJ, Fitzpatrick AM, Kamaleswaran R. RNA Sequencing Analysis of Monocytes Exposed to Airway Fluid From Children With Pediatric Acute Respiratory Distress Syndrome. Crit Care Explor 2024; 6:e1125. [PMID: 39365167 PMCID: PMC11458172 DOI: 10.1097/cce.0000000000001125] [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] [Indexed: 10/05/2024] Open
Abstract
OBJECTIVES Monocytes are plastic cells that assume different polarization states that can either promote inflammation or tissue repair and inflammation resolution. Polarized monocytes are partially defined by their transcriptional profiles that are influenced by environmental stimuli. The airway monocyte response in pediatric acute respiratory distress syndrome (PARDS) is undefined. To identify differentially expressed genes and networks using a novel transcriptomic reporter assay with donor monocytes exposed to the airway fluid of intubated children with and at-risk for PARDS. To determine differences in gene expression at two time points using the donor monocyte assay exposed to airway fluid from intubated children with PARDS obtained 48-96 hours following initial tracheal aspirate sampling. DESIGN In vitro pilot study carried out using airway fluid supernatant. SETTING Academic 40-bed PICU. PARTICIPANTS Fifty-seven children: 44 children with PARDS and 13 children at-risk for PARDS. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We performed bulk RNA sequencing using a transcriptomic reporter assay of monocytes exposed to airway fluid from intubated children to discover gene networks differentiating PARDS from at-risk for PARDS and those differentiating mild/moderate from severe PARDS. We also report differences in gene expression in children with PARDS 48-96 hours following initial tracheal aspirate sampling. We found that interleukin (IL)-10, IL-4, and IL-13, cytokine/chemokine signaling, and the senescence-associated secretory phenotype are upregulated in monocytes exposed to airway fluid from intubated children with PARDS compared with those at-risk for PARDS. Signaling by NOTCH, histone deacetylation/acetylation, DNA methylation, chromatin modifications (B-WICH complex), and RNA polymerase I transcription and its associated regulatory apparatus were upregulated in children with PARDS 48-96 hours following initial tracheal aspirate sampling. CONCLUSIONS We identified gene networks important to the PARDS airway immune response using bulk RNA sequencing from a monocyte reporter assay that exposed monocytes to airway fluid from intubated children with and at-risk for PARDS. Mechanistic investigations are needed to validate our findings.
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Affiliation(s)
- Jocelyn R. Grunwell
- Department of Pediatrics/Division of Critical Care Medicine, Egleston Hospital, Children’s Healthcare of Atlanta, Atlanta, GA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | - Min Huang
- Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA
| | | | - Mallory Tidwell
- Department of Pediatrics/Division of Critical Care Medicine, Egleston Hospital, Children’s Healthcare of Atlanta, Atlanta, GA
| | - Michael J. Ripple
- Department of Pediatrics/Division of Critical Care Medicine, Egleston Hospital, Children’s Healthcare of Atlanta, Atlanta, GA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | - Anne M. Fitzpatrick
- Department of Pediatrics/Division of Critical Care Medicine, Egleston Hospital, Children’s Healthcare of Atlanta, Atlanta, GA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | - Rishikesan Kamaleswaran
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
- Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA
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Lacinski RA, Dziadowicz SA, Stewart A, Chaharbakhshi E, Akhter H, Pisquiy JJ, Victory JH, Hardham JB, Chew C, Prorock A, Bao Y, Sol-Church K, Hobbs GR, Klein E, Nalesnik MA, Hu G, de Oliveira A, Santiago SP, Lindsey BA. Nanosphere pharmacodynamics improves safety of immunostimulatory cytokine therapy. iScience 2024; 27:108836. [PMID: 38303687 PMCID: PMC10831265 DOI: 10.1016/j.isci.2024.108836] [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: 09/26/2023] [Revised: 11/04/2023] [Accepted: 01/03/2024] [Indexed: 02/03/2024] Open
Abstract
Systemic administration of interleukin (IL)-12 induces potent anti-tumor immune responses in preclinical cancer models through the systemic activation of effector immune cells and release of proinflammatory cytokines. IL-12-loaded PLGA nanospheres (IL12ns) are hypothesized to improve therapeutic efficacy and thwart unwanted side effects observed in previous human clinical trials. Through the investigation of peripheral blood and local tissue immune responses in healthy BALB/c mice, the immune-protective pharmacodynamics of IL12ns were suggested. Nanospheres increased pro-inflammatory plasma cytokines/chemokines (IFN-γ, IL-6, TNF-α, and CXCL10) without inducing maladaptive transcriptomic signatures in circulating peripheral immune cells. Gene expression profiling revealed activation of pro-inflammatory signaling pathways in systemic tissues, the likely source of these effector cytokines. These data support that nanosphere pharmacodynamics, including shielding IL-12 from circulating immune cells, depositing peripherally in systemic immune tissues, and then slowly eluting bioactive cytokine, thereafter, are essential to safe immunostimulatory therapy.
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Affiliation(s)
- Ryan A. Lacinski
- Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
| | - Sebastian A. Dziadowicz
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26505, USA
- Bioinformatics Core, West Virginia University School of Medicine, Morgantown, WV 26505, USA
| | - Amanda Stewart
- Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
| | - Edwin Chaharbakhshi
- Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
| | - Halima Akhter
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26505, USA
- Bioinformatics Core, West Virginia University School of Medicine, Morgantown, WV 26505, USA
| | - John J. Pisquiy
- Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
| | - Jack H. Victory
- Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
| | - Joshua B. Hardham
- Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
| | - Claude Chew
- Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA
| | - Alyson Prorock
- Genome Analysis & Technology Core, University of Virginia School of Medicine, Charlottesville, VA 22904, USA
| | - Yongde Bao
- Genome Analysis & Technology Core, University of Virginia School of Medicine, Charlottesville, VA 22904, USA
| | - Katia Sol-Church
- Genome Analysis & Technology Core, University of Virginia School of Medicine, Charlottesville, VA 22904, USA
| | - Gerald R. Hobbs
- Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
| | - Edwin Klein
- Division of Laboratory Animal Resources, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Michael A. Nalesnik
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15260, USA
| | - Gangqing Hu
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26505, USA
- Bioinformatics Core, West Virginia University School of Medicine, Morgantown, WV 26505, USA
| | - Ana de Oliveira
- Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA
| | - Stell P. Santiago
- Department of Pathology, West Virginia University School of Medicine, Morgantown, WV 26505, USA
| | - Brock A. Lindsey
- Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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6
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Gaggioli MR, Jones AG, Panagi I, Washington EJ, Loney RE, Muench JH, Brennan RG, Thurston TLM, Ko DC. A single amino acid in the Salmonella effector SarA/SteE triggers supraphysiological activation of STAT3 for anti-inflammatory target gene expression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.14.580367. [PMID: 38405869 PMCID: PMC10888966 DOI: 10.1101/2024.02.14.580367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
Non-typhoidal Salmonella enterica cause an estimated 1 million cases of gastroenteritis annually in the United States. These serovars use secreted protein effectors to mimic and reprogram host cellular functions. We previously discovered that the secreted effector SarA (Salmonella anti-inflammatory response activator; also known as SteE) was required for increased intracellular replication of S. Typhimurium and production of the anti-inflammatory cytokine interleukin-10 (IL-10). SarA facilitates phosphorylation of STAT3 through a region of homology with the host cytokine receptor gp130. Here, we demonstrate that a single amino acid difference between SarA and gp130 is critical for the anti-inflammatory bias of SarA-STAT3 signaling. An isoleucine at the pY+1 position of the YxxQ motif in SarA (which binds the SH2 domain in STAT3) causes increased STAT3 phosphorylation and expression of anti-inflammatory target genes. This isoleucine, completely conserved in ~4000 Salmonella isolates, renders SarA a better substrate for tyrosine phosphorylation by GSK-3. GSK-3 is canonically a serine/threonine kinase that nonetheless undergoes tyrosine autophosphorylation at a motif that has an invariant isoleucine at the pY+1 position. Our results provide a molecular basis for how a Salmonella secreted effector achieves supraphysiological levels of STAT3 activation to control host genes during infection.
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Affiliation(s)
- Margaret R. Gaggioli
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Angela G. Jones
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Ioanna Panagi
- Department of Infectious Disease, Centre for Bacterial Resistance Biology, Imperial College London, London, UK
| | - Erica J. Washington
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
- Department of Biochemistry, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Rachel E. Loney
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
| | | | - Richard G. Brennan
- Department of Biochemistry, School of Medicine, Duke University, Durham, NC 27710, USA
| | - Teresa L. M. Thurston
- Department of Infectious Disease, Centre for Bacterial Resistance Biology, Imperial College London, London, UK
| | - Dennis C. Ko
- Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, NC 27710, USA
- Division of Infectious Diseases, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA
- Lead contact
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Cheemalavagu N, Shoger KE, Cao YM, Michalides BA, Botta SA, Faeder JR, Gottschalk RA. Predicting gene-level sensitivity to JAK-STAT signaling perturbation using a mechanistic-to-machine learning framework. Cell Syst 2024; 15:37-48.e4. [PMID: 38198893 PMCID: PMC10812086 DOI: 10.1016/j.cels.2023.12.006] [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: 05/01/2023] [Revised: 09/30/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024]
Abstract
The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway integrates complex cytokine signals via a limited number of molecular components, inspiring numerous efforts to clarify the diversity and specificity of STAT transcription factor function. We developed a computational framework to make global cytokine-induced gene predictions from STAT phosphorylation dynamics, modeling macrophage responses to interleukin (IL)-6 and IL-10, which signal through common STATs, but with distinct temporal dynamics and contrasting functions. Our mechanistic-to-machine learning model identified cytokine-specific genes associated with late pSTAT3 time frames and a preferential pSTAT1 reduction upon JAK2 inhibition. We predicted and validated the impact of JAK2 inhibition on gene expression, identifying genes that were sensitive or insensitive to JAK2 variation. Thus, we successfully linked STAT signaling dynamics to gene expression to support future efforts targeting pathology-associated STAT-driven gene sets. This serves as a first step in developing multi-level prediction models to understand and perturb gene expression outputs from signaling systems. A record of this paper's transparent peer review process is included in the supplemental information.
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Affiliation(s)
- Neha Cheemalavagu
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Karsen E Shoger
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Yuqi M Cao
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Brandon A Michalides
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Samuel A Botta
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - James R Faeder
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Rachel A Gottschalk
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
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8
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Avey AM, Devos F, Roberts AG, Essawy ESE, Baar K. Inhibiting JAK1, not NF-κB, reverses the effect of pro-inflammatory cytokines on engineered human ligament function. Matrix Biol 2024; 125:100-112. [PMID: 38151137 DOI: 10.1016/j.matbio.2023.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/23/2023] [Accepted: 12/23/2023] [Indexed: 12/29/2023]
Abstract
The role of inflammation in chronic tendon/ligament injury is hotly debated. There is less debate about inflammation following acute injury. To better understand the effect of acute inflammation, in this study we developed a multi-cytokine model of inflammatory tendinitis. The combined treatment with TNF-α, IL-1β, and IL-6, at dosages well below what are routinely used in vitro, decreased the mechanical properties and collagen content of engineered human ligaments. Treatment with this cytokine mixture resulted in an increase in phospho-NF-κB and MMP-1, did not affect procollagen production, and decreased STAT3 phosphorylation relative to controls. Using this more physiologically relevant model of acute inflammation, we inhibited NF-κB or JAK1 signaling in an attempt to reverse the negative effects of the cytokine mixture. Surprisingly, NF-κB inhibition led to an even greater decrease in mechanical function and collagen content. By contrast, inhibiting JAK1 led to an increase in mechanical properties, collagen content and thermal stability concomitant with a decrease in MMP-1. Our results suggest that inhibition of JAK1, not NF-κB, reverses the negative effects of pro-inflammatory cytokines on collagen content and mechanics in engineered human ligaments.
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Affiliation(s)
- Alec M Avey
- Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, CA 95616, United States
| | - Florence Devos
- Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, CA 95616, United States
| | - Albany G Roberts
- Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, CA 95616, United States
| | - El Sayed El Essawy
- Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, CA 95616, United States; Department of Sport Psychology, Mansoura University, Dakahlia Governorate 35516, Egypt
| | - Keith Baar
- Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, CA 95616, United States; Department of Physiology and Membrane Biology, University of California Davis, Davis, CA 95616, United States; VA Northern California Health Care System, Mather, CA 95655, United States.
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9
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Nastasi N, Pasha A, Bruno G, Subbiani A, Pietrovito L, Leo A, Scala L, de Simone L, Casazza G, Lunardi F, Taddei ML, Tamburini A, Tondo A, Favre C, Calvani M. Blockade of IL-10 Signaling Ensures Mifamurtide Efficacy in Metastatic Osteosarcoma. Cancers (Basel) 2023; 15:4744. [PMID: 37835437 PMCID: PMC10571595 DOI: 10.3390/cancers15194744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/18/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
Osteosarcoma (OS) is the most common primary malignancy of the bone, highly aggressive and metastasizing, and it mainly affects children and adolescents. The current standard of care for OS is a combination of surgery and chemotherapy. However, these treatment options are not always successful, especially in cases of metastatic or recurrent osteosarcomas. For this reason, research into new therapeutic strategies is currently underway, and immunotherapies have received considerable attention. Mifamurtide stands out among the most studied immunostimulant drugs; nevertheless, there are very conflicting opinions on its therapeutic efficacy. Here, we aimed to investigate mifamurtide efficacy through in vitro and in vivo experiments. Our results led us to identify a new possible target useful to improve mifamurtide effectiveness on metastatic OS: the cytokine interleukin-10 (IL-10). We provide experimental evidence that the synergic use of an anti-IL-10 antibody in combination with mifamurtide causes a significantly increased mortality rate in highest-grade OS cells and lower metastasis in an in vivo model compared with mifamurtide alone. Overall, our data suggest that mifamurtide in combination with an anti-IL-10 antibody could be proposed as a new treatment protocol to be studied to improve the outcomes of OS patients.
