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Duque-Wilckens N, Joseph D, Syed M, Smith B, Maradiaga N, Yeh SY, Srinivasan V, Sotomayor F, Durga K, Nestler E, Moesers AJ, Robison AJ. FosB/ΔFosB activation in mast cells regulates gene expression to modulate allergic inflammation in male mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.05.06.592755. [PMID: 38766119 PMCID: PMC11100602 DOI: 10.1101/2024.05.06.592755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Mast cells are innate immune cells that regulate physiological processes by releasing pre-stored and newly synthesized mediators in response to allergens, infection, and other stimuli. Dysregulated mast cell activity can lead to multisystemic pathologies, but the underlying regulatory mechanisms remain poorly understood. We found that FOSB and ΔFOSB, transcription factors encoded by the FosB gene, are robustly expressed in mast cells following IgE-antigen stimulation, suggesting a role in modulating stimulus-induced mast cell functions. Using phenotypic, gene binding, and gene expression analyses in wild-type and mast cell-specific FosB knockout male mice, we demonstrate that FOSB/ΔFOSB modulates mast cell functions by limiting reactivity to allergen-like stimuli both in vitro and in vivo . These effects seem to be mediated, at least in part, by FOSB/ΔFOSB-driven enhanced expression of DUSP4, a dual-specificity phosphatase that attenuates MAPK signaling. These findings highlight FOSB/ΔFOSB as critical regulators of mast cell activity and potential targets for therapeutic intervention.
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Guamán SA, Elhadi A, Salama AAK, Manuelian CL, Caja G, Albanell E. Beta-Glucans Improve the Mammary Innate Immune Response to Endotoxin Challenge in Dairy Ewes. Animals (Basel) 2024; 14:3023. [PMID: 39457952 PMCID: PMC11505092 DOI: 10.3390/ani14203023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 10/09/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024] Open
Abstract
This study evaluated short-term immune responses of dairy ewes supplemented with barley β-glucan (BG) following an intramammary Escherichia coli lipopolysaccharide (LPS) challenge. In the adaptation period, 36 ewes were fed an alfalfa hay diet ad libitum and barley grain cv. Hispanic (3.8% BG). Then, ewes were assigned into three experimental groups: (1) Control (CON), the same previous diet (13.3 g BG/d); (2) high β-glucans barley (HBG), new barley (cv. Annapurna) containing 10% BG (35 g BG/d); (3) intraperitoneally injected (INP) with a 1.4% BG solution dose (2 g BG/ewe). At d 9, all ewes were infused with an E. coli LPS or saline solution in each udder half. After the challenge, rectal temperature (RT), milk yield and composition, somatic cell count (SCC), and plasma interleukins (IL-1α and IL-1β) were monitored daily. The INP treatment revealed a transitory increase in RT and decreased milk yield by 38%. Milk fat, protein, and SCC increased in LPS-treated udders but not by BG treatment. The IL-1α plasma concentration was similar among groups but INP ewes showed a lower IL-1β concentration suggesting a lower inflammatory response. The BG administration appears more effective intraperitoneally than orally, which needs additional study.
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Affiliation(s)
- Santiago A. Guamán
- Ruminant Research Group (G2R), Department of Animal and Food Sciences, Facultat de Veterinària, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (S.A.G.); (A.E.); (A.A.K.S.); (C.L.M.)
- Sede Orellana, Escuela Superior Politécnica de Chimborazo (ESPOCH), El Coca 220150, Ecuador
| | - Abdelaali Elhadi
- Ruminant Research Group (G2R), Department of Animal and Food Sciences, Facultat de Veterinària, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (S.A.G.); (A.E.); (A.A.K.S.); (C.L.M.)
| | - Ahmed A. K. Salama
- Ruminant Research Group (G2R), Department of Animal and Food Sciences, Facultat de Veterinària, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (S.A.G.); (A.E.); (A.A.K.S.); (C.L.M.)
| | - Carmen L. Manuelian
- Ruminant Research Group (G2R), Department of Animal and Food Sciences, Facultat de Veterinària, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (S.A.G.); (A.E.); (A.A.K.S.); (C.L.M.)
| | - Gerardo Caja
- Ruminant Research Group (G2R), Department of Animal and Food Sciences, Facultat de Veterinària, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (S.A.G.); (A.E.); (A.A.K.S.); (C.L.M.)
| | - Elena Albanell
- Ruminant Research Group (G2R), Department of Animal and Food Sciences, Facultat de Veterinària, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain; (S.A.G.); (A.E.); (A.A.K.S.); (C.L.M.)
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Wang M, Sun J, Yan X, Yang W, Wang W, Li Y, Wang L, Song L. CgSHIP2 negatively regulates the mRNA expressions of CgIL-17s in response to Vibrio splendidus stimulation in Crassostrea gigas. FISH & SHELLFISH IMMUNOLOGY 2024; 149:109612. [PMID: 38705548 DOI: 10.1016/j.fsi.2024.109612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/29/2024] [Accepted: 05/03/2024] [Indexed: 05/07/2024]
Abstract
SH2 domain containing inositol polyphosphate5-phosphatase-2 (SHIP2) is a member of the 5-phosphatase family, acting as a vital negative regulator of immune response in vertebrates. In the present study, a SHIP2 homologue (designed as CgSHIP2) was identified from Pacific oyster, Crassostrea gigas. There was a SH2 domain, an IPPc domain and a SAM domain in CgSHIP2. The mRNA transcripts of CgSHIP2 were widely expressed in all the tested tissues with the highest expression in haemolymph. The mRNA expressions of CgSHIP2 in haemocytes increased significantly at 6, 12, 48 and 72 h after Vibrio splendidus stimulation. The positive green signals of CgSHIP2 protein were mainly located in cytoplasm of haemocytes. After the expression of CgSHIP2 was inhibited by RNA interference, the mRNA transcripts of interleukin 17s (CgIL-17-1, CgIL-17-2, CgIL-17-3 and CgIL-17-6) in the haemocytes increased significantly at 24 h after V. splendidus stimulation, which were 8.15-fold (p < 0.001), 3.44-fold (p < 0.05), 2.15-fold (p < 0.01) and 4.63-fold (p < 0.05) compared with that in NC-RNAi group, respectively. Obvious branchial swelling and cilium shedding in gills were observed in CgSHIP2-RNAi group at 24 h after V. splendidus stimulation. The results suggested that CgSHIP2 played an important role in controlling inflammatory response induced by bacteria in oysters.
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Affiliation(s)
- Mengjia Wang
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Jiejie Sun
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China.
| | - Xiaoxue Yan
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Wenwen Yang
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Wei Wang
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Yinan Li
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Lingling Wang
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China
| | - Linsheng Song
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China; Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian, 116023, China.
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López-Collazo E, del Fresno C. Endotoxin tolerance and trained immunity: breaking down immunological memory barriers. Front Immunol 2024; 15:1393283. [PMID: 38742111 PMCID: PMC11089161 DOI: 10.3389/fimmu.2024.1393283] [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: 02/28/2024] [Accepted: 04/09/2024] [Indexed: 05/16/2024] Open
Abstract
For decades, innate immune cells were considered unsophisticated first responders, lacking the adaptive memory of their T and B cell counterparts. However, mounting evidence demonstrates the surprising complexity of innate immunity. Beyond quickly deploying specialized cells and initiating inflammation, two fascinating phenomena - endotoxin tolerance (ET) and trained immunity (TI) - have emerged. ET, characterized by reduced inflammatory response upon repeated exposure, protects against excessive inflammation. Conversely, TI leads to an enhanced response after initial priming, allowing the innate system to mount stronger defences against subsequent challenges. Although seemingly distinct, these phenomena may share underlying mechanisms and functional implications, blurring the lines between them. This review will delve into ET and TI, dissecting their similarities, differences, and the remaining questions that warrant further investigation.
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Affiliation(s)
- Eduardo López-Collazo
- The Innate Immune Response Group, Hospital la Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
- Tumour Immunology Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER), Respiratory Diseases (CIBRES), Madrid, Spain
| | - Carlos del Fresno
- The Innate Immune Response Group, Hospital la Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain
- Immunomodulation Laboratory, IdiPAZ, La Paz University Hospital, Madrid, Spain
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Bongartz H, Bradfield C, Gross J, Fraser I, Nita-Lazar A, Meier-Schellersheim M. IL-10 dependent adaptation allows macrophages to adjust inflammatory responses to TLR4 stimulation history. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.28.587272. [PMID: 38654826 PMCID: PMC11037870 DOI: 10.1101/2024.03.28.587272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
During an infection, innate immune cells must adjust nature and strength of their responses to changing pathogen abundances. To determine how stimulation of the pathogen sensing TLR4 shapes subsequent macrophage responses, we systematically varied priming and restimulation concentrations of its ligand KLA. We find that different priming strengths have very distinct effects at multiple stages of the signaling response, including receptor internalization, MAPK activation, cytokine and chemokine production, and nuclear translocation and chromatin association of NFκB and IκB members. In particular, restimulation-induced TNF-α production required KLA doses equal to or greater than those used for prior exposure, indicating that macrophages can detect and adaptively respond to changing TLR4 stimuli. Interestingly, while such adaptation was dependent on the anti-inflammatory cytokine IL-10, exogenous concentrations of IL-10 corresponding to those secreted after strong priming did not exert suppressive effects on TNF-α without such prior priming, confirming the critical role of TLR4 stimulation history.
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Affiliation(s)
- H. Bongartz
- Computational Systems Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - C. Bradfield
- Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - J. Gross
- Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - I.D.C. Fraser
- Signaling Systems Section, Laboratory of Immune System Biology, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - A. Nita-Lazar
- Functional Cellular Networks Section, Laboratory of Immune System Biology, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - M. Meier-Schellersheim
- Computational Systems Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Yeoh WJ, Krebs P. SHIP1 and its role for innate immune regulation-Novel targets for immunotherapy. Eur J Immunol 2023; 53:e2350446. [PMID: 37742135 DOI: 10.1002/eji.202350446] [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: 06/15/2023] [Revised: 08/03/2023] [Accepted: 09/21/2023] [Indexed: 09/25/2023]
Abstract
Phosphoinositide-3-kinase/AKT (PI3K/AKT) signaling plays key roles in the regulation of cellular activity in both health and disease. In immune cells, this PI3K/AKT pathway is critically regulated by the phosphoinositide phosphatase SHIP1, which has been reported to modulate the function of most immune subsets. In this review, we summarize our current knowledge of SHIP1 with a focus on innate immune cells, where we reflect on the most pertinent aspects described in the current literature. We also present several small-molecule agonists and antagonists of SHIP1 developed over the last two decades, which have led to improved outcomes in several preclinical models of disease. We outline these promising findings and put them in relation to human diseases with unmet medical needs, where we discuss the most attractive targets for immune therapies based on SHIP1 modulation.
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Affiliation(s)
- Wen Jie Yeoh
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Philippe Krebs
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
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Chu E, Mychasiuk R, Tsantikos E, Raftery AL, L’Estrange-Stranieri E, Dill LK, Semple BD, Hibbs ML. Regulation of Microglial Signaling by Lyn and SHIP-1 in the Steady-State Adult Mouse Brain. Cells 2023; 12:2378. [PMID: 37830592 PMCID: PMC10571795 DOI: 10.3390/cells12192378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 09/21/2023] [Accepted: 09/26/2023] [Indexed: 10/14/2023] Open
Abstract
Chronic neuroinflammation and glial activation are associated with the development of many neurodegenerative diseases and neuropsychological disorders. Recent evidence suggests that the protein tyrosine kinase Lyn and the lipid phosphatase SH2 domain-containing inositol 5' phosphatase-1 (SHIP-1) regulate neuroimmunological responses, but their homeostatic roles remain unclear. The current study investigated the roles of Lyn and SHIP-1 in microglial responses in the steady-state adult mouse brain. Young adult Lyn-/- and SHIP-1-/- mice underwent a series of neurobehavior tests and postmortem brain analyses. The microglial phenotype and activation state were examined by immunofluorescence and flow cytometry, and neuroimmune responses were assessed using gene expression analysis. Lyn-/- mice had an unaltered behavioral phenotype, neuroimmune response, and microglial phenotype, while SHIP-1-/- mice demonstrated reduced explorative activity and exhibited microglia with elevated activation markers but reduced granularity. In addition, expression of several neuroinflammatory genes was increased in SHIP-1-/- mice. In response to LPS stimulation ex vivo, the microglia from both Lyn-/- and SHIP-1-/- showed evidence of hyper-activity with augmented TNF-α production. Together, these findings demonstrate that both Lyn and SHIP-1 have the propensity to control microglial responses, but only SHIP-1 regulates neuroinflammation and microglial activation in the steady-state adult brain, while Lyn activity appears dispensable for maintaining brain homeostasis.