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Affiliation(s)
- Nicoletta Nastasi
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (N.N.); (A.P.); (G.B.); (A.S.); (A.T.); (A.T.); (C.F.)
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (L.P.); (A.L.); (M.L.T.)
| | - Amada Pasha
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (N.N.); (A.P.); (G.B.); (A.S.); (A.T.); (A.T.); (C.F.)
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (L.P.); (A.L.); (M.L.T.)
| | - Gennaro Bruno
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (N.N.); (A.P.); (G.B.); (A.S.); (A.T.); (A.T.); (C.F.)
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (L.P.); (A.L.); (M.L.T.)
| | - Angela Subbiani
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (N.N.); (A.P.); (G.B.); (A.S.); (A.T.); (A.T.); (C.F.)
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (L.P.); (A.L.); (M.L.T.)
| | - Laura Pietrovito
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (L.P.); (A.L.); (M.L.T.)
| | - Angela Leo
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (L.P.); (A.L.); (M.L.T.)
| | - Lucia Scala
- Pharmaceutical Unit, A. Meyer Children’s Hospital, Scientific Institute for Research, Hospitalisation and Health Care, 50139 Florence, Italy; (L.S.); (L.d.S.)
| | - Lorena de Simone
- Pharmaceutical Unit, A. Meyer Children’s Hospital, Scientific Institute for Research, Hospitalisation and Health Care, 50139 Florence, Italy; (L.S.); (L.d.S.)
| | - Gabriella Casazza
- Pediatric Oncology–Hematology Unit, Pisa University Hospital, 56126 Pisa, Italy; (G.C.); (F.L.)
| | - Federica Lunardi
- Pediatric Oncology–Hematology Unit, Pisa University Hospital, 56126 Pisa, Italy; (G.C.); (F.L.)
| | - Maria Letizia Taddei
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (L.P.); (A.L.); (M.L.T.)
| | - Angela Tamburini
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (N.N.); (A.P.); (G.B.); (A.S.); (A.T.); (A.T.); (C.F.)
| | - Annalisa Tondo
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (N.N.); (A.P.); (G.B.); (A.S.); (A.T.); (A.T.); (C.F.)
| | - Claudio Favre
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (N.N.); (A.P.); (G.B.); (A.S.); (A.T.); (A.T.); (C.F.)
| | - Maura Calvani
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (N.N.); (A.P.); (G.B.); (A.S.); (A.T.); (A.T.); (C.F.)
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Cheemalavagu N, Shoger KE, Cao YM, Michalides BA, Botta SA, Faeder JR, Gottschalk RA. Predicting gene level sensitivity to JAK-STAT signaling perturbation using a mechanistic-to-machine learning framework. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.19.541151. [PMID: 37292918 PMCID: PMC10245690 DOI: 10.1101/2023.05.19.541151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The JAK-STAT pathway integrates complex cytokine signals via a limited number of molecular components, inspiring numerous efforts to clarify the diversity and specificity of STAT transcription factor function. We developed a computational workflow to make global cytokine-induced gene predictions from STAT phosphorylation dynamics, modeling macrophage responses to IL-6 and IL-10, which signal through common STATs, but with distinct temporal dynamics and contrasting functions. Our mechanistic-to-machine learning model identified select cytokine-induced gene sets associated with late pSTAT3 timeframes and a preferential pSTAT1 reduction upon JAK2 inhibition. We predicted and validated the impact of JAK2 inhibition on gene expression, identifying dynamically regulated genes that were sensitive or insensitive to JAK2 variation. Thus, we successfully linked STAT signaling dynamics to gene expression to support future efforts targeting pathology-associated STAT-driven gene sets. This serves as a first step in developing multi-level prediction models to understand and perturb gene expression outputs from signaling systems.
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Affiliation(s)
- Neha Cheemalavagu
- University of Pittsburgh, Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA USA
- University of Pittsburgh, Department of Immunology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA USA
- Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA USA
| | - Karsen E. Shoger
- University of Pittsburgh, Department of Immunology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA USA
- Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA USA
| | - Yuqi M. Cao
- University of Pittsburgh, Department of Immunology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA USA
- Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA USA
| | - Brandon A. Michalides
- University of Pittsburgh, Department of Immunology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA USA
- Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA USA
| | - Samuel A. Botta
- University of Pittsburgh, Department of Immunology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA USA
- Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA USA
| | - James R. Faeder
- University of Pittsburgh, Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA USA
- Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA USA
| | - Rachel A. Gottschalk
- University of Pittsburgh, Department of Immunology, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA USA
- Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA USA
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11
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Pilipović I, Stojić-Vukanić Z, Prijić I, Jasnić N, Djordjević J, Leposavić G. β-Adrenoceptor Blockade Moderates Neuroinflammation in Male and Female EAE Rats and Abrogates Sexual Dimorphisms in the Major Neuroinflammatory Pathways by Being More Efficient in Males. Cell Mol Neurobiol 2023; 43:1237-1265. [PMID: 35798933 PMCID: PMC11414456 DOI: 10.1007/s10571-022-01246-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 06/18/2022] [Indexed: 11/03/2022]
Abstract
Our previous studies showed more severe experimental autoimmune encephalomyelitis (EAE) in male compared with female adult rats, and moderating effect of propranolol-induced β-adrenoceptor blockade on EAE in females, the effect associated with transcriptional stimulation of Nrf2/HO-1 axis in spinal cord microglia. This study examined putative sexual dimorphism in propranolol action on EAE severity. Propranolol treatment beginning from the onset of clinical EAE mitigated EAE severity in rats of both sexes, but to a greater extent in males exhibiting higher noradrenaline levels and myeloid cell β2-adrenoceptor expression in spinal cord. This correlated with more prominent stimulatory effects of propranolol not only on CX3CL1/CX3CR1/Nrf2/HO-1 cascade, but also on Stat3/Socs3 signaling axis in spinal cord microglia/myeloid cells (mirrored in the decreased Stat3 and the increased Socs3 expression) from male rats compared with their female counterparts. Propranolol diminished the frequency of activated cells among microglia, increased their phagocyting/endocyting capacity, and shifted cytokine secretory profile of microglia/blood-borne myeloid cells towards an anti-inflammatory/neuroprotective phenotype. Additionally, it downregulated the expression of chemokines (CCL2, CCL19/21) driving T-cell/monocyte trafficking into spinal cord. Consequently, in propranolol-treated rats fewer activated CD4+ T cells and IL-17+ T cells, including CD4+IL17+ cells coexpressing IFN-γ/GM-CSF, were recovered from spinal cord of propranolol-treated rats compared with sex-matched saline-injected controls. All the effects of propranolol were more prominent in males. The study as a whole disclosed that sexual dimorphism in multiple molecular mechanisms implicated in EAE development may be responsible for greater severity of EAE in male rats and sexually dimorphic action of substances affecting them. Propranolol moderated EAE severity more effectively in male rats, exhibiting greater spinal cord noradrenaline (NA) levels and myeloid cell β2-adrenoceptor (β2-AR) expression than females. Propranolol affected CX3CR1/Nrf2/HO-1 and Stat3/Socs3 signaling axes in myeloid cells, favored their anti-inflammatory/neuroprotective phenotype and, consequently, reduced Th cell reactivation and differentiation into highly pathogenic IL-17/IFN-γ/GM-CSF-producing cells.
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Affiliation(s)
- Ivan Pilipović
- Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia
| | - Zorica Stojić-Vukanić
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Ivana Prijić
- Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia
| | - Nebojša Jasnić
- Institute for Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Jelena Djordjević
- Institute for Physiology and Biochemistry, Faculty of Biology, University of Belgrade, Belgrade, Serbia
| | - Gordana Leposavić
- Department of Pathobiology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221, Belgrade, Serbia.
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12
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Pilipović I, Stojić-Vukanić Z, Leposavić G. Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis. Pharmacol Ther 2023; 243:108358. [PMID: 36804434 DOI: 10.1016/j.pharmthera.2023.108358] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 02/03/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023]
Abstract
This review summarizes recent findings related to the role of the sympathetic nervous system (SNS) in pathogenesis of multiple sclerosis (MS) and its commonly used experimental model - experimental autoimmune encephalomyelitis (EAE). They indicate that noradrenaline, the key end-point mediator of the SNS, acting through β-adrenoceptor, has a contributory role in the early stages of MS/EAE development. This stage is characterized by the SNS hyperactivity (increased release of noradrenaline) reflecting the net effect of different factors, such as the disease-associated inflammation, stress, vitamin D hypovitaminosis, Epstein-Barr virus infection and dysbiosis. Thus, the administration of propranolol, a non-selective β-adrenoceptor blocker, readily crossing the blood-brain barrier, to experimental rats before the autoimmune challenge and in the early (preclinical/prodromal) phase of the disease mitigates EAE severity. This phenomenon has been ascribed to the alleviation of neuroinflammation (due to attenuation of primarily microglial activation/proinflammatory functions) and the diminution of the magnitude of the primary CD4+ T-cell autoimmune response (the effect associated with impaired autoantigen uptake by antigen presenting cells and their migration into draining lymph nodes). The former is partly related to breaking of the catecholamine-dependent self-amplifying microglial feed-forward loop and the positive feedback loop between microglia and the SNS, leading to down-regulation of the SNS hyperactivity and its enhancing influence on microglial activation/proinflammatory functions and the magnitude of autoimmune response. The effects of propranolol are shown to be more prominent in male EAE animals, the phenomenon important as males (like men) are likely to develop clinically more severe disease. Thus, these findings could serve as a firm scientific background for formulation of a new sex-specific immune-intervention strategy for the early phases of MS (characterized by the SNS hyperactivity) exploiting anti-(neuro)inflammatory and immunomodulatory properties of propranolol and other relatively cheap and safe adrenergic drugs with similar therapeutic profile.
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Affiliation(s)
- Ivan Pilipović
- Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia
| | - Zorica Stojić-Vukanić
- University of Belgrade-Faculty of Pharmacy, Department of Microbiology and Immunology, Belgrade, Serbia
| | - Gordana Leposavić
- University of Belgrade-Faculty of Pharmacy, Department of Pathobiology, Belgrade, Serbia.
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13
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Matsuzaki S, Pouly JL, Canis M. IL-10 is not anti-fibrotic but pro-fibrotic in endometriosis: IL-10 treatment of endometriotic stromal cells in vitro promotes myofibroblast proliferation and collagen type I protein expression. Hum Reprod 2023; 38:14-29. [PMID: 36413036 DOI: 10.1093/humrep/deac248] [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: 08/01/2022] [Revised: 10/25/2022] [Indexed: 11/23/2022] Open
Abstract
STUDY QUESTION Is interleukin-10 (IL-10) anti-fibrotic in endometriosis? SUMMARY ANSWER IL-10 is not anti-fibrotic but pro-fibrotic in endometriosis, because IL-10 treatment of endometriotic stromal cells in vitro promotes myofibroblast proliferation and collagen type I protein expression. WHAT IS KNOWN ALREADY We previously showed that persistent activation of signal transducer and activator of transcription 3 (STAT3) via IL-6 trans-signaling promotes fibrosis of endometriosis. Studies showed marked anti-fibrotic effects of IL-10 via the STAT3 signaling pathway, which is generally considered to be anti-inflammatory, in various organs. STUDY DESIGN, SIZE, DURATION Endometrial and/or endometriotic samples of 54 patients who had histological evidence of deep endometriosis, and endometrial samples from 30 healthy fertile women were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS The effects of IL-10/STAT3 signaling as well as inhibition of STAT3 activation by knockdown of STAT3 gene on the pro-fibrotic phenotype in endometrial and endometriotic stromal cells in vitro were investigated. Then, the effects of various time points of IL-10 treatment in combination with transforming growth factor (TGF)-β1 and/or IL-6/soluble IL-6 receptor (sIL-6R) on the profibrotic phenotype of endometrial and endometriotic stromal cells were investigated. MAIN RESULTS AND THE ROLE OF CHANCE IL-10 induced pro-fibrotic phenotype (cell proliferation, collagen type I synthesis, α-smooth muscle actin positive stress fibers and collagen gel contraction) of endometriotic stromal cells. Knockdown of STAT3 gene decreased the IL-10 induced pro-fibrotic phenotype of endometriotic stromal cells. In contrast, IL-10 had no significant effects on pro-fibrotic phenotype of endometrial stromal cells of healthy women. Sequential IL-10 treatment with or without TGF-β1 and/or IL-6/sIL-6R induced persistent activation of STAT3 and significantly increased proliferation of myofibroblasts (cells with α-smooth muscle actin positive stress fibers) and protein expression of collagen type I in endometriotic stromal cells. TGF-β1 and/or IL-6/sIL6RIL-6/sIL6R treatment significantly increased tissue inhibitor of metalloproteinase 1 (TIMP1) protein expression, whereas IL-10 had no significant effects. Knockdown of STAT3 gene significantly decreased the TGF-β1 and/or IL-6/sIL6R induced TIMP1 protein expression. In contrast, pre-treatment with IL-10 before TGF-β1 and/or IL-6/sIL-6R treatment and sequential IL-10 treatment with or without TGF-β1 and/or IL-6/sIL-6R significantly decreased proliferation of fibroblasts (cells without α-smooth muscle actin positive stress fibers) and collagen type I protein expression in endometrial stromal cells of healthy women. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Given the large number of complex interactions and signaling pathways of pro- and anti-inflammatory mediators that are involved in the pathophysiology of endometriosis, the present study investigated only a very small portion of the whole. Further in vivo studies are required to validate the present findings. WIDER IMPLICATIONS OF THE FINDINGS Inflammatory mediators in the pathophysiology of endometriosis have been extensively investigated as potential therapeutic targets. However, the present study showed that anti-inflammatory signals of IL-10 and IL-6 through persistent STAT3 activation may promote endometriosis fibrosis. Therapeutic strategies, such as suppression of 'inflammation', might dysregulate the cross-regulation of 'pro- and anti-inflammatory mediators', leading to detrimental effects in patients with endometriosis, such as fibrosis. To develop new, but not deleterious, therapeutic strategies, studies are required to investigate whether, how and what 'anti-inflammatory mediators' along with pro-inflammatory mediators are involved in individual patients with endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This study was supported in part by KARL STORZ SE & Co. KG (Tuttlingen, Germany). The authors have no conflict of interest to disclose.