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Affiliation(s)
- Erskine Chu
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
- Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; (E.T.); (A.L.R.); (E.L.-S.)
| | - Richelle Mychasiuk
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
- Department of Neurology, Alfred Health, Melbourne, VIC 3004, Australia
| | - Evelyn Tsantikos
- Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; (E.T.); (A.L.R.); (E.L.-S.)
| | - April L. Raftery
- Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; (E.T.); (A.L.R.); (E.L.-S.)
| | - Elan L’Estrange-Stranieri
- Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; (E.T.); (A.L.R.); (E.L.-S.)
| | - Larissa K. Dill
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
| | - Bridgette D. Semple
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
- Department of Neurology, Alfred Health, Melbourne, VIC 3004, Australia
- Department of Medicine, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC 3010, Australia
| | - Margaret L. Hibbs
- Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; (E.T.); (A.L.R.); (E.L.-S.)
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Yin M, Kim J, Choi JI, Bom JS, Bae HB, Jeong S. AMPK reduces macrophage endotoxin tolerance through inhibition of TGF-β1 production and its signaling pathway. Int Immunopharmacol 2023; 118:110146. [PMID: 37037116 DOI: 10.1016/j.intimp.2023.110146] [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: 01/25/2023] [Revised: 03/15/2023] [Accepted: 03/31/2023] [Indexed: 04/12/2023]
Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is involved in suppression of the development of endotoxin tolerance, which is a driver of the immunosuppression induced by sepsis. However, the mechanism by which AMPK inhibits the development of endotoxin tolerance has not been clearly elucidated. Therefore, the present study was performed to investigate the mechanism by which the AMPK activator, metformin, inhibits the development of endotoxin tolerance. Lipopolysaccharide (LPS) increased the production of transforming growth factor (TGF)-β1 in macrophages, which was inhibited by metformin and resveratrol. Knockdown of AMPKα1 inhibited the suppressive effect of metformin on LPS-induced TGF-β1 production. TGF-β neutralizing antibody and TGF-β type I receptor inhibitor increased the production of TNF-α and IL-6 via LPS restimulation in tolerized macrophages. LPS increased Smad2 phosphorylation, but this was inhibited in cells treated with TGF-β neutralizing antibody or metformin. Smad2 knockdown inhibited the development of endotoxin tolerance, as evidenced by increased TNF-α production in response to LPS restimulation in tolerized macrophages. TGF-β1 expression was increased, and the levels of TNF-α and IL-6 production induced by LPS stimulation were decreased, in splenocytes of cecal ligation and puncture (CLP) model mice compared to sham-operated controls. However, metformin treatment suppressed the production of TGF-β1, and enhanced the production of TNF-α and IL-6 induced by LPS stimulation in splenocytes of CLP mice. These results indicated that AMPK activation inhibits LPS-induced TGF-β1 production and its signaling pathway, thus suppressing the development of endotoxin tolerance in macrophages.
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Affiliation(s)
- Mei Yin
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea; Biomedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Hwasun-gun, Jeollanamdo, South Korea
| | - Joungmin Kim
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea; Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Gwangju, South Korea
| | - Jeong-Il Choi
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea; Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Gwangju, South Korea
| | - Joon-Suk Bom
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea
| | - Hong-Beom Bae
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea; Biomedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Hwasun-gun, Jeollanamdo, South Korea; Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Gwangju, South Korea.
| | - Seongtae Jeong
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea; Biomedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Hwasun-gun, Jeollanamdo, South Korea; Department of Anesthesiology and Pain Medicine, Chonnam National University Hospital, Gwangju, South Korea.
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Wu Y, Wang Q, Li M, Lao J, Tang H, Ming S, Wu M, Gong S, Li L, Liu L, Huang X. SLAMF7 regulates the inflammatory response in macrophages during polymicrobial sepsis. J Clin Invest 2023; 133:150224. [PMID: 36749634 PMCID: PMC10014109 DOI: 10.1172/jci150224] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 01/27/2023] [Indexed: 02/08/2023] Open
Abstract
Uncontrolled inflammation occurred in sepsis results in multiple organ injuries and shock, which contributes to the death of patients with sepsis. However, the regulatory mechanisms that restrict excessive inflammation are still elusive. Here, we identified an Ig-like receptor called signaling lymphocyte activation molecular family 7 (SLAMF7) as a key suppressor of inflammation during sepsis. We found that the expression of SLAMF7 on monocytes/macrophages was significantly elevated in patients with sepsis and in septic mice. SLAMF7 attenuated TLR-dependent MAPK and NF-κB signaling activation in macrophages by cooperating with Src homology 2-containing inositol-5'‑phosphatase 1 (SHIP1). Furthermore, SLAMF7 interacted with SHIP1 and TNF receptor-associated factor 6 (TRAF6) to inhibit K63 ubiquitination of TRAF6. In addition, we found that tyrosine phosphorylation sites within the intracellular domain of SLAMF7 and the phosphatase domain of SHIP1 were indispensable for the interaction between SLAMF7, SHIP1, and TRAF6 and SLAMF7-mediated modulation of cytokine production. Finally, we demonstrated that SLAMF7 protected against lethal sepsis and endotoxemia by downregulating macrophage proinflammatory cytokines and suppressing inflammation-induced organ damage. Taken together, our findings reveal a negative regulatory role of SLAMF7 in polymicrobial sepsis, thus providing sights into the treatment of sepsis.
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Affiliation(s)
- Yongjian Wu
- Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Qiaohua Wang
- Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Miao Li
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong Province, China
| | - Juanfeng Lao
- Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Huishu Tang
- Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Siqi Ming
- National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of the Southern University of Science and Technology, Shenzhen, Guangdong Province, China
| | - Minhao Wu
- Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China
| | - Sitang Gong
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Linhai Li
- The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong Province, China
| | - Lei Liu
- National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of the Southern University of Science and Technology, Shenzhen, Guangdong Province, China
| | - Xi Huang
- Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China.,National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital of the Southern University of Science and Technology, Shenzhen, Guangdong Province, China.,The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong Province, China
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Lajqi T, Köstlin-Gille N, Bauer R, Zarogiannis SG, Lajqi E, Ajeti V, Dietz S, Kranig SA, Rühle J, Demaj A, Hebel J, Bartosova M, Frommhold D, Hudalla H, Gille C. Training vs. Tolerance: The Yin/Yang of the Innate Immune System. Biomedicines 2023; 11:766. [PMID: 36979747 PMCID: PMC10045728 DOI: 10.3390/biomedicines11030766] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/26/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
For almost nearly a century, memory functions have been attributed only to acquired immune cells. Lately, this paradigm has been challenged by an increasing number of studies revealing that innate immune cells are capable of exhibiting memory-like features resulting in increased responsiveness to subsequent challenges, a process known as trained immunity (known also as innate memory). In contrast, the refractory state of endotoxin tolerance has been defined as an immunosuppressive state of myeloid cells portrayed by a significant reduction in the inflammatory capacity. Both training as well tolerance as adaptive features are reported to be accompanied by epigenetic and metabolic alterations occurring in cells. While training conveys proper protection against secondary infections, the induction of endotoxin tolerance promotes repairing mechanisms in the cells. Consequently, the inappropriate induction of these adaptive cues may trigger maladaptive effects, promoting an increased susceptibility to secondary infections-tolerance, or contribute to the progression of the inflammatory disorder-trained immunity. This review aims at the discussion of these opposing manners of innate immune and non-immune cells, describing the molecular, metabolic and epigenetic mechanisms involved and interpreting the clinical implications in various inflammatory pathologies.
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Affiliation(s)
- Trim Lajqi
- Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
| | - Natascha Köstlin-Gille
- Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
- Department of Neonatology, University of Tübingen, D-72076 Tübingen, Germany
| | - Reinhard Bauer
- Institute of Molecular Cell Biology, Jena University Hospital, D-07745 Jena, Germany
| | - Sotirios G. Zarogiannis
- Department of Physiology, School of Health Sciences, Faculty of Medicine, University of Thessaly, GR-41500 Larissa, Greece
| | - Esra Lajqi
- Department of Radiation Oncology, Heidelberg University Hospital, D-69120 Heidelberg, Germany
| | - Valdrina Ajeti
- Department of Pharmacy, Alma Mater Europaea—Campus College Rezonanca, XK-10000 Pristina, Kosovo
| | - Stefanie Dietz
- Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
- Department of Neonatology, University of Tübingen, D-72076 Tübingen, Germany
| | - Simon A. Kranig
- Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
| | - Jessica Rühle
- Department of Neonatology, University of Tübingen, D-72076 Tübingen, Germany
| | - Ardian Demaj
- Faculty of Medical Sciences, University of Tetovo, MK-1200 Tetova, North Macedonia
| | - Janine Hebel
- Department of Neonatology, University of Tübingen, D-72076 Tübingen, Germany
| | - Maria Bartosova
- Center for Pediatric and Adolescent Medicine Heidelberg, University of Heidelberg, D-69120 Heidelberg, Germany
| | - David Frommhold
- Klinik für Kinderheilkunde und Jugendmedizin, D-87700 Memmingen, Germany
| | - Hannes Hudalla
- Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
| | - Christian Gille
- Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
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11
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Fernandes S, Srivastava N, Pedicone C, Sudan R, Luke EA, Dungan OM, Pacherille A, Meyer ST, Dormann S, Schurmans S, Chambers BJ, Chisholm JD, Kerr WG. Obesity control by SHIP inhibition requires pan-paralog inhibition and an intact eosinophil compartment. iScience 2023; 26:106071. [PMID: 36818285 PMCID: PMC9929608 DOI: 10.1016/j.isci.2023.106071] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 10/18/2022] [Accepted: 01/23/2023] [Indexed: 01/29/2023] Open
Abstract
Here we extend the understanding of how chemical inhibition of SHIP paralogs controls obesity. We compare different classes of SHIP inhibitors and find that selective inhibitors of SHIP1 or SHIP2 are unable to prevent weight gain and body fat accumulation during increased caloric intake. Surprisingly, only pan-SHIP1/2 inhibitors (pan-SHIPi) prevent diet-induced obesity. We confirm that pan-SHIPi is essential by showing that dual treatment with SHIP1 and SHIP2 selective inhibitors reduced adiposity during excess caloric intake. Consistent with this, genetic inactivation of both SHIP paralogs in eosinophils or myeloid cells also reduces obesity and adiposity. In fact, pan-SHIPi requires an eosinophil compartment to prevent diet-induced adiposity, demonstrating that pan-SHIPi acts via an immune mechanism. We also find that pan-SHIPi increases ILC2 cell function in aged, obese mice to reduce their obesity. Finally, we show that pan-SHIPi also reduces hyperglycemia, but not via eosinophils, indicating a separate mechanism for glucose control.
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Affiliation(s)
- Sandra Fernandes
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Neetu Srivastava
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Chiara Pedicone
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Raki Sudan
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Elizabeth A. Luke
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Otto M. Dungan
- Department of Chemistry, Syracuse University, Syracuse, NY, USA
| | | | - Shea T. Meyer
- Department of Chemistry, Syracuse University, Syracuse, NY, USA
| | - Shawn Dormann
- Department of Chemistry, Syracuse University, Syracuse, NY, USA
| | | | - Benedict J. Chambers
- Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | | | - William G. Kerr
- Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA
- Department of Chemistry, Syracuse University, Syracuse, NY, USA
- Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, USA
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12
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Wadowska M, Dobosz E, Golda A, Bryzek D, Lech M, Fu M, Koziel J. MCP-Induced Protein 1 Participates in Macrophage-Dependent Endotoxin Tolerance. THE JOURNAL OF IMMUNOLOGY 2022; 209:1348-1358. [DOI: 10.4049/jimmunol.2101184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 07/28/2022] [Indexed: 11/06/2022]
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13
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Lipopolysaccharide-Induced Immunological Tolerance in Monocyte-Derived Dendritic Cells. IMMUNO 2022. [DOI: 10.3390/immuno2030030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Bacterial lipopolysaccharides (LPS), also referred to as endotoxins, are major outer surface membrane components present on almost all Gram-negative bacteria and are major determinants of sepsis-related clinical complications including septic shock. LPS acts as a strong stimulator of innate or natural immunity in a wide variety of eukaryotic species ranging from insects to humans including specific effects on the adaptive immune system. However, following immune stimulation, lipopolysaccharide can induce tolerance which is an essential immune-homeostatic response that prevents overactivation of the inflammatory response. The tolerance induced by LPS is a state of reduced immune responsiveness due to persistent and repeated challenges, resulting in decreased expression of pro-inflammatory modulators and up-regulation of antimicrobials and other mediators that promote a reduction of inflammation. The presence of environmental-derived LPS may play a key role in decreasing autoimmune diseases and gut tolerance to the plethora of ingested antigens. The use of LPS may be an important immune adjuvant as demonstrated by the promotion of IDO1 increase when present in the fusion protein complex of CTB-INS (a chimera of the cholera toxin B subunit linked to proinsulin) that inhibits human monocyte-derived DC (moDC) activation, which may act through an IDO1-dependent pathway. The resultant state of DC tolerance can be further enhanced by the presence of residual E. coli lipopolysaccharide (LPS) which is almost always present in partially purified CTB-INS preparations. The approach to using an adjuvant with an autoantigen in immunotherapy promises effective treatment for devastating tissue-specific autoimmune diseases like multiple sclerosis (MS) and type 1 diabetes (T1D).
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14
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De Zuani M, Dal Secco C, Tonon S, Arzese A, Pucillo CEM, Frossi B. LPS Guides Distinct Patterns of Training and Tolerance in Mast Cells. Front Immunol 2022; 13:835348. [PMID: 35251027 PMCID: PMC8891506 DOI: 10.3389/fimmu.2022.835348] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/26/2022] [Indexed: 11/17/2022] Open
Abstract
Mast cells (MCs) are tissue-resident, long lived innate immune cells with important effector and immunomodulatory functions. They are equipped with an eclectic variety of receptors that enable them to sense multiple stimuli and to generate specific responses according on the type, strength and duration of the stimulation. Several studies demonstrated that myeloid cells can retain immunological memory of their encounters – a process termed ‘trained immunity’ or ‘innate immune memory’. As MCs are among the one of first cells to come into contact with the external environment, it is possible that such mechanisms of innate immune memory might help shaping their phenotype and effector functions; however, studies on this aspect of MC biology are still scarce. In this manuscript, we investigated the ability of MCs primed with different stimuli to respond to a second stimulation with the same or different ligands, and determined the molecular and epigenetic drivers of these responses. Our results showed that, while the stimulation with IgE and β-glucan failed to induce either tolerant or trained phenotypes, LPS conditioning was able to induce a profound and long-lasting remodeling of the signaling pathways involved in the response against LPS or fungal pathogens. On one side, LPS induced a strong state of unresponsiveness to secondary LPS stimulation due to the impairment of the PI3K-AKT signaling pathway, which resulted in the reduced activation of NF-κB and the decreased release of TNF-α and IL-6, compared to naïve MCs. On the other side, LPS primed MCs showed an increased release of TNF-α upon fungal infection with live Candida albicans, thus suggesting a dual role of LPS in inducing both tolerance and training phenotypes depending on the secondary challenge. Interestingly, the inhibition of HDAC during LPS stimulation partially restored the response of LPS-primed MCs to a secondary challenge with LPS, but failed to revert the increased cytokine production of these cells in response to C. albicans. These data indicate that MCs, as other innate immune cells, can develop innate immune memory, and that different stimulatory environments can shape and direct MC specific responses towards the dampening or the propagation of the local inflammatory response.
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Affiliation(s)
- Marco De Zuani
- Department of Medicine, University of Udine, Udine, Italy.,International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czechia
| | | | - Silvia Tonon
- Department of Medicine, University of Udine, Udine, Italy
| | | | | | - Barbara Frossi
- Department of Medicine, University of Udine, Udine, Italy
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15
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Yu Z, Li Y, Li Y, Zhang J, Li M, Ji L, Tang Y, Zheng Y, Sheng J, Han Q, Li F, Guo J, Wang L, Sun X, Gao Y, Feng H. Bufalin stimulates antitumor immune response by driving tumor-infiltrating macrophage toward M1 phenotype in hepatocellular carcinoma. J Immunother Cancer 2022; 10:jitc-2021-004297. [PMID: 35618286 PMCID: PMC9125767 DOI: 10.1136/jitc-2021-004297] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2022] [Indexed: 02/06/2023] Open
Abstract
Background Immunotherapy for hepatocellular carcinoma (HCC) exhibits limited clinical efficacy due to immunosuppressive tumor microenvironment (TME). Tumor-infiltrating macrophages (TIMs) account for the major component in the TME, and the dominance of M2 phenotype over M1 phenotype in the TIMs plays the pivotal role in sustaining the immunosuppressive character. We thus investigate the effect of bufalin on promoting TIMs polarization toward M1 phenotype to improve HCC immunotherapy. Methods The impact of bufalin on evoking antitumor immune response was evaluated in the immunocompetent mouse HCC model. The expression profiling of macrophage-associated genes, surface markers and cytokines on bufalin treatment in vitro and in vivo were detected using flow cytometry, immunofluorescence, western blot analysis, ELISA and RT-qPCR. Cell signaling involved in M1 macrophage polarization was identified via the analysis of gene sequencing, and bufalin-governed target was explored by immunoprecipitation, western blot analysis and gain-and-loss of antitumor immune response. The combination of bufalin and antiprogrammed cell death protein 1 (anti-PD-1) antibody was also assessed in orthotopic HCC mouse model. Results In this study, we showed that bufalin can function as an antitumor immune modulator that governs the polarization of TIMs from tumor-promoting M2 toward tumor-inhibitory M1, which induces HCC suppression through the activation of effector T cell immune response. Mechanistically, bufalin inhibits overexpression of p50 nuclear factor kappa B (NF-κB) factor, leading to the predominance of p65-p50 heterodimers over p50 homodimers in the nuclei. The accumulation of p65-p50 heterodimers activates NF-κB signaling, which is responsible for the production of immunostimulatory cytokines, thus resulting in the activation of antitumor T cell immune response. Moreover, bufalin enhances the antitumor activity of anti-PD-1 antibody, and the combination exerts synergistic effect on HCC suppression. Conclusions These data expound a novel antitumor mechanism of bufalin, and facilitate exploitation of a new potential macrophage-based HCC immunotherapeutic modality.
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Affiliation(s)
- Zhuo Yu
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Yuyao Li
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Yue Li
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Jinghao Zhang
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Man Li
- Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Longshan Ji
- Laboratory of Cellular Immunity, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Yifei Tang
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Yanxi Zheng
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Jianguo Sheng
- Department of Ultrasound, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Qiucheng Han
- Department of Ultrasound, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Fu Li
- Department of Hepatopancreatobiliary Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Jianfeng Guo
- School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, People's Republic of China
| | - Lingtai Wang
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Xuehua Sun
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China .,Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Yueqiu Gao
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China .,Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
| | - Hai Feng
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People's Republic of China
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16
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Zhang X, Dong S. Protective effect of growth differentiation factor 15 in sepsis by regulating macrophage polarization and its mechanism. Bioengineered 2022; 13:9687-9707. [PMID: 35420978 PMCID: PMC9161903 DOI: 10.1080/21655979.2022.2059903] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
This study aims to investigate the protective effect of growth differentiation factor 15 (GDF15) in sepsis by regulating macrophage polarization and its mechanism. The mouse macrophages were cultured and treated with lipopolysaccharide (LPS), and some cells were intervened with GDF15 and LY294002. The proinflammatory activated (M1) macrophages and the anti-inflammatory activated (M2) macrophages were measured and observed, and the messenger RNA expression levels of their biomarkers, phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt) were detected. The survival rate, cardiac function, and histopathological sections were observed. In the LPS group, after GDF15 intervention, the percentage of M1 macrophages decreased and M2 macrophages increased, the infiltration of monocytes/macrophages into the heart was inhibited, systemic and cardiac inflammation was reduced, and the survival time of the mice was prolonged. GDF15 regulated macrophage polarization and played an anti-inflammatory role by activating the phosphorylation of the PI3K/Akt signaling pathway. In patients with sepsis, the serum GDF15 level increased and was closely related to the severity of the sepsis and the 28-day mortality rate and could be used as a prognostic marker of sepsis. GDF15 regulates macrophage polarization through activating the PI3K/Akt signaling pathway and has a protective effect on survival and the cardiac function of patients with sepsis and sepsis mouse models. The increase in serum GDF15 level is closely related to severity and mortality in patients with sepsis and is therefore a prognostic marker of sepsis.
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Affiliation(s)
- Xinliang Zhang
- Department of Emergency Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Shimin Dong
- Department of Emergency Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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17
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Mody D, Verma V, Rani V. Modulating host gene expression via gut microbiome-microRNA interplay to treat human diseases. Crit Rev Microbiol 2021; 47:596-611. [PMID: 34407384 DOI: 10.1080/1040841x.2021.1907739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The human gastrointestinal (GI) tract hosts trillions of microbial inhabitants involved in maintaining intestinal homeostasis, dysbiosis of which provokes a motley of pathogenic and autoimmune disorders. While the mechanisms by which the microbiota modulates human health are manifold, their liberated metabolites from ingested dietary supplements play a crucial role by bidirectionally regulating the expression of micro-ribonucleic acids (miRNAs). miRNAs are small endogenous non-coding RNAs (ncRNAs) that have been confirmed to be involved in an interplay with microbiota to regulate host gene expression. This comprehensive review focuses on key principles of miRNAs, their regulation, and crosstalk with gut microbiota to influence host gene expression in various human disorders, by bringing together important recent findings centric around miRNA-microbiota interactions in diseases along various axis of the gut with other organs. We also attempt to lay emphasis on exploiting the avenues of gut-directed miRNA therapeutics using rudimentary dietary supplements to regulate abnormal host gene expression in diseases, opening doors to an accessible and economical therapeutic strategy.
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Affiliation(s)
- Deepansh Mody
- Transcriptome Laboratory, Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, UP, India
| | - Vedika Verma
- Transcriptome Laboratory, Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, UP, India
| | - Vibha Rani
- Transcriptome Laboratory, Centre for Emerging Diseases, Department of Biotechnology, Jaypee Institute of Information Technology, Noida, UP, India
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18
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Watanabe H, Son M. The Immune Tolerance Role of the HMGB1-RAGE Axis. Cells 2021; 10:564. [PMID: 33807604 PMCID: PMC8001022 DOI: 10.3390/cells10030564] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 02/26/2021] [Accepted: 03/03/2021] [Indexed: 12/11/2022] Open
Abstract
The disruption of the immune tolerance induces autoimmunity such as systemic lupus erythematosus and vasculitis. A chromatin-binding non-histone protein, high mobility group box 1 (HMGB1), is released from the nucleus to the extracellular milieu in particular environments such as autoimmunity, sepsis and hypoxia. Extracellular HMGB1 engages pattern recognition receptors, including Toll-like receptors (TLRs) and the receptor for advanced glycation endproducts (RAGE). While the HMGB1-RAGE axis drives inflammation in various diseases, recent studies also focus on the anti-inflammatory effects of HMGB1 and RAGE. This review discusses current perspectives on HMGB1 and RAGE's roles in controlling inflammation and immune tolerance. We also suggest how RAGE heterodimers responding microenvironments functions in immune responses.