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Affiliation(s)
- Sachiko Matsuzaki
- CHU Clermont-Ferrand, Chirurgie Gynécologique, Clermont-Ferrand, France.,Université Clermont Auvergne, Institut Pascal, UMR6602, CNRS/UCA/SIGMA, Clermont-Ferrand, France
| | - Jean-Luc Pouly
- CHU Clermont-Ferrand, Chirurgie Gynécologique, Clermont-Ferrand, France.,Université Clermont Auvergne, Institut Pascal, UMR6602, CNRS/UCA/SIGMA, Clermont-Ferrand, France
| | - Michel Canis
- CHU Clermont-Ferrand, Chirurgie Gynécologique, Clermont-Ferrand, France.,Université Clermont Auvergne, Institut Pascal, UMR6602, CNRS/UCA/SIGMA, Clermont-Ferrand, France
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14
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Eskandari SK, Gaya da Costa M, Faria B, Petr V, Azzi JR, Berger SP, Seelen MAJ, Damman J, Poppelaars F. An interleukin 6-based genetic risk score strengthened with interleukin 10 polymorphisms associated with long-term kidney allograft outcomes. Am J Transplant 2022; 22 Suppl 4:45-57. [PMID: 36453708 PMCID: PMC10107952 DOI: 10.1111/ajt.17212] [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: 08/15/2022] [Revised: 10/03/2022] [Accepted: 10/21/2022] [Indexed: 12/05/2022]
Abstract
Of all kidney transplants, half are still lost in the first decade after transplantation. Here, using genetics, we probed whether interleukin 6 (IL-6) could be a target in kidney transplantation to improve graft survival. Additionally, we investigated if a genetic risk score (GRS) based on IL6 and IL10 variants could improve prognostication of graft loss. In a prospective cohort study, DNA of 1271 donor-recipient kidney transplant pairs was analyzed for the presence of IL6, IL6R, IL10, IL10RA, and IL10RB variants. These polymorphisms and their GRS were then associated with 15-year death-censored allograft survival. The C|C-genotype of the IL6 polymorphism in donor kidneys and the combined C|C-genotype in donor-recipient pairs were both associated with a reduced risk of graft loss (p = .043 and p = .042, respectively). Additionally, the GRS based on IL6, IL6R, IL10, IL10RA, and IL10RB variants was independently associated with the risk of graft loss (HR 1.53, 95%-CI [1.32-1.84]; p < .001). Notably, the GRS improved risk stratification and prediction of graft loss beyond the level of contemporary clinical markers. Our findings reveal the merits of a polygenic IL-6-based risk score strengthened with IL-10- polymorphisms for the prognostication and risk stratification of late graft failure in kidney transplantation.
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Affiliation(s)
- Siawosh K. Eskandari
- Division of Nephrology, Department of Internal MedicineUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
- Transplantation Research CenterBrigham and Women's Hospital, Harvard Medical SchoolBostonMassachusettsUSA
| | - Mariana Gaya da Costa
- Division of Nephrology, Department of Internal MedicineUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
- Department of AnesthesiologyUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | - Bernardo Faria
- Division of Nephrology, Department of Internal MedicineUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
- Nephrology R&D GroupInstitute for Research and Innovation in Health (i3S), São João University Hospital Center, University of PortoPortoPortugal
| | - Vojtech Petr
- Department of NephrologyInstitute for Clinical and Experimental MedicinePragueCzech Republic
| | - Jamil R. Azzi
- Transplantation Research CenterBrigham and Women's Hospital, Harvard Medical SchoolBostonMassachusettsUSA
| | - Stefan P. Berger
- Division of Nephrology, Department of Internal MedicineUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | - Marc A. J. Seelen
- Division of Nephrology, Department of Internal MedicineUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | - Jeffrey Damman
- Department of PathologyErasmus University Medical Center, Erasmus UniversityRotterdamThe Netherlands
| | - Felix Poppelaars
- Division of Nephrology, Department of Internal MedicineUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
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15
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Allen JK, Sutherland TC, Prater AR, Geoffroy CG, Pellois JP. In vivo peptide-based delivery of a gene-modifying enzyme into cells of the central nervous system. SCIENCE ADVANCES 2022; 8:eabo2954. [PMID: 36170360 PMCID: PMC9519033 DOI: 10.1126/sciadv.abo2954] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 08/10/2022] [Indexed: 06/16/2023]
Abstract
We report on the successful delivery of the Cre recombinase enzyme in the neural cells of mice in vivo by simple coinjection with peptides derived from HIV-TAT. Cre delivery activates the expression of a reporter gene in both neurons and astrocytes of the cortex without tissue damage and with a transduction efficiency that parallels or exceeds that of a commonly used adeno-associated virus. Our data indicate that the delivery peptides mediate efficient endosomal leakage and cytosolic escape in cells that have endocytosed Cre. The peptides, therefore, act in trans and do not require conjugation to the payload, greatly simplifying sample preparation. Moreover, the delivery peptides are exclusively composed of natural amino acids and are consequently readily degradable and processed by cells. We envision that this approach will be beneficial to applications that require the transient introduction of proteins into cells in vivo.
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Affiliation(s)
- Jason K. Allen
- Department of Biochemistry and Biophysics, and Department of Chemistry, Texas A&M University, College Station, TX 77843, USA
| | - Theresa C. Sutherland
- Department of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University, Bryan, TX 77807, USA
| | - Austin R. Prater
- Department of Biochemistry and Biophysics, and Department of Chemistry, Texas A&M University, College Station, TX 77843, USA
| | - Cédric G. Geoffroy
- Department of Neuroscience and Experimental Therapeutics, School of Medicine, Texas A&M University, Bryan, TX 77807, USA
| | - Jean-Philippe Pellois
- Department of Biochemistry and Biophysics, and Department of Chemistry, Texas A&M University, College Station, TX 77843, USA
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16
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Matsumura Y, Watanabe R, Fujimoto M. Suppressive mechanisms of regulatory B cells in mice and humans. Int Immunol 2022; 35:55-65. [PMID: 36153768 PMCID: PMC9918854 DOI: 10.1093/intimm/dxac048] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/23/2022] [Indexed: 11/14/2022] Open
Abstract
B cells include immune-suppressive fractions, called regulatory B cells (Bregs), which regulate inflammation primarily through an interleukin 10 (IL-10)-mediated inhibitory mechanism. Several B-cell fractions have been reported as IL-10-producing Bregs in murine disease models and human inflammatory responses including autoimmune diseases, infectious diseases, cancer and organ-transplant rejection. Although the suppressive functions of Bregs have been explored through the hallmark molecule IL-10, inhibitory cytokines and membrane-binding molecules other than IL-10 have also been demonstrated to contribute to Breg activities. Transcription factors and surface antigens that are characteristically expressed in Bregs are also being elucidated. Nevertheless, defining Bregs is still challenging because their active periods and differentiation stages vary among disease models. The identity of the diverse Breg fractions is also under debate. In the first place, since regulatory functions of Bregs are mostly evaluated by ex vivo stimulation, the actual in vivo phenotypes and functions may not be reflected by the ex vivo observations. In this article, we provide a historical overview of studies that established the characteristics of Bregs and review the various suppressive mechanisms that have been reported to be used by Bregs in murine and human disease conditions. We are only part-way through but the common phenotypes and functions of Bregs are still emerging.
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Affiliation(s)
- Yutaka Matsumura
- Department of Dermatology, Graduate School of Medicine, Faculty of Medicine, Osaka University, Osaka, 565-0871, Japan
| | - Rei Watanabe
- Department of Dermatology, Graduate School of Medicine, Faculty of Medicine, Osaka University, Osaka, 565-0871, Japan,Department of Integrative Medicine for Allergic and Immunological Diseases, Graduate School of Medicine/Faculty of Medicine, Osaka University, Osaka, 565-0871, Japan
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Ma Y, Zhang Y, Bi Y, He L, Li D, Wang D, Wang M, Wang X. Diagnostic value of carcinoembryonic antigen combined with cytokines in serum of patients with colorectal cancer. Medicine (Baltimore) 2022; 101:e30787. [PMID: 36123861 PMCID: PMC9478299 DOI: 10.1097/md.0000000000030787] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
In clinical practice, colorectal cancer (CRC) is difficult to distinguish from ulcerative colitis and colon polyps. Practical markers are useful for diagnosing and treating patients with CRC. Carcinoembryonic antigen (CEA) is a biomarker for diagnosing patients with CRC. However, the diagnostic sensitivity and specificity of CEA are not high. Interleukin (IL)-10, IL-17A, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and transforming growth factor beta (TGF-β) are assumed to be closely related to the occurrence and development of human cancer. Some have been used as diagnostic markers in CRC. It remains unclear whether cytokines in combination with CEA could be used as biomarkers for the diagnosis of CRC. Serum levels of IL-10, IL-17, TNF-α, IFN-γ, and TGF-β in patients with CRC, ulcerative colitis, colonic polyps, stomach cancer, and healthy controls were measured by enzyme-linked immunosorbent assay. The serum level of CEA was detected using electrochemiluminescence. The value of the cytokines combined with CEA as a biomarker panel for the diagnosis of CRC was assessed. CEA, IL-10, IL-17A, TNF-α, and TGF-β levels were significantly increased in CRC. CEA displayed a higher specificity than the other cytokines. IL-17A, TNF-α, and TGF-β displayed higher sensitivities than CEA, IL-10, and IFN-γ in the diagnosis of CRC. The combination of serum CEA, IL-17A, and TNF-α achieved higher diagnostic efficacy for CRC (area under the curve = 0.935). The combination of CEA, IL-17, and TNF-α has better diagnostic efficacy than CEA alone in CRC. A panel containing IL-17A, TNF-α, and CEA could be a promising molecular biomarker panel to diagnostically differentiate CRC from ulcerative colitis, colon polyps, and stomach cancer.
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Affiliation(s)
- Yunfeng Ma
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi Province, China
- *Correspondence: Yunfeng Ma, Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, 76 West Yanta Road, Xi’an, Shaanxi, Province, 710061, China (e-mail: )
| | - Ya Zhang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi Province, China
- Department of Clinical Laboratory, An’kang Central Hospital, An’kang, Shaanxi Province, China
| | - Yu Bi
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi Province, China
| | - Longmei He
- Department of Clinical Laboratory, Shaanxi Provincial Hospital of Chinese Medicine, Xi’an, Shaanxi Province, China
| | - Dandan Li
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi Province, China
| | - Dan Wang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi Province, China
| | - Mengying Wang
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi Province, China
| | - Xiaoqin Wang
- The Clinical Laboratory, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
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18
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COVID-19 vs. Cancer Immunosurveillance: A Game of Thrones within an Inflamed Microenviroment. Cancers (Basel) 2022; 14:cancers14174330. [PMID: 36077865 PMCID: PMC9455004 DOI: 10.3390/cancers14174330] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
The COVID-19 pandemic accounts for more than 500 million confirmed infections and over 6 million deaths worldwide in the last 2 years. SARS-CoV-2 causes a highly complex form of inflammation that affects the human organism both acutely and chronically. In the same line, cancer as an inflammation-induced and immune-editing disease appears to cross-react with immune system at different levels including early interactions during carcinogenesis and later cross-talks within the tumor microenvironment. With all that in mind, a reasonable question one might address is whether the SARS-CoV-2 infection and the derived "long lasting inflammatory status" that is frequently observed in patients, might affect the cancer immunosurveillance mechanisms and consequently their risk of developing cancer, as well as the tumor and immune cell behaviors within the inflamed microenvironment. On this context, this review intends to outline and discuss the existing knowledge on SARS-CoV-2-mediated immunomodulation under the prism of changes that might be able to interfere with cancer cell immunoescape and the overall tumor progression and response to conventional therapeutics. Our goal is to highlight a potential interplay between the COVID-19 immunopathology and cancer immune-microenvironment that may pave the way for thorough investigation in the future.
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19
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Thanki KK, Johnson P, Higgins EJ, Maskey M, Phillips C, Dash S, Almenas FA, Govar AA, Tian B, Villéger R, Beswick E, Wang R, Szabo C, Chao C, Pinchuk IV, Hellmich MR, Módis K. Deletion of cystathionine-γ-lyase in bone marrow-derived cells promotes colitis-associated carcinogenesis. Redox Biol 2022; 55:102417. [PMID: 35933902 PMCID: PMC9357841 DOI: 10.1016/j.redox.2022.102417] [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: 05/09/2022] [Revised: 06/27/2022] [Accepted: 07/17/2022] [Indexed: 11/24/2022] Open
Abstract
Ulcerative colitis (UC) is characterized by widespread relapsing inflammation of the colonic mucosa. Colitis-associated cancer (CAC) is one of the most serious complications of a prolonged history of UC. Hydrogen sulfide (H2S) has emerged as an important physiological mediator of gastrointestinal homeostasis, limiting mucosal inflammation and promoting tissue healing in response to injury. Inhibition of cystathionine-γ-lyase (CSE)-dependent H2S production in animal models of UC has been shown to exacerbate colitis and delay tissue repair. It is unknown whether CSE plays a role in CAC, or the downregulation of CSE expression and/or activity promotes CAC development. In humans, we observed a significant decrease in CSE expression in colonic biopsies from patients with UC. Using the dextran sodium sulfate (DSS) model of epithelium injury-induced colitis and global CSE KO mouse strain, we demonstrated that CSE is critical in limiting mucosal inflammation and stimulating epithelial cell proliferation in response to injury. In vitro studies showed that CSE activity stimulates epithelial cell proliferation, basal and cytokine-stimulated cell migration, as well as cytokine regulation of transepithelial permeability. In the azoxymethane (AOM)/DSS model of CAC, the loss of CSE expression accelerated both the development and progression of CAC. The increased tumor multiplicity and severity of CAC observed in CSE-KO mice were associated with reduced levels of mucosal IL-10 expression and increased levels of IL-6. Restoring CSE expression in bone marrow (BM) cells of CSE-KO mice through reciprocal BM transplantation raised mucosal IL-10 expression, decreased IL-6 level, and reduced the number of aberrant crypt foci and tumors in AOM/DSS-treated mice. These studies demonstrate that CSE expression in BM cells plays a critical role in suppressing CAC in mice. Furthermore, the data suggest that the inhibitory effects of CSE on the development of CAC are due, in part, to the modulation of mucosal pro-and anti-inflammatory cytokine expression.