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Affiliation(s)
- Haruki Watanabe
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA;
| | - Myoungsun Son
- Center for Autoimmune Musculoskeletal and Hematopoietic Diseases, The Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA;
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
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Quan H, Yin M, Kim J, Jang EA, Yang SH, Bae HB, Jeong S. Resveratrol suppresses the reprogramming of macrophages into an endotoxin-tolerant state through the activation of AMP-activated protein kinase. Eur J Pharmacol 2021; 899:173993. [PMID: 33675782 DOI: 10.1016/j.ejphar.2021.173993] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 02/20/2021] [Accepted: 02/28/2021] [Indexed: 12/14/2022]
Abstract
Resveratrol has been reported to have beneficial effects on sepsis by regulating the inflammatory response. However, it remains unclear if resveratrol plays a role in the development of endotoxin tolerance. Treatment with resveratrol in macrophages stimulated with primary lipopolysaccharide (LPS) resulted in the increased production of TNF-α and IL-6 induced by a 2nd dose of LPS (by 74.5 ± 12.9% and 63.4 ± 12%, respectively, compared to untreated cells, P < 0.05). This effect was inhibited by compound C, an AMPK inhibitor, and STO609, a calcium/calmodulin-dependent protein kinase-kinase (CaMKK) inhibitor. Resveratrol diminished the expression of interleukin-1 receptor-associated kinase M (IRAK-M) and Src homology 2 (SH2) domain-containing inositol-5-phosphatase 1 (SHIP1) by prolonging the exposure of cells to LPS (by 60.8 ± 16.3% and 70.3 ± 18.1%, respectively, compared to LPS only). The effect of resveratrol on the LPS-induced expression of IRAK-M and SHIP1 was inhibited by compound C or STO609. After a 2nd dose of LPS, resveratrol increased phosphorylation of ERK1/2, p38, and JNK in endotoxin tolerant macrophages. In vivo systemic administration of resveratrol prevented a significant increase in mortality rate by cecal ligation and puncture in LPS-induced endotoxin-tolerant mice. These results indicate that resveratrol induces AMPK activation through the Ca2+/CaMKKβ pathway and suppresses the development of endotoxin tolerance by inhibiting LPS-induced expression of IRAK-M and SHIP1.
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Affiliation(s)
- Hui Quan
- Department of Plastic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China; Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea
| | - Mei Yin
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea; The Brain Korea 21 Project, Center for Biomedical Human Resources at Chonnam National University, Gwangju, South Korea
| | - Joungmin Kim
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea
| | - Eun-A Jang
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea
| | - Si-Ho Yang
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea
| | - Hong-Beom Bae
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea; The Brain Korea 21 Project, Center for Biomedical Human Resources at Chonnam National University, Gwangju, South Korea; Department of Anesthesiology and Pain Medicine, Chonnam National University Hwasun Hospital, Hwasun-gun, Jeollanamdo, South Korea.
| | - Seongtae Jeong
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea; Department of Anesthesiology and Pain Medicine, Chonnam National University Hwasun Hospital, Hwasun-gun, Jeollanamdo, South Korea.
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Preexisting and inducible endotoxemia as crucial contributors to the severity of COVID-19 outcomes. PLoS Pathog 2021; 17:e1009306. [PMID: 33600486 PMCID: PMC7891777 DOI: 10.1371/journal.ppat.1009306] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
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21
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Kuprys PV, Cannon AR, Shieh J, Iftekhar N, Park SK, Eberhardt JM, Ding X, Choudhry MA. Alcohol decreases intestinal ratio of Lactobacillus to Enterobacteriaceae and induces hepatic immune tolerance in a murine model of DSS-colitis. Gut Microbes 2020; 12:1-16. [PMID: 33180663 PMCID: PMC7671045 DOI: 10.1080/19490976.2020.1838236] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 09/22/2020] [Accepted: 10/01/2020] [Indexed: 02/08/2023] Open
Abstract
Alcohol can potentiate disease in a mouse model of dextran sodium sulfate (DSS) colitis; however, the underlying mechanism remains to be established. In this study, we assessed whether the potentiated disease could be related to Enterobacteriaceae and Lactobacillus, as changes in their relative abundance can impact intestinal health. We also assessed whether the intestinal barrier is compromised after alcohol and DSS as it may increase bacterial translocation and liver inflammation. Mice were administered DSS followed by binge ethanol or water vehicle, generating four experimental groups: (Control+Vehicle, Control+Ethanol, DSS+Vehicle, DSS+Ethanol). DNA was isolated from colon and cecal contents followed by qPCR for levels of Enterobacteriaceae and Lactobacillus. Colon and liver sections were taken for histology. Intestinal epithelial cells were isolated from the colon for RNA expression. DSS+Ethanol cecal contents exhibited a 1 log increase in Enterobacteriaceae (p < .05), a 0.5 log decrease in Lactobacillus, and a 1.5 log decrease (p < .05) in the Lactobacillus:Enterobacteriaceae ratio compared to DSS+Vehicle, with similar trends in colon contents. These changes correlated with shorter colons and more weight loss. Irrespective of ethanol administration, DSS compromised the mucosal barrier integrity, however only DSS+Ethanol exhibited significant increases in circulating endotoxin. Furthermore, the livers of DSS+Ethanol mice had significantly increased levels of triglycerides, mononuclear cells, yet exhibited significantly depressed expression of liver inflammatory pathways, suggestive of tolerance induction, compared to mice receiving DSS+Vehicle. Our results suggest that ethanol after DSS colitis increases the intestinal burden of Enterobacteriaceae which may contribute to intestinal and liver damage, and the induction of immune tolerance.
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Affiliation(s)
- Paulius V. Kuprys
- Alcohol Research Program, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
- Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
- Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
- Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
| | - Abigail R. Cannon
- Alcohol Research Program, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
- Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
- Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
- Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
| | - Jennifer Shieh
- Alcohol Research Program, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
- Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
| | - Noama Iftekhar
- Alcohol Research Program, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
- Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
| | - Sun K. Park
- Alcohol Research Program, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
- Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
| | - Joshua M. Eberhardt
- Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
| | - Xianzhong Ding
- Department of Pathology, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
| | - Mashkoor A. Choudhry
- Alcohol Research Program, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
- Burn and Shock Trauma Research Institute, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
- Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
- Integrative Cell Biology Program, Loyola University Chicago Health Sciences Campus, Maywood, IL, USA
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Espinosa-Riquer ZP, Segura-Villalobos D, Ramírez-Moreno IG, Pérez Rodríguez MJ, Lamas M, Gonzalez-Espinosa C. Signal Transduction Pathways Activated by Innate Immunity in Mast Cells: Translating Sensing of Changes into Specific Responses. Cells 2020; 9:E2411. [PMID: 33158024 PMCID: PMC7693401 DOI: 10.3390/cells9112411] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/21/2020] [Accepted: 10/28/2020] [Indexed: 12/17/2022] Open
Abstract
Mast cells (MCs) constitute an essential cell lineage that participates in innate and adaptive immune responses and whose phenotype and function are influenced by tissue-specific conditions. Their mechanisms of activation in type I hypersensitivity reactions have been the subject of multiple studies, but the signaling pathways behind their activation by innate immunity stimuli are not so well described. Here, we review the recent evidence regarding the main molecular elements and signaling pathways connecting the innate immune receptors and hypoxic microenvironment to cytokine synthesis and the secretion of soluble or exosome-contained mediators in this cell type. When known, the positive and negative control mechanisms of those pathways are presented, together with their possible implications for the understanding of mast cell-driven chronic inflammation. Finally, we discuss the relevance of the knowledge about signaling in this cell type in the recognition of MCs as central elements on innate immunity, whose remarkable plasticity converts them in sensors of micro-environmental discontinuities and controllers of tissue homeostasis.
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Affiliation(s)
| | | | | | | | | | - Claudia Gonzalez-Espinosa
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Unidad Sede Sur. Calzada de los Tenorios No. 235, Col. Granjas Coapa, Mexico City 14330, Mexico; (Z.P.E.-R.); (D.S.-V.); (I.G.R.-M.); (M.J.P.R.); (M.L.)
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Lajqi T, Pöschl J, Frommhold D, Hudalla H. The Role of Microbiota in Neutrophil Regulation and Adaptation in Newborns. Front Immunol 2020; 11:568685. [PMID: 33133082 PMCID: PMC7550463 DOI: 10.3389/fimmu.2020.568685] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 08/31/2020] [Indexed: 12/16/2022] Open
Abstract
Newborns are highly susceptible to infections and mainly rely on innate immune functions. Reduced reactivity, delayed activation and subsequent failure to resolve inflammation however makes the neonatal immune system a very volatile line of defense. Perinatal microbiota, nutrition and different extra-uterine factors are critical elements that define long-term outcomes and shape the immune system during the neonatal period. Neutrophils are first responders and represent a vital component of the immune system in newborns. They have long been regarded as merely executive immune cells, however this notion is beginning to shift. Neutrophils are shaped by their surrounding and adaptive elements have been described. The role of “innate immune memory” and the main triangle connection microbiome—neutrophil—adaptation will be discussed in this review.
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Affiliation(s)
- Trim Lajqi
- Heidelberg University Children's Hospital, Department of Neonatology, Heidelberg, Germany
| | - Johannes Pöschl
- Heidelberg University Children's Hospital, Department of Neonatology, Heidelberg, Germany
| | - David Frommhold
- Klinik für Kinderheilkunde und Jugendmedizin, Memmingen, Germany
| | - Hannes Hudalla
- Heidelberg University Children's Hospital, Department of Neonatology, Heidelberg, Germany
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24
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Chen-Fei L, Chou-Min C, Jiun-Yan L. Feasibility of vaccination against Macrobrachium rosenbergii nodavirus infection in giant freshwater prawn. FISH & SHELLFISH IMMUNOLOGY 2020; 104:431-438. [PMID: 32580003 DOI: 10.1016/j.fsi.2020.06.039] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/14/2020] [Accepted: 06/17/2020] [Indexed: 06/11/2023]
Abstract
The giant freshwater prawn/giant river prawn, Macrobrachium rosenbergii is one of the high market value crustaceans cultured worldwide. The intensified aquaculture of the species has led to the outbreak of infectious diseases, prominently, the white tail disease (WTD). It is caused by the infection of Macrobrachium rosenbergii nodavirus (MrNV), which was classified in the family of Nodaviridae. To-date, there are no effective prophylactic and therapeutic agents available against MrNV infection. Vaccination is known to be the most effective prophylactic agent in disease prevention. However, vaccine development against virus infection in crustaceans is equivocal. The feasibility of vaccination in conferring immune protection in crustaceans against infectious diseases is disputable. The argument lies in the fact that crustaceans do not possess adaptive immunity, which is the main immune component that functions to establish immunological memory upon vaccination. Nevertheless, an increasing number of literatures has been documented, which concerns the development of vaccines against infectious diseases in crustaceans. The current review deliberates different approaches in vaccine development against MrNV, which were documented in the past years. It is noteworthy that the live-attenuated MrNV vaccine has not been experimented by far. Thus, the potential of live-attenuated MrNV vaccine in conferring long-term immune protection through the establishment of innate immune memory is currently being discussed.
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Affiliation(s)
- Low Chen-Fei
- Institute of Systems Biology, Universiti Kebangsaan Malaysia, 43600 UKM, Bangi, Selangor, Malaysia.
| | - Chong Chou-Min
- Laboratory of Marine Biotechnology, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.
| | - Loh Jiun-Yan
- Faculty of Applied Sciences, UCSI University, 56000 Cheras, Kuala Lumpur, Malaysia
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25
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Low CF, Chong CM. Peculiarities of innate immune memory in crustaceans. FISH & SHELLFISH IMMUNOLOGY 2020; 104:605-612. [PMID: 32619624 DOI: 10.1016/j.fsi.2020.06.047] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/31/2020] [Accepted: 06/23/2020] [Indexed: 06/11/2023]
Abstract
Classical characteristic of the innate immune system is the lack of ability to build up immunological memory, contrast to the adaptive immune system that is capable of "remembering" antigens, and rapidly mount a greater magnitude of immune response upon subsequent exposure to the same antigens. Peculiarly, immunological memory of innate immunity is evidenced in invertebrates. At least three different memory phenomena have been described, namely sustained unique response, recalled response, and immune shift. Studies attended to decipher the mechanistic biology of the innate immune memory reveals the role of epigenetics, which modulates the response of immune memory, and the heritability of immune memory to subsequent generations. A parthenogenetic Artemia model demonstrated successful transgenerational epigenetic inheritance of resistance trait against Vibrio campbellii. Following, the role of invertebrate hemocytes and Down syndrome cell adhesion molecule (Dscam) in innate immune memory is reviewed. While there is no vertebrate antibody homolog found in invertebrates, Dscam was found to resemble the functionality of vertebrate antibody. Insight of Dscam as immune factor was illustrated further in the current review.
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Affiliation(s)
- Chen Fei Low
- Institute of Systems Biology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia.
| | - Chou Min Chong
- Laboratory of Marine Biotechnology, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
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26
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Fan C, Zhang X, Zhang P, Zhao J, Shen H, Zhang Y, Wu X, Jia Z, Wang Y. LPS stimulation during HCV infection induces MMP/TIMP1 imbalance in macrophages. J Med Microbiol 2020; 69:759-766. [PMID: 32242792 PMCID: PMC7451043 DOI: 10.1099/jmm.0.001185] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 03/07/2020] [Indexed: 01/23/2023] Open
Abstract
Introduction. During chronic hepatitis C virus (HCV) infections, HCV antigens establish cross-tolerance of endotoxins, but additional lipopolysaccharide (LPS) stimulation effects in this condition are poorly understood.Aim. This study aims to investigate the effects of the upregulated LPS on MMP and TIMP expression during chronic hepatitis C infection.Methodology. In the present study, we analysed the effect of HCV antigens and LPS stimulation on peripheral blood mononuclear cells (PBMCs) both in vivo and in vitro. Macrophages from HCV patients were isolated and their association with endotoxin tolerance was examined. MMP/TIMP1 expression and the related signalling pathways in macrophages were analysed. The macrophage and Huh7.5 cell co-culture model was used to analyse the effects of the cross-tolerance on collagen I deposition.Results. LPS levels were found to be significantly higher in HCV patients, particularly in those with HCV-induced liver fibrosis. In addition, although LPS serum level was occasionally upregulated in the patients, it did not induce intense immune response in PBMCs due to endotoxin cross-tolerance, and this was measured according to the changes in IL-6 and TNF-α levels. However, TIMP1 expression increased significantly during stimulation, exhibiting a tolerance/resistance phenotype, which was associated with TGF-β/Erk activation in macrophages. However, MMP levels did not increase due to endotoxin tolerance, which ultimately led to MMP/TIMP imbalance and influenced the deposition of collagen I.Conclusion. Increased LPS stimulation of macrophage during HCV antigen-induced endotoxin cross-tolerance contributes to MMP/TIMP1 imbalance and collagen I deposition.
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Affiliation(s)
- Chao Fan
- Institute of Cancer Research, School of Basical Medical Science of Xian Jiaotong University, Xian, PR China
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, PR China
| | - Xiaoxiao Zhang
- Department of Microbiology, Fourth Military Medical University, Xian, PR China
| | - Peixin Zhang
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, PR China
| | - Jieru Zhao
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, PR China
| | - Huanjun Shen
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, PR China
| | - Ying Zhang
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, PR China
| | - Xingan Wu
- Department of Microbiology, Fourth Military Medical University, Xian, PR China
| | - Zhansheng Jia
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xian, PR China
| | - Yili Wang
- Institute of Cancer Research, School of Basical Medical Science of Xian Jiaotong University, Xian, PR China
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Qin S, Li J, Zhou C, Privratsky B, Schettler J, Deng X, Xia Z, Zeng Y, Wu H, Wu M. SHIP-1 Regulates Phagocytosis and M2 Polarization Through the PI3K/Akt-STAT5-Trib1 Circuit in Pseudomonas aeruginosa Infection. Front Immunol 2020; 11:307. [PMID: 32256487 PMCID: PMC7093384 DOI: 10.3389/fimmu.2020.00307] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 02/06/2020] [Indexed: 02/05/2023] Open
Abstract
SHIP-1 is an inositol phosphatase that hydrolyzes phosphatidylinositol 3-kinase (PI3K) products and negatively regulates protein kinase B (Akt) activity, thereby modulating a variety of cellular processes in mammals. However, the role of SHIP-1 in bacterial-induced sepsis is largely unknown. Here, we show that SHIP-1 regulates inflammatory responses during Gram-negative bacterium Pseudomonas aeruginosa infection. We found that infected-SHIP-1-/- mice exhibited decreased survival rates, increased inflammatory responses, and susceptibility owing to elevated expression of PI3K than wild-type (WT) mice. Inhibiting SHIP-1 via siRNA silencing resulted in lipid raft aggregates, aggravated oxidative damage, and bacterial burden in macrophages after PAO1 infection. Mechanistically, SHIP-1 deficiency augmented phosphorylation of PI3K and nuclear transcription of signal transducer and activator of transcription 5 (STAT5) to induce the expression of Trib1, which is critical for differentiation of M2 but not M1 macrophages. These findings reveal a previously unrecognized role of SHIP-1 in inflammatory responses and macrophage homeostasis during P. aeruginosa infection through a PI3K/Akt-STAT5-Trib1 axis.
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Affiliation(s)
- Shugang Qin
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, United States
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jiaxin Li
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, United States
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Chuanmin Zhou
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, United States
| | - Breanna Privratsky
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, United States
| | - Jacob Schettler
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, United States
| | - Xin Deng
- Department of Pediatrics and Department of Pulmonary & Critical Care Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenwei Xia
- Department of Pediatrics and Department of Pulmonary & Critical Care Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yong Zeng
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Wu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Min Wu
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, United States
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Excessive CD11c +Tbet + B cells promote aberrant T FH differentiation and affinity-based germinal center selection in lupus. Proc Natl Acad Sci U S A 2019; 116:18550-18560. [PMID: 31451659 DOI: 10.1073/pnas.1901340116] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Excessive self-reactive and inadequate affinity-matured antigen-specific antibody responses have been reported to coexist in lupus, with elusive cellular and molecular mechanisms. Here, we report that the antigen-specific germinal center (GC) response-a process critical for antibody affinity maturation-is compromised in murine lupus models. Importantly, this defect can be triggered by excessive autoimmunity-relevant CD11c+Tbet+ age-associated B cells (ABCs). In B cell-intrinsic Ship-deficient (ShipΔB) lupus mice, excessive CD11c+Tbet+ ABCs induce deregulated follicular T-helper (TFH) cell differentiation through their potent antigen-presenting function and consequently compromise affinity-based GC selection. Excessive CD11c+Tbet+ ABCs and deregulated TFH cell are also present in other lupus models and patients. Further, over-activated Toll-like receptor signaling in Ship-deficient B cells is critical for CD11c+Tbet+ ABC differentiation, and blocking CD11c+Tbet+ ABC differentiation in ShipΔB mice by ablating MyD88 normalizes TFH cell differentiation and rescues antigen-specific GC responses, as well as prevents autoantibody production. Our study suggests that excessive CD11c+Tbet+ ABCs not only contribute significantly to autoantibody production but also compromise antigen-specific GC B-cell responses and antibody-affinity maturation, providing a cellular link between the coexisting autoantibodies and inadequate affinity-matured antigen-specific antibodies in lupus models and a potential target for treating lupus.
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29
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Triptolide Inhibits Preformed Fibril-Induced Microglial Activation by Targeting the MicroRNA155-5p/SHIP1 Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:6527638. [PMID: 31182996 PMCID: PMC6512043 DOI: 10.1155/2019/6527638] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 02/11/2019] [Indexed: 02/07/2023]
Abstract
Evidence suggests that various forms of α-synuclein- (αSyn-) mediated microglial activation are associated with the progression of Parkinson's disease. MicroRNA-155-5p (miR155-5p) is one of the most important microRNAs and enables a robust inflammatory response. Triptolide (T10) is a natural anti-inflammatory component, isolated from a traditional Chinese herb. The objective of the current study was to identify the role and potential regulatory mechanism of T10 in αSyn-induced microglial activation via the miR155-5p mediated SHIP1 signaling pathway. Mouse primary microglia were exposed to monomers, oligomers, and preformed fibrils (PFFs) of human wild-type αSyn, respectively. The expressions of TNFα and IL-1β, measured by enzyme-linked immunosorbent assay (ELISA) and qPCR, demonstrated that PFFs initiated the strongest immunogenicity in microglia. Application of inhibitors of toll-like receptor (TLR) 1/2, TLR4, and TLR9 indicated that PFFs activated microglia mainly via the NF-κB pathway by binding TLR1/2 and TLR4. Treatment with T10 significantly suppressed PFF-induced microglial activation and attenuated the release of proinflammatory cytokines including TNFα and IL-1β. Levels of IRAK1, TRAF6, IKKα/β, p-IKKα/β, NF-κB, p-NF-κB, PI3K, p-PI3K, t-Akt, p-Akt and SHIP1 were measured via Western blot. Levels of miR155-5p were measured by qPCR. The results demonstrated that SHIP1 acted as a downstream target molecule of miR155-5p. Treatment with T10 did not alter the expression of IRAK1 and TRAF6, but significantly decreased the expression of miR155-5p, resulting in upregulation of SHIP1 and repression of NF-κB activity, suggesting inhibition of inflammation and microglial activation. The protective effects of T10 were abolished by the use of SHIP1 siRNA and its inhibitor, 3AC, and miR155-5p mimics. In conclusion, our results demonstrated that treatment with T10 suppressed microglial activation and attenuated the release of proinflammatory cytokines by suppressing NF-κB activity via targeting the miR155-5p/SHIP1 pathway in PFFs-induced microglial activation.
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30
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Morris G, Maes M, Berk M, Puri BK. Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop? Metab Brain Dis 2019; 34:385-415. [PMID: 30758706 PMCID: PMC6428797 DOI: 10.1007/s11011-019-0388-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 01/23/2019] [Indexed: 12/19/2022]
Abstract
A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals. The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities. Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation. The role of chronic stress and the development of endotoxin tolerance via indoleamine 2,3-dioxygenase upregulation and the characteristics of neutrophils, monocytes, macrophages and T cells, including regulatory T cells, in endotoxin tolerance are detailed next. Finally, it is shown how the immune and metabolic abnormalities of chronic fatigue syndrome can be explained by endotoxin tolerance, thus completing the model.
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Affiliation(s)
- Gerwyn Morris
- IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Victoria, Australia
| | - Michael Maes
- IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Victoria, Australia
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Michael Berk
- IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Victoria, Australia
- Department of Psychiatry, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
- Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
- Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, Victoria, Australia
| | - Basant K Puri
- Department of Medicine, Imperial College London, Hammersmith Hospital, London, England, W12 0HS, UK.
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31
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Challenges of using lipopolysaccharides for cancer immunotherapy and potential delivery-based solutions thereto. Ther Deliv 2019; 10:165-187. [DOI: 10.4155/tde-2018-0076] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Despite being one of the earliest Toll-like receptor (TLR)-based cancer immunotherapeutics discovered and investigated, the full extent of lipopolysaccharide (LPS) potentials within this arena remains hitherto unexploited. In this review, we will debate the challenges that have complicated the improvement of LPS-based immunotherapeutic approaches in cancer therapy. Based on their nature, those will be discussed with a focus on side effect-related, tolerance-related and in vivo model-related challenges. We will then explore how drug delivery strategies can be integrated within this domain to address such challenges in order to improve the therapeutic outcome, and will present a summary of the studies that have been dedicated thereto. This paper may inspire further developments based on reconciling the advantages of drug delivery and LPS-based cancer immunotherapy.
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32
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Espinosa-Riquer ZP, Ibarra-Sánchez A, Vibhushan S, Bratti M, Charles N, Blank U, Rodríguez-Manzo G, González-Espinosa C. TLR4 Receptor Induces 2-AG-Dependent Tolerance to Lipopolysaccharide and Trafficking of CB2 Receptor in Mast Cells. THE JOURNAL OF IMMUNOLOGY 2019; 202:2360-2371. [PMID: 30814309 DOI: 10.4049/jimmunol.1800997] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 01/30/2019] [Indexed: 12/16/2022]
Abstract
Mast cells (MCs) contribute to the control of local inflammatory reactions and become hyporesponsive after prolonged TLR4 activation by bacterial LPS. The molecular mechanisms involved in endotoxin tolerance (ET) induction in MCs are not fully understood. In this study, we demonstrate that the endocannabinoid 2-arachidonoylglycerol (2-AG) and its receptor, cannabinoid receptor 2 (CB2), play a role in the establishment of ET in bone marrow-derived MCs from C57BL/6J mice. We found that CB2 antagonism prevented the development of ET and that bone marrow-derived MCs produce 2-AG in a TLR4-dependent fashion. Exogenous 2-AG induced ET similarly to LPS, blocking the phosphorylation of IKK and the p65 subunit of NF-κB and inducing the synthesis of molecular markers of ET. LPS caused CB2 receptor trafficking in Rab11-, Rab7-, and Lamp2-positive vesicles, indicating recycling and degradation of the receptor. 2-AG also prevented LPS-induced TNF secretion in vivo, in a MC-dependent model of endotoxemia, demonstrating that TLR4 engagement leads to 2-AG secretion, which contributes to the negative control of MCs activation. Our study uncovers a functional role for the endocannabinoid system in the inhibition of MC-dependent innate immune responses in vivo.