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Affiliation(s)
- Ketan K Thanki
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Paul Johnson
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Edward J Higgins
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Manjit Maskey
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Ches'Nique Phillips
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Swetaleena Dash
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | | | | | - Bing Tian
- Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA.
| | - Romain Villéger
- Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA.
| | - Ellen Beswick
- Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
| | - Rui Wang
- Department of Biology, York University, Toronto, ON, Canada.
| | - Csaba Szabo
- Chair of Pharmacology, Section of Science and Medicine, University of Fribourg, Fribourg, Switzerland.
| | - Celia Chao
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Irina V Pinchuk
- Department of Internal Medicine, University of Texas Medical, Galveston, TX, USA.
| | - Mark R Hellmich
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
| | - Katalin Módis
- Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
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20
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Old and New Aspects of H. pylori-Associated Inflammation and Gastric Cancer. CHILDREN 2022; 9:children9071083. [PMID: 35884067 PMCID: PMC9322908 DOI: 10.3390/children9071083] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 12/16/2022]
Abstract
H. pylori is involved in the development of 80% of gastric cancers and 5.5% of all malignant conditions worldwide. Its persistence within the host’s stomach causes chronic inflammation, which is a well-known hallmark of carcinogenesis. A wide range of cytokines was reported to be involved in the initiation and long-term persistence of this local and systemic inflammation. IL-8 was among the first cytokines described to be increased in patients with H. pylori infection. Although, this cytokine was initially identified to exert a chemoattracting effect that represents a trigger for the activation of inflammatory cells within H.-pylori-infected mucosa, more recent studies failed in encountering any association between IL-8 and H. pylori infection. IL-6 is a multifunctional, pleiotropic and multipotent cytokine involved in mediating the interaction between innate and adaptive immunity with a dichotomous role acting as both a proinflammatory and an anti-inflammatory cytokine depending on the signaling pathway. IL-1α functions as a promoter of angiogenesis and vascular endothelial cell proliferation in gastric carcinoma since it is closely related to H.-pylori-induced inflammation in children. IL-1β is an essential trigger and enhancer of inflammation. The association between a low IL-1β level and an increased TNF-α level might be considered a risk factor for peptic ulcer disease in the setting of H. pylori infection. IL-10 downregulates both cytotoxic inflammatory responses and cell-mediated immune responses. H. pylori uses the immunosuppressive role of IL-10 to favor its escape from the host’s immune system. TGFβ is a continuous inflammatory mediator that promotes the adherence of H. pylori to the host’s cells and their subsequent colonization. The role of H.-pylori-induced inflammatory responses in the onset of gastric carcinogenesis seems to represent the missing puzzle piece for designing effective preventive and therapeutic strategies in patients with H.-pylori-associated gastric cancer.
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21
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Serra A, del Giudice G, Kinaret PAS, Saarimäki LA, Poulsen SS, Fortino V, Halappanavar S, Vogel U, Greco D. Characterization of ENM Dynamic Dose-Dependent MOA in Lung with Respect to Immune Cells Infiltration. NANOMATERIALS 2022; 12:nano12122031. [PMID: 35745370 PMCID: PMC9228743 DOI: 10.3390/nano12122031] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/08/2022] [Accepted: 06/09/2022] [Indexed: 02/01/2023]
Abstract
The molecular effects of exposures to engineered nanomaterials (ENMs) are still largely unknown. In classical inhalation toxicology, cell composition of bronchoalveolar lavage (BAL) is a toxicity indicator at the lung tissue level that can aid in interpreting pulmonary histological changes. Toxicogenomic approaches help characterize the mechanism of action (MOA) of ENMs by investigating the differentially expressed genes (DEG). However, dissecting which molecular mechanisms and events are directly induced by the exposure is not straightforward. It is now generally accepted that direct effects follow a monotonic dose-dependent pattern. Here, we applied an integrated modeling approach to study the MOA of four ENMs by retrieving the DEGs that also show a dynamic dose-dependent profile (dddtMOA). We further combined the information of the dddtMOA with the dose dependency of four immune cell populations derived from BAL counts. The dddtMOA analysis highlighted the specific adaptation pattern to each ENM. Furthermore, it revealed the distinct effect of the ENM physicochemical properties on the induced immune response. Finally, we report three genes dose-dependent in all the exposures and correlated with immune deregulation in the lung. The characterization of dddtMOA for ENM exposures, both for apical endpoints and molecular responses, can further promote toxicogenomic approaches in a regulatory context.
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Affiliation(s)
- Angela Serra
- Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (A.S.); (G.d.G.); (L.A.S.)
- BioMediTech Institute, Tampere University, 33520 Tampere, Finland
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), 33520 Tampere, Finland
| | - Giusy del Giudice
- Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (A.S.); (G.d.G.); (L.A.S.)
- BioMediTech Institute, Tampere University, 33520 Tampere, Finland
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), 33520 Tampere, Finland
| | | | - Laura Aliisa Saarimäki
- Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (A.S.); (G.d.G.); (L.A.S.)
- BioMediTech Institute, Tampere University, 33520 Tampere, Finland
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), 33520 Tampere, Finland
| | - Sarah Søs Poulsen
- National Research Centre for the Working Environment, 2100 Copenhagen, Denmark; (S.S.P.); (U.V.)
| | - Vittorio Fortino
- Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland;
| | - Sabina Halappanavar
- Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON K1A 0K9, Canada;
| | - Ulla Vogel
- National Research Centre for the Working Environment, 2100 Copenhagen, Denmark; (S.S.P.); (U.V.)
| | - Dario Greco
- Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (A.S.); (G.d.G.); (L.A.S.)
- BioMediTech Institute, Tampere University, 33520 Tampere, Finland
- Finnish Hub for Development and Validation of Integrated Approaches (FHAIVE), 33520 Tampere, Finland
- Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland;
- Correspondence:
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22
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Lei W, Zhao C, Sun J, Jin Y, Duan Z. Activation of α7nAChR preserves intestinal barrier integrity by enhancing the HO-1 / STAT3 signaling to inhibit NF-κB activation in mice. Biomed Pharmacother 2022; 149:112733. [DOI: 10.1016/j.biopha.2022.112733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 02/10/2022] [Accepted: 02/15/2022] [Indexed: 11/02/2022] Open
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23
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Lee HH, Cho H. Apigenin Increases Natural Killer Cytotoxicity to Human Hepatocellular Carcinoma Expressing HIF-1α through High Interaction of CD95/CD95L. J Microbiol Biotechnol 2022; 32:397-404. [PMID: 35283421 PMCID: PMC9628789 DOI: 10.4014/jmb.2201.01010] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/21/2022] [Accepted: 02/25/2022] [Indexed: 12/15/2022]
Abstract
Natural killer (NK) cell activity is more attenuated in hepatocellular carcinoma (HCC) patients than normal. Hypoxic-inducible factor (HIF)-1α is highly expressed in tumors to maintain their metabolism in a hypoxic environment. The expression of HIF-1α in cancers can lead to cell growth, proliferation, invasion/metastasis and immune escape. Although apigenin, a flavonoid, is known to have various biological activities, it has not been demonstrated in NK cell immune activity in HCC cells. In this study, NK-92 cells were directly cocultured with HCC SK-Hep1 cells for 24 h to evaluate NK cell activity in HCC cells or HCC cells expressing HIF-1α by apigenin. NK cell cytotoxicity to HCC cells expressing HIF-1α was significantly increased, and NK cell-activating receptors, NKG2D, NKp30 and NKp44 were highly expressed. The activating effect of apigenin on NK cells substantially induced apoptosis in HCC cells expressing HIF-1α through high expression of CD95L on the surface of NK-92 cells. Moreover, apigenin excellently inhibited the level of TGF-β1 in a coculture of NK cells and HCC cells. In conclusion, apigenin seems to be a good compound that increases NK cell cytotoxicity to HCC cells by controlling HIF-1α expression.
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Affiliation(s)
- Hwan Hee Lee
- Department of Pharmacy, Duksung Women’s University, Seoul 01369, Republic of Korea,Duksung Innovative Drug Center, Duksung Women’s University, Seoul 01369, Republic of Korea,Corresponding authors H.H. Lee Phone: +82-2-901-8734 Fax: +82-2-901-8386 E-mail:
| | - Hyosun Cho
- Department of Pharmacy, Duksung Women’s University, Seoul 01369, Republic of Korea,Duksung Innovative Drug Center, Duksung Women’s University, Seoul 01369, Republic of Korea,
H. Cho Phone: +82-2-901-8678 Fax: +82-2-901-8386 E-mail:
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24
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Naderi M, Kordestani H, Sahebi Z, Khedmati Zare V, Amani-Shalamzari S, Kaviani M, Wiskemann J, Molanouri Shamsi M. Serum and gene expression profile of cytokines following combination of yoga training and vitamin D supplementation in breast cancer survivors: a randomized controlled trial. BMC Womens Health 2022; 22:90. [PMID: 35331230 PMCID: PMC8952887 DOI: 10.1186/s12905-022-01671-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 03/17/2022] [Indexed: 01/21/2023] Open
Abstract
Background This study aimed to examine the effect of the combination of yoga training with high vitamin D dose supplementation on the expression and systemic levels of inflammatory cytokines and psychophysical status of breast cancer survivors. Methods Thirty volunteered breast cancer survivors (48 ± 8 years) were randomly allocated to a high dose (4000 IU) of vitamin D supplementation (HD) group (n = 10), yoga with a high dose of vitamin D (YHD) group (n = 10), and yoga with a low dose (2000 IU) of vitamin D (YLD) group (n = 10). Participants performed the Hatha yoga style for 12 weeks, twice a week. Blood samples, quality of life (QoL) questionnaire, and physical performance tests were taken before and after the intervention. Results Body fat percentage (ηp2 = 0.36), handgrip strength (ηp2 = 0.41) and QoL indicators include global health (ηp2 = 0.54), functional scales (ηp2 = 0.49), and symptoms scales (ηp2 = 0.50) were significantly improved in the both YHD and YLD groups compared to the HD group (p < 0.05). Also, interleukin-10 (IL-10) levels were markedly increased in the Y-HVD group compared to the Y-LVD and HVD groups. Moreover, there were significant decreases in tumor necrosis factor-α (TNF-α) and interleukin-6 levels in the Y-HVD group after the intervention. The anti-inflammatory index (IL-10/TNF-α) was significantly increased in both the yoga groups (P < 0.05). Conclusion Yoga promotes physical and psychological fitness and, in combination with a high dose of vitamin D, improves the cytokine profile, which can effectively manage the side effects associated with cancer. Trial registration IRCT20210726051993N2. Registration date: 2022/02/27. URL: https://www.irct.ir/trial/62079
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Affiliation(s)
- Mahdi Naderi
- Departement of Exercise Physiology, Faculty of Physical Education and Sports Sciences, Kharazmi University, Tehran, Iran
| | - Hajar Kordestani
- Departement of Exercise Physiology, Faculty of Physical Education and Sports Sciences, Kharazmi University, Tehran, Iran
| | - Zahra Sahebi
- Departement of Exercise Physiology, Faculty of Physical Education and Sports Sciences, Kharazmi University, Tehran, Iran
| | - Vahid Khedmati Zare
- Departement of Exercise Physiology, Faculty of Physical Education and Sports Sciences, Kharazmi University, Tehran, Iran
| | - Sadegh Amani-Shalamzari
- Department of Exercise Physiology, Faculty of Physical Education and Sports Science, Kharazmi University, Tehran, Iran.
| | - Mojtaba Kaviani
- School of Nutrition and Dietetics, Faculty of Pure and Applied Science, Acadia University, Wolfville, NS, Canada
| | - Joachim Wiskemann
- Working Group Exercise Oncology, Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany
| | - Mahdieh Molanouri Shamsi
- Department of Physical Education and Sport Sciences, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran
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25
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Yan S, Xie N, Aleem MT, Ji X, Zhang C, Cao X, Zhang Y. Overexpression of angiotensin-converting enzyme 2 contributes to the amelioration of Streptococcus uberis-induced inflammatory injury in mammary epithelial cells. Vet Microbiol 2022; 268:109398. [DOI: 10.1016/j.vetmic.2022.109398] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 03/01/2022] [Accepted: 03/15/2022] [Indexed: 12/16/2022]
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26
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Silva SP, Martins OG, Medeiros LF, Crespo PC, do Couto CAT, de Freitas JS, de Souza A, Morastico A, Cruz LAX, Sanches PRS, Caumo W, Gamaro GD, Torres ILDS, de Souza ICC. Evidence of Anti-Inflammatory Effect of Transcranial Direct Current Stimulation in a CFA-Induced Chronic Inflammatory Pain Model in Wistar Rats. Neuroimmunomodulation 2022; 29:500-514. [PMID: 35108707 DOI: 10.1159/000520581] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 11/01/2021] [Indexed: 01/06/2023] Open
Abstract
INTRODUCTION Given that chronic inflammatory pain is highly prevalent worldwide, it is important to study new techniques to treat or relieve this type of pain. The present study evaluated the effect of transcranial direct current stimulation (tDCS) in rats submitted to a chronic inflammatory model by nociceptive response, biomarker levels (brain-derived neurotrophic factor [BDNF] and interleukin [IL]-6 and IL-10), and by histological parameters. METHODS Sixty-day-old male Wistar rats were used in this study and randomized by weight into 6 major groups: total control, control + sham-tDCS, control + active tDCS, total CFA, CFA + sham-tDCS, and CFA + active tDCS. After inflammatory pain was established, the animals were submitted to the treatment protocol for 8 consecutive days, according to the experimental group. The nociceptive tests (von Frey and hot plate) were assessed, and euthanasia by decapitation occurred at day 8 after the end of tDCS treatment, and the blood serum and central nervous structures were collected for BDNF and IL measurements. All experiments and procedures were approved by the Institutional Committee for Animal Care and Use (UFPel #4538). RESULTS The tDCS treatment showed a complete reversal of the mechanical allodynia induced by the pain model 24 h and 8 days after the last tDCS session, and there was partial reversal of the thermal hyperalgesia at all time points. Serum BDNF levels were decreased in CFA + sham-tDCS and CFA + tDCS groups compared to the control + tDCS group. The control group submitted to tDCS exhibited an increase in serum IL-6 levels in relation to the other groups. In addition, there was a significant decrease in IL-10 striatum levels in control + tDCS, CFA, and CFA + sham-tDCS groups in relation to the control group, with a partial tDCS effect on the CFA pain model. Local histology demonstrated tDCS effects in decreasing lymphocytic infiltration and neovascularization and tissue regeneration in animals exposed to CFA. CONCLUSION tDCS was able to reverse the mechanical allodynia and decrease thermal hyperalgesia and local inflammation in a chronic inflammatory pain model, with a modest effect on striatum IL-10 levels. As such, we suggest that analgesic tDCS mechanisms may be related to tissue repair by modulating the local inflammatory process.