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Affiliation(s)
- Zyanya P Espinosa-Riquer
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, CP 14330 Mexico City, Mexico
| | - Alfredo Ibarra-Sánchez
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, CP 14330 Mexico City, Mexico
| | - Shamila Vibhushan
- INSERM U1149, Centre de Recherche sur l'Inflammation, 75018 Paris, France.,CNRS ERL8252, 75018 Paris, France; and.,Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Sorbonne Paris Cité, Université Paris Diderot, 75018 Paris, France
| | - Manuela Bratti
- INSERM U1149, Centre de Recherche sur l'Inflammation, 75018 Paris, France.,CNRS ERL8252, 75018 Paris, France; and.,Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Sorbonne Paris Cité, Université Paris Diderot, 75018 Paris, France
| | - Nicolas Charles
- INSERM U1149, Centre de Recherche sur l'Inflammation, 75018 Paris, France.,CNRS ERL8252, 75018 Paris, France; and.,Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Sorbonne Paris Cité, Université Paris Diderot, 75018 Paris, France
| | - Ulrich Blank
- INSERM U1149, Centre de Recherche sur l'Inflammation, 75018 Paris, France.,CNRS ERL8252, 75018 Paris, France; and.,Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Sorbonne Paris Cité, Université Paris Diderot, 75018 Paris, France
| | - Gabriela Rodríguez-Manzo
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, CP 14330 Mexico City, Mexico;
| | - Claudia González-Espinosa
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, CP 14330 Mexico City, Mexico;
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Vergadi E, Vaporidi K, Tsatsanis C. Regulation of Endotoxin Tolerance and Compensatory Anti-inflammatory Response Syndrome by Non-coding RNAs. Front Immunol 2018; 9:2705. [PMID: 30515175 PMCID: PMC6255943 DOI: 10.3389/fimmu.2018.02705] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Accepted: 11/01/2018] [Indexed: 12/17/2022] Open
Abstract
The onset and the termination of innate immune response must be tightly regulated to maintain homeostasis and prevent excessive inflammation, which can be detrimental to the organism, particularly in the context of sepsis. Endotoxin tolerance and compensatory anti-inflammatory response syndrome (CARS) describe a state of hypo-responsiveness characterized by reduced capacity of myeloid cells to respond to inflammatory stimuli, particularly those initiated by bacterial lipopolysaccharide (LPS). To achieve endotoxin tolerance, extensive reprogramming otherwise termed as “innate immune training”, is required that leads to both modifications of the intracellular components of TLR signaling and also to alterations in extracellular soluble mediators. Non-coding RNAs (ncRNAs) have been recognized as critical regulators of TLR signaling. Specifically, several microRNAs (miR-146, miR-125b, miR-98, miR-579, miR-132, let-7e and others) are induced upon TLR activation and reciprocally promote endotoxin tolerance and/or cross tolerance. Many other miRNAs have been also shown to negatively regulate TLR signaling. The long non-coding (lnc)RNAs (Mirt2, THRIL, MALAT1, lincRNA-21 and others) are also altered upon TLR activation and negatively regulate TLR signaling. Furthermore, the promotion or termination of myeloid cell tolerance is not only regulated by intracellular mediators but is also affected by other TLR-independent soluble signals that often achieve their effect via modulation of intracellular ncRNAs. In this article, we review recent evidence on the role of different ncRNAs in the context of innate immune cell tolerance and trained immunity, and evaluate their impact on immune system homeostasis.
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Affiliation(s)
- Eleni Vergadi
- Department of Paediatrics, Medical School, University of Crete, Heraklion, Greece.,Department of Clinical Chemistry, Medical School, University of Crete, Heraklion, Greece
| | - Katerina Vaporidi
- Department of Intensive Care Medicine, Medical School, University of Crete, Heraklion, Greece
| | - Christos Tsatsanis
- Department of Clinical Chemistry, Medical School, University of Crete, Heraklion, Greece
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34
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So EY, Sun C, Reginato AM, Dubielecka PM, Ouchi T, Liang OD. Loss of lipid phosphatase SHIP1 promotes macrophage differentiation through suppression of dendritic cell differentiation. Cancer Biol Ther 2018; 20:201-211. [PMID: 30277839 DOI: 10.1080/15384047.2018.1523846] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
SH2-containing inositol 5'-phosphatase-1 (SHIP1) deficiency in mice results in abnormal myeloid expansion, and proinflammatory conditions in the lung. However, the mechanisms involved in SHIP1-mediated regulation of myeloid differentiation remain unclear. Here we show that SHIP1 is a key regulator of early differentiation for dendritic cells (DCs). We also provide critical evidence to modify the function of SHIP1 in in vitro development of BMDCs using the recent framework of defining DCs. We found that loss of SHIP1 suppresses GM-CSF-induced formation of bone marrow-derived DC (BMDC) colonies, leading to reduced BMDC number in BM cell culture. The number of maturated BMDCs decreased in SHIP1-KO culture, due to reduction of immature BMDCs, suggesting SHIP1 is critical for lineage commitment rather than for maturation from myeloid precursors to DCs. We further showed that F4/80+/MHCIIlow BM macrophage-like cells (BMMs) were the main population of SHIP1-KO BM culture. Treatment of wild-type BM culture with 3 α-aminocholestane (3AC), a specific inhibitor for functional activity of SHIP1, caused a similar developmental defect in BMDCs as seen in SHIP1-KO cells, resulting in the absence of BMDC colony, and increased number of BMMs in BM culture. In conclusion, our results suggest that differentiation of BMDCs are markedly impaired under SHIP1 deficient condition, which causes skewed development of myeloid lineage cells manifested as pathological conditions associated with an excess of macrophage population.
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Affiliation(s)
- Eui Young So
- a Division of Hematology and Oncology, Department of Medicine, Rhode Island Hospital , Warren Alpert Medical School of Brown University , Providence , USA
| | - Changqi Sun
- b Division of Rheumatology, Department of Medicine, Rhode Island Hospital , Warren Alpert Medical School of Brown University , Providence , USA
| | - Anthony M Reginato
- b Division of Rheumatology, Department of Medicine, Rhode Island Hospital , Warren Alpert Medical School of Brown University , Providence , USA
| | - Patrycia M Dubielecka
- a Division of Hematology and Oncology, Department of Medicine, Rhode Island Hospital , Warren Alpert Medical School of Brown University , Providence , USA
| | - Toru Ouchi
- c Department of Cancer Genetics , Roswell Park Cancer Institute , Buffalo , USA
| | - Olin D Liang
- a Division of Hematology and Oncology, Department of Medicine, Rhode Island Hospital , Warren Alpert Medical School of Brown University , Providence , USA
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Liu D, Cao S, Zhou Y, Xiong Y. Recent advances in endotoxin tolerance. J Cell Biochem 2018; 120:56-70. [PMID: 30246452 DOI: 10.1002/jcb.27547] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 08/02/2018] [Indexed: 12/13/2022]
Abstract
Endotoxin tolerance is defined as a reduced capacity of a cell to respond endotoxin (lipopolysaccharide, LPS) challenge after an initial encounter with endotoxin in advance. The body becomes tolerant to subsequent challenge with a lethal dose of endotoxin and cytokines release and cell/tissue damage induced by inflammatory reaction are significantly reduced in the state of endotoxin tolerance. The main characteristics of endotoxin tolerance are downregulation of inflammatory mediators such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and C-X-C motif chemokine 10 (CXCL10) and upregulation of anti-inflammatory cytokines such as IL-10 and transforming growth factor β (TGF-β). Therefore, endotoxin tolerance is often regarded as the regulatory mechanism of the host against excessive inflammation. Endotoxin tolerance is a complex pathophysiological process and involved in multiple cellular signal pathways, receptor alterations, and biological molecules. However, the exact mechanism remains elusive up to date. To better understand the underlying cellular and molecular mechanisms of endotoxin tolerance, it is crucial to investigate the comprehensive cellular signal pathways, signaling proteins, cell surface molecules, proinflammatory and anti-inflammatory cytokines, and other mediators. Endotoxin tolerance plays an important role in reducing the mortality of sepsis, endotoxin shock, and other endotoxin-related diseases. Recent reports indicated that endotoxin tolerance is also related to other diseases such as cystic fibrosis, acute coronary syndrome, liver ischemia-reperfusion injury, and cancer. The aim of this review is to discuss the recent advances in endotoxin tolerance mainly based on the cellular and molecular mechanisms by outline the current state of the knowledge of the involvement of the toll-like receptor 4 (TLR4) signaling pathways, negative regulate factor, microRNAs, apoptosis, chromatin modification, and gene reprogramming of immune cells in endotoxin tolerance. We hope to provide a new idea and scientific basis for the rational treatment of endotoxin-related diseases such as endotoxemia, sepsis, and endotoxin shock clinically.
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Affiliation(s)
- Dan Liu
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Shousong Cao
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yejiang Zhou
- Gastrointestinal Surgery, Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, China
| | - Yuxia Xiong
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
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36
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Petes C, Mintsopoulos V, Finnen RL, Banfield BW, Gee K. The effects of CD14 and IL-27 on induction of endotoxin tolerance in human monocytes and macrophages. J Biol Chem 2018; 293:17631-17645. [PMID: 30242126 DOI: 10.1074/jbc.ra118.003501] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 09/11/2018] [Indexed: 12/26/2022] Open
Abstract
Upon repeated exposure to endotoxin or lipopolysaccharide (LPS), myeloid cells enter a refractory state called endotoxin tolerance as a homeostatic mechanism. In innate immune cells, LPS is recognized by co-receptors Toll-like receptor 4 (TLR4) and CD-14 to initiate an inflammatory response for subsequent cytokine production. One such cytokine, interleukin (IL)-27, is produced by myeloid cells in response to bacterial infection. In monocytes, IL-27 has proinflammatory functions such as up-regulating TLR4 expression for enhanced LPS-mediated cytokine production; alternatively, IL-27 induces inhibitory functions in activated macrophages. This study investigated the effects of IL-27 on the induction of endotoxin tolerance in models of human monocytes compared with macrophages. Our data demonstrate that IL-27 inhibits endotoxin tolerance by up-regulating cell surface TLR4 expression and soluble CD14 production to mediate stability of the surface LPS-TLR4-CD14 complex in THP-1 cells. In contrast, elevated basal expression of membrane-bound CD14 in phorbol 12-myristate 13-acetate (PMA)-THP-1 cells, primary monocytes, and primary macrophages may promote CD14-mediated endocytosis and be responsible for the preservation of an endotoxin-tolerized state in the presence of IL-27. Overall, the efficacy of IL-27 in inhibiting endotoxin tolerance in human THP-1 monocytes and PMA-THP-1 macrophages is affected by membrane-bound and soluble CD14 expression.
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Affiliation(s)
- Carlene Petes
- From the Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada
| | - Victoria Mintsopoulos
- From the Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada
| | - Renée L Finnen
- From the Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada
| | - Bruce W Banfield
- From the Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada
| | - Katrina Gee
- From the Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada
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Ye F, Winchester D, Stalvey C, Jansen M, Lee A, Khuddus M, Mazza J, Yale S. Proposed mechanisms of relative bradycardia. Med Hypotheses 2018; 119:63-67. [PMID: 30122494 DOI: 10.1016/j.mehy.2018.07.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 06/18/2018] [Accepted: 07/14/2018] [Indexed: 12/17/2022]
Abstract
Relative bradycardia is the term used to describe the mechanism where there is dissociation between pulse and temperature. This finding is important to recognize since it may provide further insights into the potential underlying causes of disease. There is no known proposed mechanism to explain this phenomenon. We hypothesize that relative bradycardia is the central mechanism reflecting and influenced potentially by the direct pathogenic effect on the sinoatrial node as well as cross-talk between the autonomic nervous system and immune system. Cardiac pacemaker cells may act as a target for inflammatory cytokines leading to alteration in heart rate dynamics or their responsiveness to neurotransmitters during systemic inflammation. These factors account for the important role of how the host response to infectious and non-infectious causes influences the appearance of relative bradycardia. We propose several methods that may be useful to confirm the proposed theoretical framework to further enhance our understanding of this paradoxical phenomenon. This includes measuring, during the episode of relative bradycardia, proinflammatory and anti-inflammatory cytokines, monitoring heart rate variability (HRV), and assessing underlying comorbidities and outcomes in patients with the same disease.