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Affiliation(s)
- Sabrina Pereira Silva
- Laboratory of Cell Neuromodulation: Basic Research, Department of Morphology, Biology Institute, Universidade Federal de Pelotas, Pelotas, Brazil
- Postgraduate Program in Bioprospecting and Biochemistry, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Otávio Garcia Martins
- Laboratory of Cell Neuromodulation: Basic Research, Department of Morphology, Biology Institute, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Liciane Fernandes Medeiros
- Postgraduate Program in Health and Human Development, Unilasalle, Canoas, Brazil,
- Laboratory of Pain Pharmacology and Neuromodulation: Preclinical Research, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil,
| | - Priscila Centeno Crespo
- Laboratory of Cell Neuromodulation: Basic Research, Department of Morphology, Biology Institute, Universidade Federal de Pelotas, Pelotas, Brazil
- Postgraduate Program in Bioprospecting and Biochemistry, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Carlus Augustu Tavares do Couto
- Laboratory of Cell Neuromodulation: Basic Research, Department of Morphology, Biology Institute, Universidade Federal de Pelotas, Pelotas, Brazil
- Postgraduate Program in Bioprospecting and Biochemistry, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Joice Soares de Freitas
- Laboratory of Pain Pharmacology and Neuromodulation: Preclinical Research, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Andressa de Souza
- Postgraduate Program in Health and Human Development, Unilasalle, Canoas, Brazil
| | - Amanda Morastico
- Laboratory of Cell Neuromodulation: Basic Research, Department of Morphology, Biology Institute, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Luis Augusto Xavier Cruz
- Laboratory of Cell Neuromodulation: Basic Research, Department of Morphology, Biology Institute, Universidade Federal de Pelotas, Pelotas, Brazil
| | | | - Wolnei Caumo
- Postgraduate Program in Medicine, Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Giovana Duzzo Gamaro
- Laboratory of Cell Neuromodulation: Basic Research, Department of Morphology, Biology Institute, Universidade Federal de Pelotas, Pelotas, Brazil
- Postgraduate Program in Bioprospecting and Biochemistry, Universidade Federal de Pelotas, Pelotas, Brazil
| | - Iraci Lucena da Silva Torres
- Laboratory of Pain Pharmacology and Neuromodulation: Preclinical Research, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Postgraduate Program in Medicine, Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Izabel Cristina Custódio de Souza
- Laboratory of Cell Neuromodulation: Basic Research, Department of Morphology, Biology Institute, Universidade Federal de Pelotas, Pelotas, Brazil
- Postgraduate Program in Bioprospecting and Biochemistry, Universidade Federal de Pelotas, Pelotas, Brazil
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27
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Myers SA, Gottschalk RA. Mechanisms encoding STAT functional diversity for context-specific inflammatory responses. Curr Opin Immunol 2022; 74:150-155. [DOI: 10.1016/j.coi.2022.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 12/29/2021] [Accepted: 01/04/2022] [Indexed: 01/22/2023]
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28
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Wen Z, Xie X, Aleem MT, Aimulajiang K, Chen C, Liang M, Song X, Xu L, Li X, Yan R. In vitro characterization of Haemonchus contortus trehalose-6-phosphate phosphatase and its immunomodulatory effects on peripheral blood mononuclear cells (PBMCs). Parasit Vectors 2021; 14:611. [PMID: 34930417 PMCID: PMC8685816 DOI: 10.1186/s13071-021-05115-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/04/2021] [Indexed: 12/15/2022] Open
Abstract
Background Trehalose-6-phosphate phosphatase (TPP6) is a key enzyme in the trehalose biosynthesis pathway. The accumulation of TPP6 inside the body is harmful to the pathogen, but almost nothing is currently known about the function of TPP6 from Haemonchus contortus (CRE-GOB-1). Methods The H. contortus CRE-GOB-1 (HcGOB) gene was cloned and recombinant protein of GOB (rHcGOB) was expressed; transcription of the HcGOB gene at different developmental stages of H. contortus was then studied. The spatial expression pattern of the HcGOB gene in adult female and male worms was determined by both quantitative real-time PCR (qPCR) and immunofluorescence. The binding of the rHcGOB protein to goat PBMCs was assessed by immunofluorescence assay. The immunomodulatory impacts of rHcGOB on cell proliferation, nitric oxide generation and cytokine secretion were assessed by co-culture of rHcGOB protein with goat PBMCs. Results The HcGOB protein was transcribed in eggs, infective third-stage larvae (iL3s) and adults of H. contortus, with the highest transcript levels found in the egg stage. The transcript levels were significantly elevated in iL3s after manual desheathing. HcGOB was widely distributed in adult worms where it was mainly localized in the gut and gonads. rHcGOB was observed to bind to PBMCs and also to be recognized by sera collected from a goat infected with H. contortus. rHcGOB significantly activated the interleukin-10/transforming growth factor β/signal transducer and activator of transcription 3 (IL-10/TGF-β/STAT3) pathway in PBMCs while suppressing the transcription and expression of IL-4 and IL-17. Conclusions These results suggest that the HcGOB gene plays an important role in the development, parasitism and reproduction of H. contortus. The rHcGOB protein affected the immunomodulatory function of PBMCs in the in vitro study, suggesting that this protein would be a promising vaccine target. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13071-021-05115-4.
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Affiliation(s)
- ZhaoHai Wen
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - XinRan Xie
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - Muhammad Tahir Aleem
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - Kalibixiati Aimulajiang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China.,State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi, 830011, Xinjiang, People's Republic of China
| | - Cheng Chen
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - Meng Liang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - XiaoKai Song
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - LiXin Xu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - XiangRui Li
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China
| | - RuoFeng Yan
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, People's Republic of China.
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Sarma U, Maiti M, Nair A, Bhadange S, Bansode Y, Srivastava A, Saha B, Mukherjee D. Regulation of STAT3 signaling in IFNγ and IL10 pathways and in their cross-talk. Cytokine 2021; 148:155665. [PMID: 34366205 DOI: 10.1016/j.cyto.2021.155665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 11/17/2022]
Abstract
The pro-inflammatory IFNγ-STAT1 pathway and anti-inflammatory IL10-STAT3 pathway elicit cellular responses primarily utilizing their canonical STATs. However IL10 mediated STAT1 and IFNγ mediated STAT3 activation is also observed, suggesting crosstalk of these functionally opposing signaling pathways can potentially reshape the canonical dynamics both STATs and alter the expression of their target genes. Herein, we measured the dynamics of STATs in response to different doses of IL10 or IFNγ and in their co-stimulation and employed quantitative modeling to understand the regulatory mechanisms controlling signal responses in individual and co-simulation scenarios. Our experiments show, STAT3 in particular, exhibits a bell-shaped dose-response while treated with IFNγ or IL10 and our model quantiatively captured the dose-dependent dynamics of both the STATs in both pathways. The model next predicted and subsequent experiments validated that STAT3 dynamics would robustly remain IL10 specific when subjected to a co-stimulation of both IFNγ and IL10. Genes common to both pathways also exhibited IL10 specific expression during the co-stimulation. The findings thus uncover anovel feature of the IL10-STAT3 signaling axis during pathway crosstalk. Finally, parameter sampling coupled to information theory based analysis showed that bell-shaped signal-response of STAT3 in both pathways is primarily dependent on receptor concentration whereas robustness of IL10-STAT3 signaling axis in co-stimulation results from the negative regulation of the IFNγ pathway.
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Affiliation(s)
- U Sarma
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India.
| | - M Maiti
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - A Nair
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - S Bhadange
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - Y Bansode
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - A Srivastava
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - B Saha
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India
| | - D Mukherjee
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune 411007, India.
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30
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Abdo Cuza AA, Ávila JP, Martínez RM, González JJ, Aspuro GP, Gutiérrez Martínez JA, Suzarte MR, Hernández DS, Añé-Kouri AL, Ramos TC. Nimotuzumab for COVID-19: case series. Immunotherapy 2021; 14:10.2217/imt-2021-0269. [PMID: 34806405 PMCID: PMC8628863 DOI: 10.2217/imt-2021-0269] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022] Open
Abstract
Background: In COVID-19, EGFR production is upregulated in the alveolar epithelial cells. EGFR overexpression further activates STAT-3 and increases lung pathology. The EGFR pathway is also one of the major nodes in pulmonary fibrosis. Methods: Nimotuzumab, a humanized anti-EGFR antibody, was used to treat three patients with severe or moderate COVID-19. The antibody was administered in combination with other drugs included in the national COVID-19 protocol. Results: Nimotuzumab was well tolerated. IL-6 decreased from the first antibody infusion. Clinical symptoms significantly improved after nimotuzumab administration, and the CT scans at discharge showed major resolution of the lung lesions and no signs of fibrosis. Conclusion: Safe anti-EGFR antibodies like nimotuzumab may modulate COVID-19-associated hyperinflammation and prevent fibrosis. Clinical Trial Registration: RPCEC00000369 (RPCEC rpcec.sld.cu).
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Affiliation(s)
- Anselmo A Abdo Cuza
- Intensive Care Unit. Medical & Surgical Research Center (CIMEQ), Havana, Cuba
| | - Jonathan Pi Ávila
- Intensive Care Unit. Medical & Surgical Research Center (CIMEQ), Havana, Cuba
| | | | | | | | | | - Mayra Ramos Suzarte
- Clinical Research Direction. Center of Molecular Immunology (CIM), Havana, Cuba
| | | | - Ana L Añé-Kouri
- Clinical Research Direction. Center of Molecular Immunology (CIM), Havana, Cuba
| | - Tania Crombet Ramos
- Clinical Research Direction. Center of Molecular Immunology (CIM), Havana, Cuba
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31
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Nikolskii AA, Shilovskiy IP, Barvinskaia ED, Korneev AV, Sundukova MS, Khaitov MR. Role of STAT3 Transcription Factor in Pathogenesis of Bronchial Asthma. BIOCHEMISTRY. BIOKHIMIIA 2021; 86:1489-1501. [PMID: 34906042 DOI: 10.1134/s0006297921110122] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 09/21/2021] [Accepted: 10/12/2021] [Indexed: 06/14/2023]
Abstract
Bronchial asthma is a heterogeneous chronic inflammatory disease of airways. The studies of molecular and cellular mechanisms of bronchial asthma have established that a wide range of immune (T and B cells, eosinophils, neutrophils, macrophages, etc.) and structural (epithelial and endothelial) cells are involved in its pathogenesis. These cells are activated in response to external stimuli (bacteria, viruses, allergens, and other pollutants) and produce pro-inflammatory factors (cytokines, chemokines, metalloproteinases, etc.), which ultimately leads to the initiation of pathological processes in the lungs. Genes encoding transcription factors of the STAT family (signal transducer and activator of transcription), that includes seven representatives, are involved in the cell activation. Recent studies have shown that the transcription factor STAT3 plays an important role in the activation of the abovementioned cells, thus contributing to the development of asthma. In animal studies, selective inhibition of STAT3 significantly reduces the severity of lung inflammation, which indicates its potential as a therapeutic target. In this review, we describe the mechanisms of STAT3 activation and its role in polarization of Th2/Th17 cells and M2 macrophages, as well as in the dysfunction of endothelial cells, which ultimately leads to development of bronchial asthma symptoms, such as infiltration of neutrophils and eosinophils into the lungs, bronchial hyperreactivity, and the respiratory tract remodeling.
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Affiliation(s)
- Aleksandr A Nikolskii
- National Research Center - Institute of Immunology Federal Medical-Biological Agency of Russia, Moscow, 115522, Russia
| | - Igor P Shilovskiy
- National Research Center - Institute of Immunology Federal Medical-Biological Agency of Russia, Moscow, 115522, Russia.
| | - Ekaterina D Barvinskaia
- National Research Center - Institute of Immunology Federal Medical-Biological Agency of Russia, Moscow, 115522, Russia
| | - Artem V Korneev
- National Research Center - Institute of Immunology Federal Medical-Biological Agency of Russia, Moscow, 115522, Russia
| | - Maria S Sundukova
- National Research Center - Institute of Immunology Federal Medical-Biological Agency of Russia, Moscow, 115522, Russia
| | - Musa R Khaitov
- National Research Center - Institute of Immunology Federal Medical-Biological Agency of Russia, Moscow, 115522, Russia
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Tofacitinib Suppresses IL-10/IL-10R Signaling and Modulates Host Defense Responses in Human Macrophages. J Invest Dermatol 2021; 142:559-570.e6. [PMID: 34536483 DOI: 10.1016/j.jid.2021.07.180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/12/2021] [Accepted: 07/15/2021] [Indexed: 12/20/2022]
Abstract
Jak inhibitors are increasingly used in dermatology. Despite broad inhibitory effects on cytokine signaling cascades, they only modestly increase the risk for infectious diseases. To address the molecular mechanisms underlying this unexpected clinical observation, we investigated how tofacintib (tofa), a first-in-class Jak inhibitor, regulates host defense responses in toll-like receptor 4-activated human macrophages. Specifically, we asked whether tofa inhibits anti-inflammatory IL-10 signaling, thereby counteracting the downregulation of inflammatory, host-protective pathways. We found that tofa blocked macrophage responses to IL-10 at the level of signal transducer and activator of transcription 3 phosphorylation. Furthermore, toll-like receptor 4-induced, autocrine/paracrine IL-10/IL-10R activation promoted the expression of hepcidin, the master regulator of iron metabolism, resulting in intracellular iron sequestration. In contrast, autocrine/paracrine IL-10/IL-10R activation repressed the expression of cathelicidin antimicrobial peptide as well as antigen-presenting molecules, thus together, inducing a pathogen-favoring environment. Although tofa further repressed cathelicidin, it prevented the induction of intracellular HAMP and restored the expression of antigen-presentation molecules in toll-like receptor 4-activated macrophages. Our study supports the concept that induction of IL-10/IL-10R signaling drives a complex immune evasion strategy of intracellular microbes. Moreover, we conclude that tofa has diverging effects on macrophage host response pathways, and we identify the toll-like receptor 4-IL-10-signal transducer and activator of transcription 3-HAMP axis as a potential therapeutic target to counteract immune evasion.
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McCallum RT, Perreault ML. Glycogen Synthase Kinase-3: A Focal Point for Advancing Pathogenic Inflammation in Depression. Cells 2021; 10:cells10092270. [PMID: 34571919 PMCID: PMC8470361 DOI: 10.3390/cells10092270] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/26/2021] [Accepted: 08/28/2021] [Indexed: 01/03/2023] Open
Abstract
Increasing evidence indicates that the host immune response has a monumental role in the etiology of major depressive disorder (MDD), motivating the development of the inflammatory hypothesis of depression. Central to the involvement of chronic inflammation in MDD is a wide range of signaling deficits induced by the excessive secretion of pro-inflammatory cytokines and imbalanced T cell differentiation. Such signaling deficits include the glutamatergic, cholinergic, insulin, and neurotrophin systems, which work in concert to initiate and advance the neuropathology. Fundamental to the communication between such systems is the protein kinase glycogen synthase kinase-3 (GSK-3), a multifaceted protein critically linked to the etiology of MDD and an emerging target to treat pathogenic inflammation. Here, a consolidated overview of the widespread multi-system involvement of GSK-3 in contributing to the neuropathology of MDD will be discussed, with the feed-forward mechanistic links between all major neuronal signaling pathways highlighted.
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Affiliation(s)
- Ryan T. McCallum
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada;
| | - Melissa L. Perreault
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada;
- Collaborative Program in Neuroscience, University of Guelph, Guelph, ON N1G 2W1, Canada
- Correspondence: ; Tel.: +1-(519)-824-4120 (ext. 52013)
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34
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Kartikasari AER, Huertas CS, Mitchell A, Plebanski M. Tumor-Induced Inflammatory Cytokines and the Emerging Diagnostic Devices for Cancer Detection and Prognosis. Front Oncol 2021; 11:692142. [PMID: 34307156 PMCID: PMC8294036 DOI: 10.3389/fonc.2021.692142] [Citation(s) in RCA: 175] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/22/2021] [Indexed: 12/14/2022] Open
Abstract
Chronic inflammation generated by the tumor microenvironment is known to drive cancer initiation, proliferation, progression, metastasis, and therapeutic resistance. The tumor microenvironment promotes the secretion of diverse cytokines, in different types and stages of cancers. These cytokines may inhibit tumor development but alternatively may contribute to chronic inflammation that supports tumor growth in both autocrine and paracrine manners and have been linked to poor cancer outcomes. Such distinct sets of cytokines from the tumor microenvironment can be detected in the circulation and are thus potentially useful as biomarkers to detect cancers, predict disease outcomes and manage therapeutic choices. Indeed, analyses of circulating cytokines in combination with cancer-specific biomarkers have been proposed to simplify and improve cancer detection and prognosis, especially from minimally-invasive liquid biopsies, such as blood. Additionally, the cytokine signaling signatures of the peripheral immune cells, even from patients with localized tumors, are recently found altered in cancer, and may also prove applicable as cancer biomarkers. Here we review cytokines induced by the tumor microenvironment, their roles in various stages of cancer development, and their potential use in diagnostics and prognostics. We further discuss the established and emerging diagnostic approaches that can be used to detect cancers from liquid biopsies, and additionally the technological advancement required for their use in clinical settings.
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Affiliation(s)
- Apriliana E. R. Kartikasari
- Translational Immunology and Nanotechnology Research Program, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
| | - Cesar S. Huertas
- Integrated Photonics and Applications Centre (InPAC), School of Engineering, RMIT University, Melbourne, VIC, Australia
| | - Arnan Mitchell
- Integrated Photonics and Applications Centre (InPAC), School of Engineering, RMIT University, Melbourne, VIC, Australia
| | - Magdalena Plebanski
- Translational Immunology and Nanotechnology Research Program, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
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35
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Reyes M, Filbin MR, Bhattacharyya RP, Sonny A, Mehta A, Billman K, Kays KR, Pinilla-Vera M, Benson ME, Cosimi LA, Hung DT, Levy BD, Villani AC, Sade-Feldman M, Baron RM, Goldberg MB, Blainey PC, Hacohen N. Plasma from patients with bacterial sepsis or severe COVID-19 induces suppressive myeloid cell production from hematopoietic progenitors in vitro. Sci Transl Med 2021; 13:eabe9599. [PMID: 34103408 PMCID: PMC8432955 DOI: 10.1126/scitranslmed.abe9599] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/17/2020] [Accepted: 05/28/2021] [Indexed: 12/16/2022]
Abstract
Bacterial sepsis and severe COVID-19 share similar clinical manifestations and are both associated with dysregulation of the myeloid cell compartment. We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis and validated expansion of this cell subpopulation in publicly available transcriptomics data. Here, using published datasets, we show that the gene expression program associated with MS1 correlated with sepsis severity and was up-regulated in monocytes from patients with severe COVID-19. To examine the ontogeny and function of MS1 cells, we developed a cellular model for inducing CD14+ MS1 monocytes from healthy bone marrow hematopoietic stem and progenitor cells (HSPCs). We found that plasma from patients with bacterial sepsis or COVID-19 induced myelopoiesis in HSPCs in vitro and expression of the MS1 gene program in monocytes and neutrophils that differentiated from these HSPCs. Furthermore, we found that plasma concentrations of IL-6, and to a lesser extent IL-10, correlated with increased myeloid cell output from HSPCs in vitro and enhanced expression of the MS1 gene program. We validated the requirement for these two cytokines to induce the MS1 gene program through CRISPR-Cas9 editing of their receptors in HSPCs. Using this cellular model system, we demonstrated that induced MS1 cells were broadly immunosuppressive and showed decreased responsiveness to stimulation with a synthetic RNA analog. Our in vitro study suggests a potential role for systemic cytokines in inducing myelopoiesis during severe bacterial or SARS-CoV-2 infection.
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Affiliation(s)
- Miguel Reyes
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Michael R Filbin
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Roby P Bhattacharyya
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Bacterial Pathogenesis, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Abraham Sonny
- Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Arnav Mehta
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | | | - Kyle R Kays
- Department of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Mayra Pinilla-Vera
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Maura E Benson
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Lisa A Cosimi
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Deborah T Hung
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Bruce D Levy
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Alexandra-Chloe Villani
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Moshe Sade-Feldman
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Rebecca M Baron
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Marcia B Goldberg
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Bacterial Pathogenesis, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Paul C Blainey
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
- Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA
| | - Nir Hacohen
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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36
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Johnson BM, Uchimura T, Gallovic MD, Thamilarasan M, Chou WC, Gibson SA, Deng M, Tam JW, Batty CJ, Williams J, Matsushima GK, Bachelder EM, Ainslie KM, Markovic-Plese S, Ting JPY. STING Agonist Mitigates Experimental Autoimmune Encephalomyelitis by Stimulating Type I IFN-Dependent and -Independent Immune-Regulatory Pathways. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 206:2015-2028. [PMID: 33820855 PMCID: PMC8406342 DOI: 10.4049/jimmunol.2001317] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/09/2021] [Indexed: 12/11/2022]
Abstract
The cGAS-cyclic GMP-AMP (cGAMP)-stimulator of IFN genes (STING) pathway induces a powerful type I IFN (IFN-I) response and is a prime candidate for augmenting immunity in cancer immunotherapy and vaccines. IFN-I also has immune-regulatory functions manifested in several autoimmune diseases and is a first-line therapy for relapsing-remitting multiple sclerosis. However, it is only moderately effective and can induce adverse effects and neutralizing Abs in recipients. Targeting cGAMP in autoimmunity is unexplored and represents a challenge because of the intracellular location of its receptor, STING. We used microparticle (MP)-encapsulated cGAMP to increase cellular delivery, achieve dose sparing, and reduce potential toxicity. In the C57BL/6 experimental allergic encephalomyelitis (EAE) model, cGAMP encapsulated in MPs (cGAMP MPs) administered therapeutically protected mice from EAE in a STING-dependent fashion, whereas soluble cGAMP was ineffective. Protection was also observed in a relapsing-remitting model. Importantly, cGAMP MPs protected against EAE at the peak of disease and were more effective than rIFN-β. Mechanistically, cGAMP MPs showed both IFN-I-dependent and -independent immunosuppressive effects. Furthermore, it induced the immunosuppressive cytokine IL-27 without requiring IFN-I. This augmented IL-10 expression through activated ERK and CREB. IL-27 and subsequent IL-10 were the most important cytokines to mitigate autoreactivity. Critically, cGAMP MPs promoted IFN-I as well as the immunoregulatory cytokines IL-27 and IL-10 in PBMCs from relapsing-remitting multiple sclerosis patients. Collectively, this study reveals a previously unappreciated immune-regulatory effect of cGAMP that can be harnessed to restrain T cell autoreactivity.
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MESH Headings
- Animals
- CD4-Positive T-Lymphocytes/drug effects
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- Cell-Derived Microparticles/immunology
- Cell-Derived Microparticles/metabolism
- Cells, Cultured
- Cytokines/immunology
- Cytokines/metabolism
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/prevention & control
- Female
- Humans
- Interferon Type I/immunology
- Interferon Type I/metabolism
- Leukocytes, Mononuclear/drug effects
- Leukocytes, Mononuclear/immunology
- Leukocytes, Mononuclear/metabolism
- Membrane Proteins/agonists
- Membrane Proteins/immunology
- Membrane Proteins/metabolism
- Mice, Inbred C57BL
- Mice, Inbred Strains
- Mice, Knockout
- Nucleotides, Cyclic/administration & dosage
- Nucleotides, Cyclic/immunology
- Nucleotides, Cyclic/metabolism
- Signal Transduction/drug effects
- Signal Transduction/immunology
- Mice
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Affiliation(s)
- Brandon M Johnson
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Toru Uchimura
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Matthew D Gallovic
- Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Madhan Thamilarasan
- Department of Neurology, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Wei-Chun Chou
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Sara A Gibson
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Meng Deng
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
- Oral and Craniofacial Biomedicine Program, School of Dentistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Jason W Tam
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Cole J Batty
- Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Jonathan Williams
- Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Glenn K Matsushima
- Neuroscience Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Eric M Bachelder
- Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Kristy M Ainslie
- Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Silva Markovic-Plese
- Department of Neurology, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Jenny P-Y Ting
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC;
- Neuroscience Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC
- Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC
- Center for Translational Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC; and
- Institute for Inflammatory Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, NC
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37
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Skovbjerg G, Roostalu U, Hansen HH, Lutz TA, Le Foll C, Salinas CG, Skytte JL, Jelsing J, Vrang N, Hecksher-Sørensen J. Whole-brain mapping of amylin-induced neuronal activity in receptor activity-modifying protein 1/3 knockout mice. Eur J Neurosci 2021; 54:4154-4166. [PMID: 33905587 DOI: 10.1111/ejn.15254] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 03/08/2021] [Accepted: 04/16/2021] [Indexed: 09/29/2022]
Abstract
The pancreatic hormone amylin plays a central role in regulating energy homeostasis and glycaemic control by stimulating satiation and reducing food reward, making amylin receptor agonists attractive for the treatment of metabolic diseases. Amylin receptors consist of heterodimerized complexes of the calcitonin receptor and receptor-activity modifying proteins subtype 1-3 (RAMP1-3). Neuronal activation in response to amylin dosing has been well characterized, but only in selected regions expressing high levels of RAMPs. The current study identifies global brain-wide changes in response to amylin and by comparing wild type and RAMP1/3 knockout mice reveals the importance of RAMP1/3 in mediating this response. Amylin dosing resulted in neuronal activation as measured by an increase in c-Fos labelled cells in 20 brain regions, altogether making up the circuitry of neuronal appetite regulation (e.g., area postrema (AP), nucleus of the solitary tract (NTS), parabrachial nucleus (PB), and central amygdala (CEA)). c-Fos response was also detected in distinct nuclei across the brain that typically have not been linked with amylin signalling. In RAMP1/3 knockout amylin induced low-level neuronal activation in seven regions, including the AP, NTS and PB, indicating the existence of RAMP1/3-independent mechanisms of amylin response. Under basal conditions RAMP1/3 knockout mice show reduced neuronal activity in the hippocampal formation as well as reduced hippocampal volume, suggesting a role for RAMP1/3 in hippocampal physiology and maintenance. Altogether these data provide a global map of amylin response in the mouse brain and establishes the significance of RAMP1/3 receptors in relaying this response.