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Affiliation(s)
- Fan Ye
- Graduate Medical Education, University of Central Florida College of Medicine, 6850 Lake Nona Blvd, Orlando, FL 32827, United States
| | - David Winchester
- Department of Cardiology, University of Florida, College of Medicine, Gainesville, FL 32610, United States
| | - Carolyn Stalvey
- Department of General Internal Medicine, University of Florida, College of Medicine, Gainesville, FL 32610, United States
| | - Michael Jansen
- The Cardiac and Vascular Institute, Gainesville, 4645 NW 8th Ave., Gainesville, FL 32605, United States
| | - Arthur Lee
- The Cardiac and Vascular Institute, Gainesville, 4645 NW 8th Ave., Gainesville, FL 32605, United States
| | - Matheen Khuddus
- The Cardiac and Vascular Institute, Gainesville, 4645 NW 8th Ave., Gainesville, FL 32605, United States
| | - Joseph Mazza
- Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, WI 54449, United States
| | - Steven Yale
- Department of Internal Medicine, University of Central Florida College of Medicine, 6850 Lake Nona Blvd, Orlando, FL 32827, United States.
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Domínguez-Soto Á, Simón-Fuentes M, de Las Casas-Engel M, Cuevas VD, López-Bravo M, Domínguez-Andrés J, Saz-Leal P, Sancho D, Ardavín C, Ochoa-Grullón J, Sánchez-Ramón S, Vega MA, Corbí AL. IVIg Promote Cross-Tolerance against Inflammatory Stimuli In Vitro and In Vivo. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 201:41-52. [PMID: 29743313 DOI: 10.4049/jimmunol.1701093] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 04/18/2018] [Indexed: 01/25/2023]
Abstract
IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte-derived anti-inflammatory macrophages by inducing JNK activation and activin A production and limits proinflammatory macrophage differentiation by inhibiting GM-CSF-driven STAT5 activation. In vivo, IVIg provokes a rapid increase in peripheral blood activin A, CCL2, and IL-6 levels, an effect that can be recapitulated in vitro on human monocytes. On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR-initiated intracellular signaling. In line with these effects, in vivo IVIg infusion induces a state tolerant toward subsequent stimuli that results in reduced inflammatory cytokine production after LPS challenge in human peripheral blood and significant protection from LPS-induced death in mice. Therefore, IVIg conditions human macrophages toward the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that correlates with the net anti-inflammatory action of IVIg in vivo.
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Affiliation(s)
- Ángeles Domínguez-Soto
- Departamento de Biología Celular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain;
| | - Miriam Simón-Fuentes
- Departamento de Biología Celular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain
| | - Mateo de Las Casas-Engel
- Departamento de Biología Celular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain
| | - Víctor D Cuevas
- Departamento de Biología Celular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain
| | - María López-Bravo
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificas, 28049 Madrid, Spain
| | - Jorge Domínguez-Andrés
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificas, 28049 Madrid, Spain
| | - Paula Saz-Leal
- Fundación Centro Nacional de Investigaciones Cardiovasculares, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain; and
| | - David Sancho
- Fundación Centro Nacional de Investigaciones Cardiovasculares, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain; and
| | - Carlos Ardavín
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificas, 28049 Madrid, Spain
| | - Juliana Ochoa-Grullón
- Departamento de Inmunología Clínica, Hospital Universitario Clínico San Carlos, 28040 Madrid, Spain
| | - Silvia Sánchez-Ramón
- Departamento de Inmunología Clínica, Hospital Universitario Clínico San Carlos, 28040 Madrid, Spain
| | - Miguel A Vega
- Departamento de Biología Celular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain
| | - Angel L Corbí
- Departamento de Biología Celular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain;
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Fernandes S, Srivastava N, Sudan R, Middleton FA, Shergill AK, Ryan JC, Kerr WG. SHIP1 Deficiency in Inflammatory Bowel Disease Is Associated With Severe Crohn's Disease and Peripheral T Cell Reduction. Front Immunol 2018; 9:1100. [PMID: 29872435 PMCID: PMC5972310 DOI: 10.3389/fimmu.2018.01100] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 05/02/2018] [Indexed: 12/19/2022] Open
Abstract
In our previous study, we observed a severe reduction in the Src homology 2-containing-inositol-phosphatase-1 (SHIP1) protein in a subpopulation of subjects from a small adult Crohn’s Disease (CD) cohort. This pilot study had been undertaken since we had previously demonstrated that engineered deficiency of SHIP1 in mice results in a spontaneous and severe CD-like ileitis. Here, we extend our analysis of SHIP1 expression in peripheral blood mononuclear cells in a second much larger adult Inflammatory Bowel Disease (IBD) cohort, comprised of both CD and Ulcerative Colitis patients, to assess contribution of SHIP1 to the pathogenesis of human IBD. SHIP1 protein and mRNA levels were evaluated from blood samples obtained from IBD subjects seen at UCSF/SFVA, and compared to healthy control samples. Western blot analyses revealed that ~15% of the IBD subjects are severely SHIP1-deficient, with less than 10% of normal SHIP1 protein present in PBMC. Further analyses by flow cytometry and sequencing were performed on secondary samples obtained from the same subjects. Pan-hematolymphoid SHIP1 deficiency was a stable phenotype and was not due to coding changes in the INPP5D gene. A very strong association between SHIP1 deficiency and the presence of a novel SHIP1:ATG16L1 fusion transcript was seen. Similar to SHIP1-deficient mice, SHIP1-deficient subjects had reduced numbers of circulating CD4+ T cell numbers. Finally, SHIP1-deficient subjects with CD had a history of severe disease requiring multiple surgeries. These studies reveal that the SHIP1 protein is crucial for normal T cell homeostasis in both humans and mice, and that it is also a potential therapeutic and/or diagnostic target in human IBD.
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Affiliation(s)
- Sandra Fernandes
- Department of Microbiology and Immunology, Upstate Medical University, Syracuse, NY, United States
| | - Neetu Srivastava
- Department of Microbiology and Immunology, Upstate Medical University, Syracuse, NY, United States
| | - Raki Sudan
- Department of Microbiology and Immunology, Upstate Medical University, Syracuse, NY, United States
| | - Frank A Middleton
- Department of Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, United States.,Department of Biochemistry and Molecular Biology, Upstate Medical University, Syracuse, NY, United States.,Department of Psychiatry and Behavioral Sciences, Upstate Medical University, Syracuse, NY, United States
| | - Amandeep K Shergill
- Department of Medicine, University of California San Francisco, San Francisco, CA, United States
| | - James C Ryan
- Department of Medicine, University of California San Francisco, San Francisco, CA, United States.,Division of Gastroenterology, Medicine, US Department of Veterans Affairs, San Francisco, CA, United States
| | - William G Kerr
- Department of Microbiology and Immunology, Upstate Medical University, Syracuse, NY, United States.,Department of Chemistry, Syracuse University, Syracuse, NY, United States.,Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, United States
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40
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Tsantikos E, Lau M, Castelino CM, Maxwell MJ, Passey SL, Hansen MJ, McGregor NE, Sims NA, Steinfort DP, Irving LB, Anderson GP, Hibbs ML. Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease. J Clin Invest 2018; 128:2406-2418. [PMID: 29708507 DOI: 10.1172/jci98224] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Accepted: 03/06/2018] [Indexed: 12/13/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is an incurable inflammatory lung disease that afflicts millions of people worldwide, and it is the fourth leading cause of death. Systemic comorbidities affecting the heart, skeletal muscle, bone, and metabolism are major contributors to morbidity and mortality. Given the surprising finding in large prospective clinical biomarker studies that peripheral white blood cell count is more closely associated with disease than inflammatory biomarkers, we probed the role of blood growth factors. Using the SHIP-1-deficient COPD mouse model, which manifests a syndrome of destructive lung disease and a complex of comorbid pathologies, we have identified a critical and unexpected role for granulocyte-CSF (G-CSF) in linking these conditions. Deletion of G-CSF greatly reduced airway inflammation and lung tissue destruction, and attenuated systemic inflammation, right heart hypertrophy, loss of fat reserves, and bone osteoporosis. In human clinical translational studies, bronchoalveolar lavage fluid of patients with COPD demonstrated elevated G-CSF levels. These studies suggest that G-CSF may play a central and unforeseen pathogenic role in COPD and its complex comorbidities, and identify G-CSF and its regulators as potential therapeutic targets.
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Affiliation(s)
- Evelyn Tsantikos
- Department of Immunology and Pathology, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia
| | - Maverick Lau
- Department of Immunology and Pathology, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia.,Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, Victoria, Australia
| | - Cassandra Mn Castelino
- Department of Immunology and Pathology, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia
| | - Mhairi J Maxwell
- Department of Immunology and Pathology, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia
| | - Samantha L Passey
- Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, Victoria, Australia
| | - Michelle J Hansen
- Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, Victoria, Australia
| | - Narelle E McGregor
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
| | - Natalie A Sims
- St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
| | - Daniel P Steinfort
- Department of Respiratory and Sleep Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Louis B Irving
- Department of Respiratory and Sleep Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Gary P Anderson
- Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, Victoria, Australia
| | - Margaret L Hibbs
- Department of Immunology and Pathology, Alfred Medical Research and Education Precinct, Monash University, Melbourne, Victoria, Australia
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Xu H, Chen J, Si X, Chen M, Pei F, Qiu C, Wu J, Guan X. PKR inhibition mediates endotoxin tolerance in macrophages through inactivation of PI3K/AKT signaling. Mol Med Rep 2018; 17:8548-8556. [PMID: 29658572 DOI: 10.3892/mmr.2018.8869] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 03/09/2018] [Indexed: 11/05/2022] Open
Abstract
Following long‑term exposure to endotoxins, macrophages enter an immunosuppressive state that renders them unable respond to subsequent exposures to endotoxin, a phenomenon that is termed 'endotoxin tolerance'. Endotoxin tolerance increases the risks of secondary infection and mortality in patients with sepsis. In endotoxin‑tolerant macrophages, the mixed variation of gene transcription is referred to as macrophage reprogramming. The mechanisms underlying macrophage reprogramming remain unclear at present. Interferon‑induced double‑stranded RNA‑dependent protein kinase (PKR) is a widely expressed serine/threonine protein kinase. In addition to antiviral effects, PKR regulates the transcription of inflammatory cytokines by affecting transcription factors. However, the role of PKR in macrophage reprogramming remains to be elucidated. In the present study, the expression of inflammatory cytokines differed in lipopolysaccharide (LPS)‑tolerant RAW264.7 macrophages compared with LPS‑activated macrophages. Specifically, reverse transcription‑quantitative polymerase chain reaction results demonstrated that the mRNA levels of tumor necrosis factor‑α, interleukin‑1β (IL‑1β), C‑X‑C motif chemokine ligand 11, C‑C motif chemokine ligand (CCL17), CCL22 and suppressor of cytokine signaling 3 were decreased, and mRNAs levels of arginase‑1 (Arg1) and nitric oxide synthase 2 (iNOS) were increased, in LPS‑tolerant macrophages compared with LPS‑activated macrophages. Furthermore, western blot analysis demonstrated that the protein levels of phosphorylated (p)‑PKR were significantly decreased in the LPS‑tolerant cells. PKR activation with rotenone (10 µM) abrogated endotoxin tolerance by increasing the levels of the IL‑1β, CCL17 and CCL22 mRNAs and decreasing the levels of the Arg1 and iNOS mRNAs. Furthermore, western blotting demonstrated that AKT was markedly inactivated in endotoxin‑tolerant cells, as indicated by reduced p‑AKT levels. However, levels of p‑AKT were markedly increased following rotenone‑induced PKR activation in endotoxin‑tolerant cells. Ly294002 (10 µM), a phosphatidylinositol‑4,5‑bisphosphate 3‑kinase (PI3K)/AKT signaling inhibitor, partially reversed the rotenone‑induced alleviation of endotoxin tolerance. These results demonstrated that PKR inhibition mediated endotoxin tolerance in macrophages, and these effects were partially mediated by PI3K/AKT signaling. PKR may be a potential target for the treatment of endotoxin tolerance in patients with sepsis.