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Affiliation(s)
| | | | | | - Thomas A Lutz
- Institute of Veterinary Physiology, University of Zurich, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
| | - Christelle Le Foll
- Institute of Veterinary Physiology, University of Zurich, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
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McCarty MF, Lerner A. The second phase of brain trauma can be controlled by nutraceuticals that suppress DAMP-mediated microglial activation. Expert Rev Neurother 2021; 21:559-570. [PMID: 33749495 DOI: 10.1080/14737175.2021.1907182] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION A delayed second wave of brain trauma is mediated in large part by microglia that are activated to a pro-inflammatory M1 phenotype by DAMP proteins released by dying neurons. These microglia can promote apoptosis or necrosis in neighboring neurons by producing a range of pro-inflammatory cytokines and the deadly oxidant peroxynitrite. This second wave could therefore be mitigated with agents that blunt the post-traumatic M1 activation of microglia and that preferentially promote a pro-healing M2 phenotype. AREAS COVERED The literature on nutraceuticals that might have clinical potential in this regard. EXPERT OPINION The chief signaling pathway whereby DAMPs promote M1 microglial activation involves activation of toll-like receptor 4 (TLR4), NADPH oxidase, NF-kappaB, and the stress activated kinases JNK and p38. The green tea catechin EGCG can suppress TLR4 expression. Phycocyanobilin can inhibit NOX2-dependent NADPH oxidase, ferulate and melatonin can oppose pro-inflammatory signal modulation by NADPH oxidase-derived oxidants. Long-chain omega-3 fatty acids, the soy isoflavone genistein, the AMPK activator berberine, glucosamine, and ketone bodies can down-regulate NF-kappaB activation. Vitamin D activity can oppose JNK/p38 activation. A sophisticated program of nutraceutical supplementation may have important potential for mitigating the second phase of neuronal death and aiding subsequent healing.
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Affiliation(s)
- Mark F McCarty
- Department of research, Catalytic Longevity Foundation, San Diego, California, USA
| | - Aaron Lerner
- Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases, Tel Hashomer, Israel
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A data-driven computational model enables integrative and mechanistic characterization of dynamic macrophage polarization. iScience 2021; 24:102112. [PMID: 33659877 PMCID: PMC7895754 DOI: 10.1016/j.isci.2021.102112] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/01/2020] [Accepted: 01/21/2021] [Indexed: 01/09/2023] Open
Abstract
Macrophages are highly plastic immune cells that dynamically integrate microenvironmental signals to shape their own functional phenotypes, a process known as polarization. Here we develop a large-scale mechanistic computational model that for the first time enables a systems-level characterization, from quantitative, temporal, dose-dependent, and single-cell perspectives, of macrophage polarization driven by a complex multi-pathway signaling network. The model was extensively calibrated and validated against literature and focused on in-house experimental data. Using the model, we generated dynamic phenotype maps in response to numerous combinations of polarizing signals; we also probed into an in silico population of model-based macrophages to examine the impact of polarization continuum at the single-cell level. Additionally, we analyzed the model under an in vitro condition of peripheral arterial disease to evaluate strategies that can potentially induce therapeutic macrophage repolarization. Our model is a key step toward the future development of a network-centric, comprehensive "virtual macrophage" simulation platform.
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Yang N, Xiong Y, Wang Y, Yi Y, Zhu J, Ma F, Li J, Liu H. ADAP Y571 Phosphorylation Is Required to Prime STAT3 for Activation in TLR4-Stimulated Macrophages. THE JOURNAL OF IMMUNOLOGY 2021; 206:814-826. [PMID: 33431658 DOI: 10.4049/jimmunol.2000569] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 12/07/2020] [Indexed: 12/24/2022]
Abstract
Adhesion and degranulation-promoting adapter protein (ADAP), originally identified as an essential adaptor molecule in TCR signaling and T cell adhesion, has emerged as a critical regulator in innate immune cells such as macrophages; however, its role in macrophage polarization and inflammatory responses remains unknown. In this study, we show that ADAP plays an essential role in TLR4-mediated mouse macrophage polarization via modulation of STAT3 activity. Macrophages from ADAP-deficient mice exhibit enhanced M1 polarization, expression of proinflammatory cytokines and capacity in inducing Th1 responses, but decreased levels of anti-inflammatory cytokines in response to TLR4 activation by LPS. Furthermore, overexpression of ADAP enhances, whereas loss of ADAP reduces, the LPS-mediated phosphorylation and activity of STAT3, suggesting ADAP acts as a coactivator of STAT3 activity and function. Furthermore, the coactivator function of ADAP mostly depends on the tyrosine phosphorylation at Y571 in the motif YDSL induced by LPS. Mutation of Y571 to F severely impairs the stimulating effect of ADAP on STAT3 activity and the ability of ADAP to inhibit M1-like polarization in TLR4-activated mouse macrophages. Moreover, ADAP interacts with STAT3, and loss of ADAP renders mouse macrophages less sensitive to IL-6 stimulation for STAT3 phosphorylation. Collectively, our findings revealed an additional layer of regulation of TLR4-mediated mouse macrophage plasticity whereby ADAP phosphorylation on Y571 is required to prime STAT3 for activation in TLR4-stimulated mouse macrophages.
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Affiliation(s)
- Naiqi Yang
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, China.,Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou 215123, Jiangsu Province, China
| | - Yiwei Xiong
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, China
| | - Yan Wang
- Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou 215123, Jiangsu Province, China
| | - Yulan Yi
- Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou 215123, Jiangsu Province, China
| | - Jingfei Zhu
- Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; and.,Suzhou Institute of Systems Medicine, Suzhou 215123, China
| | - Feng Ma
- Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China; and.,Suzhou Institute of Systems Medicine, Suzhou 215123, China
| | - Jing Li
- Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou 215123, Jiangsu Province, China
| | - Hebin Liu
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu Province, China; .,Department of Biological Sciences, Xi'an Jiaotong-Liverpool University, Suzhou 215123, Jiangsu Province, China
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41
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Li Q, Lan X, Han X, Durham F, Wan J, Weiland A, Koehler RC, Wang J. Microglia-derived interleukin-10 accelerates post-intracerebral hemorrhage hematoma clearance by regulating CD36. Brain Behav Immun 2021; 94:437-457. [PMID: 33588074 PMCID: PMC8058329 DOI: 10.1016/j.bbi.2021.02.001] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 12/13/2020] [Accepted: 02/06/2021] [Indexed: 12/19/2022] Open
Abstract
Hematoma size after intracerebral hemorrhage (ICH) significantly affects patient outcome. However, our knowledge of endogenous mechanisms that underlie hematoma clearance and the potential role of the anti-inflammatory cytokine interleukin-10 (IL-10) is limited. Using organotypic hippocampal slice cultures and a collagenase-induced ICH mouse model, we investigated the role of microglial IL-10 in phagocytosis ex vivo and hematoma clearance in vivo. In slice culture, exposure to hemoglobin induced IL-10 expression in microglia and enhanced phagocytosis that depended on IL-10-regulated expression of CD36. Following ICH, IL-10-deficient mice had more severe neuroinflammation, brain edema, iron deposition, and neurologic deficits associated with delayed hematoma clearance. Intranasal administration of recombinant IL-10 accelerated hematoma clearance and improved neurologic function. Additionally, IL-10-deficient mice had weakened in vivo phagocytic ability owing to decreased expression of microglial CD36. Moreover, loss of IL-10 significantly increased monocyte-derived macrophage infiltration and enhanced brain inflammation in vivo. These results indicate that IL-10 regulates microglial phagocytosis and monocyte-derived macrophage infiltration after ICH and that CD36 is a key phagocytosis effector regulated by IL-10. Leveraging the innate immune response to ICH by augmenting IL-10 signaling may provide a useful strategy for accelerating hematoma clearance and improving neurologic outcome in clinical translation studies.
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Affiliation(s)
| | | | | | | | | | | | - Raymond C. Koehler
- Corresponding author at: Department of
Anesthesiology and Critical Care Medicine, The Johns Hopkins University School
of Medicine, 600 North Wolfe Street Blalock 1404, Baltimore, MD 21287, USA,
(R.C. Koehler)
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Liu H, Lin S, Ao X, Gong X, Liu C, Xu D, Huang Y, Liu Z, Zhao B, Liu X, Han X, Ye H. Meta-analysis of transcriptome datasets: An alternative method to study IL-6 regulation in coronavirus disease 2019. Comput Struct Biotechnol J 2020; 19:767-776. [PMID: 33520118 PMCID: PMC7836900 DOI: 10.1016/j.csbj.2020.12.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 12/08/2020] [Accepted: 12/13/2020] [Indexed: 02/07/2023] Open
Abstract
In coronavirus disease 2019 (COVID-19) patients, interleukin (IL)-6 is one of the leading factors causing death through cytokine release syndrome. Hence, identification of IL-6 downstream from clinical patients’ transcriptome is very valid for analyses of its mechanism. However, clinical study is conditional and time consuming to collect optional size of samples, as patients have the clinical heterogeneity. A possible solution is to deeply mine the relative existing data. Several transcriptome-based studies on other diseases or treatments have revealed different genes to be regulated by IL-6. Through our meta-analysis of these transcriptome datasets, 352 genes were suggested to be regulated by IL-6 in different biological conditions, some of which were related to virus infection and cardiovascular disease. Among them, 232 genes were not identified by current transcriptome studies from clinical research. ICAM1 and PFKFB3 were the most significantly upregulated genes in our meta-analysis and could be employed as biomarkers in patients with severe COVID-19. In general, a meta-analysis of transcriptome datasets could be an alternative way to analyze the immune response and complications of patients suffering from severe COVID-19 and other emergency diseases.
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Affiliation(s)
- Hui Liu
- Ganzhou Fifth People's Hospital, China
| | - Shujin Lin
- Mengchao Hepatobiliary Hospital of Fujian Medical University, China
| | - Xiulan Ao
- Mengchao Hepatobiliary Hospital of Fujian Medical University, China
| | | | | | | | | | - Zhiqiang Liu
- Mengchao Hepatobiliary Hospital of Fujian Medical University, China
| | - Bixing Zhao
- Mengchao Hepatobiliary Hospital of Fujian Medical University, China
| | - Xiaolong Liu
- Mengchao Hepatobiliary Hospital of Fujian Medical University, China
| | - Xiao Han
- College of Biological Science and Engineering, Fuzhou University, China
| | - Hanhui Ye
- Mengchao Hepatobiliary Hospital of Fujian Medical University, China
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Freitas RA, Junior RRP, Justina VD, Bressan AFM, Bomfim GF, Carneiro FS, Giachini FR, Lima VV. Angiotensin (1-7)-attenuated vasoconstriction is associated with the Interleukin-10 signaling pathway. Life Sci 2020; 262:118552. [PMID: 33035583 DOI: 10.1016/j.lfs.2020.118552] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 09/23/2020] [Accepted: 09/30/2020] [Indexed: 10/23/2022]
Abstract
AIMS Angiotensin-1-7 [Ang-(1-7)] is an essential peptide of the renin-angiotensin system that promotes benefits modulating effects in different tissues. Similarly, interleukin-10 (IL-10) exhibits an immunomodulatory action on the vasculature. This study aimed to evaluate whether Ang-(1-7) levels attenuates vascular contractile response, mediated by IL-10-pathway (JAK1/STAT3/IL-10). MAIN METHODS Aortas from male mice C57BL/6J and knockout for IL-10 (IL-10-/-) were incubated with Ang-(1-7) [10 μM] or vehicle, during 5 min, 1 h, 6 h, 12 h, and 24 h. Concentration-response curves to phenylephrine, western blotting, and flow cytometry analysis was performed to evaluate the contractile response, protein expression, and IL-10 levels, respectively. KEY FINDINGS Incubation with Ang-(1-7) produced a time-dependent increase in Janus kinases 1 (JAK1) expression, as well as increased expression and activity of the signal transducer and activator of transcription 3 (STAT3) protein. However, this effect was not observed in knockout animals for IL-10. After 12 h of Ang-(1-7) treatment, arteries from control mice displayed decreased vascular reactivity to phenylephrine, but this effect was not observed in the absence of endogenous IL-10. Additionally, incubation with Ang-(1-7) augments IL-10 levels after 6 h, 12 h, and 24 h of incubation. SIGNIFICANCE These results demonstrated the role of Ang-(1-7) in the IL-10 signaling pathway and its effects in the vascular contractility response. Thus, these findings suggest a new synergic action where Ang-(1-7) and IL-10 converge into a protective mechanism against vascular dysfunction.
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Affiliation(s)
- Raiany A Freitas
- Institute of Biological and Health Sciences, Federal University of Mato Grosso, Barra do Garças, MT, Brazil
| | - Rinaldo R P Junior
- Institute of Biological and Health Sciences, Federal University of Mato Grosso, Barra do Garças, MT, Brazil
| | - Vanessa D Justina
- Institute of Biological and Health Sciences, Federal University of Mato Grosso, Barra do Garças, MT, Brazil
| | - Alecsander F M Bressan
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Gisele F Bomfim
- Institute of Health Sciences, Federal University of Mato Grosso, Sinop, MT, Brazil
| | - Fernando S Carneiro
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Fernanda R Giachini
- Institute of Biological and Health Sciences, Federal University of Mato Grosso, Barra do Garças, MT, Brazil
| | - Victor V Lima
- Institute of Biological and Health Sciences, Federal University of Mato Grosso, Barra do Garças, MT, Brazil.
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Minucci S, Heise RL, Valentine MS, Kamga Gninzeko FJ, Reynolds AM. Mathematical modeling of ventilator-induced lung inflammation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2020. [PMID: 33236015 DOI: 10.1101/2020.06.03.132258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Respiratory infections, such as the novel coronavirus (SARS-COV-2) and other lung injuries, damage the pulmonary epithelium. In the most severe cases this leads to acute respiratory distress syndrome (ARDS). Due to respiratory failure associated with ARDS, the clinical intervention is the use of mechanical ventilation. Despite the benefits of mechanical ventilators, prolonged or misuse of these ventilators may lead to ventilation-associated/ventilation-induced lung injury (VILI). Damage caused to epithelial cells within the alveoli can lead to various types of complications and increased mortality rates. A key component of the immune response is recruitment of macrophages, immune cells that differentiate into phenotypes with unique pro- and/or anti-inflammatory roles based on the surrounding environment. An imbalance in pro- and anti-inflammatory responses can have deleterious effects on the individual's health. To gain a greater understanding of the mechanisms of the immune response to VILI and post-ventilation outcomes, we develop a mathematical model of interactions between the immune system and site of damage while accounting for macrophage polarization. Through Latin hypercube sampling we generate a virtual cohort of patients with biologically feasible dynamics. We use a variety of methods to analyze the results, including a random forest decision tree algorithm and parameter sensitivity with eFAST. Analysis shows that parameters and properties of transients related to epithelial repair and M1 activation and de-activation best predicted outcome. Using this new information, we hypothesize inter-ventions and use these treatment strategies to modulate damage in select virtual cases.
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Abstract
Viruses commonly antagonize the antiviral type I interferon response by targeting signal transducer and activator of transcription 1 (STAT1) and STAT2, key mediators of interferon signaling. Other STAT family members mediate signaling by diverse cytokines important to infection, but their relationship with viruses is more complex. Importantly, virus-STAT interaction can be antagonistic or stimulatory depending on diverse viral and cellular factors. While STAT antagonism can suppress immune pathways, many viruses promote activation of specific STATs to support viral gene expression and/or produce cellular conditions conducive to infection. It is also becoming increasingly clear that viruses can hijack noncanonical STAT functions to benefit infection. For a number of viruses, STAT function is dynamically modulated through infection as requirements for replication change. Given the critical role of STATs in infection by diverse viruses, the virus-STAT interface is an attractive target for the development of antivirals and live-attenuated viral vaccines. Here, we review current understanding of the complex and dynamic virus-STAT interface and discuss how this relationship might be harnessed for medical applications.
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Reyes M, Filbin MR, Bhattacharyya RP, Sonny A, Mehta A, Billman K, Kays KR, Pinilla-Vera M, Benson ME, Cosimi LA, Hung DT, Levy BD, Villani AC, Sade-Feldman M, Baron RM, Goldberg MB, Blainey PC, Hacohen N. Induction of a regulatory myeloid program in bacterial sepsis and severe COVID-19. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2020. [PMID: 32908980 DOI: 10.1101/2020.09.02.280180] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
A recent estimate suggests that one in five deaths globally are associated with sepsis 1 . To date, no targeted treatment is available for this syndrome, likely due to substantial patient heterogeneity 2,3 and our lack of insight into sepsis immunopathology 4 . These issues are highlighted by the current COVID-19 pandemic, wherein many clinical manifestations of severe SARS-CoV-2 infection parallel bacterial sepsis 5-8 . We previously reported an expanded CD14+ monocyte state, MS1, in patients with bacterial sepsis or non-infectious critical illness, and validated its expansion in sepsis across thousands of patients using public transcriptomic data 9 . Despite its marked expansion in the circulation of bacterial sepsis patients, its relevance to viral sepsis and association with disease outcomes have not been examined. In addition, the ontogeny and function of this monocyte state remain poorly characterized. Using public transcriptomic data, we show that the expression of the MS1 program is associated with sepsis mortality and is up-regulated in monocytes from patients with severe COVID-19. We found that blood plasma from bacterial sepsis or COVID-19 patients with severe disease induces emergency myelopoiesis and expression of the MS1 program, which are dependent on the cytokines IL-6 and IL-10. Finally, we demonstrate that MS1 cells are broadly immunosuppressive, similar to monocytic myeloid-derived suppressor cells (MDSCs), and have decreased responsiveness to stimulation. Our findings highlight the utility of regulatory myeloid cells in sepsis prognosis, and the role of systemic cytokines in inducing emergency myelopoiesis during severe bacterial and SARS-CoV-2 infections.
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Velikova TV, Miteva L, Stanilov N, Spassova Z, Stanilova SA. Interleukin-6 compared to the other Th17/Treg related cytokines in inflammatory bowel disease and colorectal cancer. World J Gastroenterol 2020; 26:1912-1925. [PMID: 32390702 PMCID: PMC7201144 DOI: 10.3748/wjg.v26.i16.1912] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Revised: 01/24/2020] [Accepted: 04/04/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The connection between inflammatory bowel disease (IBD) and colorectal cancer (CRC) is well-established, as persistent intestinal inflammation plays a substantial role in both disorders. Cytokines may further influence the inflammation and the carcinogenesis process.
AIM To compare cytokine patterns of active IBD patients with early and advanced CRC.
METHODS Choosing a panel of cytokines crucial for Th17/Treg differentiation and behavior, in colon specimens, as mRNA biomarkers, and their serum protein levels.
RESULTS We found a significant difference between higher gene expression of FoxP3, TGFb1, IL-10, and IL-23, and approximately equal level of IL-6 in CRC patients in comparison with IBD patients. After stratification of CRC patients, we found a significant difference in FoxP3, IL-10, IL-23, and IL-17A mRNA in early cases compared to IBD, and IL-23 alone in advanced CRC. The protein levels of the cytokines were significantly higher in CRC patients compared to IBD patients.
CONCLUSION Our findings showed that IL-6 upregulation is essential for both IBD and CRC development until the upregulation of other Th17/Treg related genes (TGFb1, IL-10, IL-23, and transcription factor FoxP3) is a crucial primarily for CRC development. The significantly upregulated IL-6 could be a potential drug target for IBD and prevention of CRC development as well.
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Affiliation(s)
| | - Lyuba Miteva
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora 6000, Bulgaria
| | - Noyko Stanilov
- Oncoplastic Unit, University College London Hospital, London 235, United Kingdom
| | - Zoya Spassova
- Clinic of Gastroenterology, University Hospital “St. Ivan Rilski”, Sofia 1431, Bulgaria
| | - Spaska Angelova Stanilova
- Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty, Trakia University, Stara Zagora 6000, Bulgaria
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Wu GC, Peng CK, Liao WI, Pao HP, Huang KL, Chu SJ. Melatonin receptor agonist protects against acute lung injury induced by ventilator through up-regulation of IL-10 production. Respir Res 2020; 21:65. [PMID: 32143642 PMCID: PMC7059294 DOI: 10.1186/s12931-020-1325-2] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 02/17/2020] [Indexed: 02/06/2023] Open
Abstract
Background It is well known that ventilation with high volume or pressure may damage healthy lungs or worsen injured lungs. Melatonin has been reported to be effective in animal models of acute lung injury. Melatonin exerts its beneficial effects by acting as a direct antioxidant and via melatonin receptor activation. However, it is not clear whether melatonin receptor agonist has a protective effect in ventilator-induced lung injury (VILI). Therefore, in this study, we determined whether ramelteon (a melatonin receptor agonist) can attenuate VILI and explore the possible mechanism for protection. Methods VILI was induced by high tidal volume ventilation in a rat model. The rats were randomly allotted into the following groups: control, control+melatonin, control+ramelteon, control+luzindole, VILI, VILI+luzindole, VILI + melatonin, VILI + melatonin + luzindole (melatonin receptor antagonist), VILI + ramelteon, and VILI + ramelteon + luzindole (n = 6 per group). The role of interleukin-10 (IL-10) in the melatonin- or ramelteon-mediated protection against VILI was also investigated. Results Ramelteon treatment markedly reduced lung edema, serum malondialdehyde levels, the concentration of inflammatory cytokines in bronchoalveolar lavage fluid (BALF), NF-κB activation, iNOS levels, and apoptosis in the lung tissue. Additionally, ramelteon treatment significantly increased heat shock protein 70 expression in the lung tissue and IL-10 levels in BALF. The protective effect of ramelteon was mitigated by the administration of luzindole or an anti-IL-10 antibody. Conclusions Our results suggest that a melatonin receptor agonist has a protective effect against VILI, and its protective mechanism is based on the upregulation of IL-10 production.
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Affiliation(s)
- Geng-Chin Wu
- The Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.,Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - Chung-Kan Peng
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Wen-I Liao
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Hsin-Ping Pao
- The Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Kun-Lun Huang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. .,Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan.
| | - Shi-Jye Chu
- Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Section 2, Chenggong Road, Neihu, Taipei, 114, Taiwan.
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Yang J, Kunimoto H, Katayama B, Zhao H, Shiromizu T, Wang L, Ozawa T, Tomonaga T, Tsuruta D, Nakajima K. Phospho-Ser727 triggers a multistep inactivation of STAT3 by rapid dissociation of pY705-SH2 through C-terminal tail modulation. Int Immunol 2020; 32:73-88. [PMID: 31555812 PMCID: PMC10689346 DOI: 10.1093/intimm/dxz061] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 09/18/2019] [Indexed: 12/21/2022] Open
Abstract
Signal transducer and activator of transcription 3 (STAT3) is involved in many biological processes, including immunity and cancer. STAT3 becomes phosphorylated at Tyr705 and Ser727 on IL-6 stimulation. Phospho-Tyr705 (pY705) stabilizes the STAT3 dimer with reciprocal interactions between pY705 and the SH2 of the other molecule and phospho-Ser727 (pS727) accelerates pY705 dephosphorylation. We study how pS727 regulates STAT3 in both structural and biological perspectives. Using STAT3 reconstituted in HepG2-stat3-knockout cells, we show that pS727, together with a handshake N-terminal domain (NTD) interaction, causes rapid inactivation of STAT3 for pY705 dephosphorylation and a chromosome region maintenance 1 (CRM1)-independent nuclear export, which is critical for faithful STAT3 response to the cellular signals. The various N-terminal tags, GFP-related Ruby and FLAG, rendered the export CRM1-dependent and especially FLAG-tag caused nuclear accumulation of STAT3, indicating the presence of conformational changes in inactivation. Impaired reactivation of STAT3 by S727A or FLAG-tag delayed or inhibited the IL-6-induced saa1 mRNA expression, respectively. The detailed analysis of the pY705-SH2 structure identified the C-terminal tail (CTT) from L706 to P715 as a key regulator of the CTT-CTT intermolecular and the CTT-SH2 intramolecular interactions that support pY705-SH2 association. The functional studies using multiple STAT3 mutants indicated that the degree of the two interactions determines the stability of pY705-SH2 interaction. Importantly, Pro715 was critical for the pS727's destabilizing activity and the known phosphorylation and acetylation at the CTT structurally inhibited the pY705-SH2 interaction. Thus, pS727 triggers pY705-SH2 dissociation by weakening the supportive interactions likely through CTT modulation, inducing rapid cycles of STAT3 activation-inactivation for proper function of STAT3.
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Affiliation(s)
- Junhao Yang
- Department of Immunology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroyuki Kunimoto
- Department of Immunology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Bumpei Katayama
- Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hong Zhao
- Department of Immunology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Takashi Shiromizu
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
| | - Lingyu Wang
- Department of Immunology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Toshiyuki Ozawa
- Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Takeshi Tomonaga
- Laboratory of Proteome Research, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
| | - Daisuke Tsuruta
- Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koichi Nakajima
- Department of Immunology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Ren Y, Yang J, Li M, Huang N, Chen Y, Wu X, Wang X, Qiu S, Wang H, Li X. Viral IL-10 promotes cell proliferation and cell cycle progression via JAK2/STAT3 signaling pathway in nasopharyngeal carcinoma cells. Biotechnol Appl Biochem 2020; 67:929-938. [PMID: 31737947 DOI: 10.1002/bab.1856] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 11/13/2019] [Indexed: 11/09/2022]
Abstract
Epstein-Barr virus (EBV) is positively related to the morbidity of nasopharyngeal carcinoma (NPC) in Asia. After infection, EBV can produce several proteins, including viral interleukin-10 (vIL-10). But the mechanism by which vIL-10 contributes to NPC cell proliferation and cell cycle progression is not well understood. In this study, EBV negative and positive cell lines, and the JAK2/STAT3 signal pathway inhibitor AG490 were used to illustrate the role of vIL-10 in NPC. Cell proliferation and cell cycle were measured by CCK-8 and flow cytometry. The expression levels of related protein were measured by Western blotting. High concentrations of vIL-10 and IL-6 were found in the EBV positive patients. The expression level of IL-6 was positively related to the presence of concentration of vIL-10. vIL-10 can promote cancer cell proliferation and G1 to S phase transmission via upregulating the IL-6 protein level by activating the JAK2/STAT3 signal pathway. Furthermore, EBV can induce the formation of cytotoxic T cells, whereas vIL-10 can block the function of cytotoxic T cells. Taken together, these results suggest that vIL-10 promotes cell proliferation and cell cycle progression via JAK2/STAT3 signaling pathway in NPC.
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Affiliation(s)
- Yanxin Ren
- Department of Head and Neck Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Jie Yang
- Department of Head and Neck Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Mei Li
- Department of Pathology, Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Ning Huang
- Department of Pharmacology, Kunming Medical University, Kunming, People's Republic of China
| | - Yun Chen
- Department of Pathology, Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Xifang Wu
- Department of Head and Neck Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Xiaoli Wang
- Department of Radiation Oncology, Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Shun Qiu
- Department of Head and Neck Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Hu Wang
- Department of Head and Neck Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Xiaojiang Li
- Department of Head and Neck Surgery, Third Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
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