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Affiliation(s)
- Hailin Xu
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Juan Chen
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xiang Si
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Minying Chen
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Fei Pei
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Chunfang Qiu
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Jianfeng Wu
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xiangdong Guan
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
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Mortazavi-Jahromi SS, Farazmand A, Motamed N, Navabi SS, Mirshafiey A. Effects of guluronic acid (G2013) on SHIP1, SOCS1 induction and related molecules in TLR4 signaling pathway. Int Immunopharmacol 2018; 55:323-329. [DOI: 10.1016/j.intimp.2018.01.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Revised: 12/18/2017] [Accepted: 01/03/2018] [Indexed: 12/19/2022]
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STAC2 negatively regulates osteoclast formation by targeting the RANK signaling complex. Cell Death Differ 2018; 25:1364-1374. [PMID: 29348675 DOI: 10.1038/s41418-017-0048-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 11/21/2017] [Accepted: 11/27/2017] [Indexed: 11/08/2022] Open
Abstract
The receptor activator of nuclear factor-κB (RANK) protein activates various protein kinase signaling cascades, including those involving NF-κB, mitogen-activated protein kinase (MAPK), and Bruton tyrosine kinase (Btk)/tyrosine-protein kinase Tec. However, the mechanism underlying the negative regulation of RANK by downstream signaling molecules remains unclear. Here, we report that Src homology 3 domain and cysteine-rich domain-containing protein 2 (STAC2) is a novel RANK ligand-inducible protein that negatively regulates RANK-mediated osteoclast formation. STAC2 physically interacts with RANK and inhibits the formation of the RANK signaling complex, which contains Grb-2-associated binder 2 (Gab2) and phospholipase Cγ2 (PLCγ2), thus leading to the suppression of RANK-mediated NF-κB and MAPK activation. Furthermore, STAC2 overexpression limits Btk/Tec-mediated PLCγ2 phosphorylation via the interaction between STAC2 and Btk/Tec. Taken together, our results reveal a novel mechanism whereby RANK signaling is restricted by its physical interaction with STAC2.
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44
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Dobranowski P, Sly LM. SHIP negatively regulates type II immune responses in mast cells and macrophages. J Leukoc Biol 2018; 103:1053-1064. [PMID: 29345374 DOI: 10.1002/jlb.3mir0817-340r] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 12/11/2017] [Accepted: 12/14/2017] [Indexed: 12/13/2022] Open
Abstract
SHIP is a hematopoietic-specific lipid phosphatase that dephosphorylates PI3K-generated PI(3,4,5)-trisphosphate. SHIP removes this second messenger from the cell membrane blunting PI3K activity in immune cells. Thus, SHIP negatively regulates mast cell activation downstream of multiple receptors. SHIP has been referred to as the "gatekeeper" of mast cell degranulation as loss of SHIP dramatically increases degranulation or permits degranulation in response to normally inert stimuli. SHIP also negatively regulates Mϕ activation, including both pro-inflammatory cytokine production downstream of pattern recognition receptors, and alternative Mϕ activation by the type II cytokines, IL-4, and IL-13. In the SHIP-deficient (SHIP-/- ) mouse, increased mast cell and Mϕ activation leads to spontaneous inflammatory pathology at mucosal sites, which is characterized by high levels of type II inflammatory cytokines. SHIP-/- mast cells and Mϕs have both been implicated in driving inflammation in the SHIP-/- mouse lung. SHIP-/- Mϕs drive Crohn's disease-like intestinal inflammation and fibrosis, which is dependent on heightened responses to innate immune stimuli generating IL-1, and IL-4 inducing abundant arginase I. Both lung and gut pathology translate to human disease as low SHIP levels and activity have been associated with allergy and with Crohn's disease in people. In this review, we summarize seminal literature and recent advances that provide insight into SHIP's role in mast cells and Mϕs, the contribution of these cell types to pathology in the SHIP-/- mouse, and describe how these findings translate to human disease and potential therapies.
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Affiliation(s)
- Peter Dobranowski
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Laura M Sly
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
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Distinct pattern of immune tolerance in dendritic cells treated with lipopolysaccharide or lipoteichoic acid. Mol Immunol 2017; 91:57-64. [DOI: 10.1016/j.molimm.2017.08.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Revised: 08/20/2017] [Accepted: 08/23/2017] [Indexed: 11/17/2022]
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46
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Mann M, Mehta A, Zhao JL, Lee K, Marinov GK, Garcia-Flores Y, Lu LF, Rudensky AY, Baltimore D. An NF-κB-microRNA regulatory network tunes macrophage inflammatory responses. Nat Commun 2017; 8:851. [PMID: 29021573 PMCID: PMC5636846 DOI: 10.1038/s41467-017-00972-z] [Citation(s) in RCA: 198] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 08/10/2017] [Indexed: 01/02/2023] Open
Abstract
The innate inflammatory response must be tightly regulated to ensure effective immune protection. NF-κB is a key mediator of the inflammatory response, and its dysregulation has been associated with immune-related malignancies. Here, we describe a miRNA-based regulatory network that enables precise NF-κB activity in mouse macrophages. Elevated miR-155 expression potentiates NF-κB activity in miR-146a-deficient mice, leading to both an overactive acute inflammatory response and chronic inflammation. Enforced miR-155 expression overrides miR-146a-mediated repression of NF-κB activation, thus emphasizing the dominant function of miR-155 in promoting inflammation. Moreover, miR-155-deficient macrophages exhibit a suboptimal inflammatory response when exposed to low levels of inflammatory stimuli. Importantly, we demonstrate a temporal asymmetry between miR-155 and miR-146a expression during macrophage activation, which creates a combined positive and negative feedback network controlling NF-κB activity. This miRNA-based regulatory network enables a robust yet time-limited inflammatory response essential for functional immunity. MicroRNAs (miR) are important regulators of gene transcription, with miR-155 and miR-146a both implicated in macrophage activation. Here the authors show that NF-κB signalling, miR-155 and miR-146a form a complex network of cross-regulations to control gene transcription in macrophages for modulating inflammatory responses.
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Affiliation(s)
- Mati Mann
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
| | - Arnav Mehta
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.,David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA
| | - Jimmy L Zhao
- Department of Medicine, New York Presbyterian Hospital, Weill Cornell Medical College, 525 E 68th Street, New York, NY, 10065, USA.,Division of Hematology Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA
| | - Kevin Lee
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Georgi K Marinov
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Yvette Garcia-Flores
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Li-Fan Lu
- Division of Biological Sciences, University of California, La Jolla, San Diego, CA, 92093, USA.,Moores Cancer Center, University of California, La Jolla, San Diego, CA, 92093, USA.,Center for Microbiome Innovation, University of California, La Jolla, San Diego, CA, 92093, USA
| | - Alexander Y Rudensky
- Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA
| | - David Baltimore
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
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47
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Alexander M, Ramstead AG, Bauer KM, Lee SH, Runtsch MC, Wallace J, Huffaker TB, Larsen DK, Tolmachova T, Seabra MC, Round JL, Ward DM, O'Connell RM. Rab27-Dependent Exosome Production Inhibits Chronic Inflammation and Enables Acute Responses to Inflammatory Stimuli. THE JOURNAL OF IMMUNOLOGY 2017; 199:3559-3570. [PMID: 28978688 DOI: 10.4049/jimmunol.1700904] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 09/11/2017] [Indexed: 01/21/2023]
Abstract
Extracellular vesicles, including exosomes, have recently been implicated as novel mediators of immune cell communication in mammals. However, roles for endogenously produced exosomes in regulating immune cell functions in vivo are just beginning to be identified. In this article, we demonstrate that Rab27a and Rab27b double-knockout (Rab27DKO) mice that are deficient in exosome secretion have a chronic, low-grade inflammatory phenotype characterized by elevated inflammatory cytokines and myeloproliferation. Upon further investigation, we found that some of these phenotypes could be complemented by wild-type (WT) hematopoietic cells or administration of exosomes produced by GM-CSF-expanded bone marrow cells. In addition, chronically inflamed Rab27DKO mice had a blunted response to bacterial LPS, resembling endotoxin tolerance. This defect was rescued by bone marrow exosomes from WT, but not miR-155-/-, cells, suggesting that uptake of miR-155-containing exosomes is important for a proper LPS response. Further, we found that SHIP1 and IRAK-M, direct targets of miR-155 that are known negative regulators of the LPS response, were elevated in Rab27DKO mice and decreased after treatment with WT, but not miR-155-/-, exosomes. Together, our study finds that Rab27-dependent exosome production contributes to homeostasis within the hematopoietic system and appropriate responsiveness to inflammatory stimuli.
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Affiliation(s)
- Margaret Alexander
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112; and
| | - Andrew G Ramstead
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112; and
| | - Kaylyn M Bauer
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112; and
| | - Soh-Hyun Lee
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112; and
| | - Marah C Runtsch
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112; and
| | - Jared Wallace
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112; and
| | - Thomas B Huffaker
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112; and
| | - Dane K Larsen
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112; and
| | - Tanya Tolmachova
- Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom
| | - Miguel C Seabra
- Molecular Medicine Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom
| | - June L Round
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112; and
| | - Diane M Ward
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112; and
| | - Ryan M O'Connell
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112; and
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48
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Poplutz M, Levikova M, Lüscher-Firzlaff J, Lesina M, Algül H, Lüscher B, Huber M. Endotoxin tolerance in mast cells, its consequences for IgE-mediated signalling, and the effects of BCL3 deficiency. Sci Rep 2017; 7:4534. [PMID: 28674400 PMCID: PMC5495797 DOI: 10.1038/s41598-017-04890-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 05/30/2017] [Indexed: 11/30/2022] Open
Abstract
Stimulation with lipopolysaccharide (LPS; endotoxin) not only causes rapid production of proinflammatory cytokines, but also induces a state of LPS hypo-responsiveness to a second LPS stimulation (endotoxin tolerance (ET)). Murine bone marrow-derived MCs (BMMCs) and peritoneal MCs (PMCs) developed ET as shown by an abrogated production of Il6/Tnf RNAs and IL-6/TNF-α proteins. In naive BMMCs, LPS stimulation induced a transient decline in the trimethylation of lysine 9 of the core histone H3 (H3K9me3), a suppressive chromatin mark, at the Il6/Tnf promoters, which correlated with p50(NFκB) and p65(NFκB) binding. Both demethylation and NFκB binding were abrogated in tolerant cells. In addition, cytosolic NFκB activation was suppressed in tolerant BMMCs. Intriguingly, antigen stimulation of naive and tolerant MCs induced comparable production of Il6/Tnf and IL-6/TNF-α, although ET also affected antigen-triggered activation of NFκB; pharmacological analysis indicated the importance of Ca2+-dependent transcription in this respect. In macrophages, the IκB member BCL3 is induced by LPS and known to be involved in ET, which was not corroborated comparing wild-type and Bcl3-deficient BMMCs. Interestingly, Bcl3-deficient PMCs produce markedly increased amounts of IL-6/TNF-α after LPS stimulation. Collectively, ET in MCs is BCL3-independent, however, in PMCs, BCL3 negatively regulates immediate LPS-induced cytokine production and quantitatively affects ET.
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Affiliation(s)
- Magdalena Poplutz
- Institute of Biochemistry and Molecular Immunology, Medical School, RWTH Aachen University, Aachen, Germany
| | - Maryna Levikova
- Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany
- Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland
| | - Juliane Lüscher-Firzlaff
- Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany
| | - Marina Lesina
- Molecular Gastroenterology, Medical Clinic II, University Hospital Klinikum Rechts der Isar, TU Munich, Munich, Germany
| | - Hana Algül
- Molecular Gastroenterology, Medical Clinic II, University Hospital Klinikum Rechts der Isar, TU Munich, Munich, Germany
| | - Bernhard Lüscher
- Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Aachen, Germany
| | - Michael Huber
- Institute of Biochemistry and Molecular Immunology, Medical School, RWTH Aachen University, Aachen, Germany.
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49
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Kern K, Pierre S, Schreiber Y, Angioni C, Thomas D, Ferreirós N, Geisslinger G, Scholich K. CD200 selectively upregulates prostaglandin E 2 and D 2 synthesis in LPS-treated bone marrow-derived macrophages. Prostaglandins Other Lipid Mediat 2017; 133:53-59. [PMID: 28583890 DOI: 10.1016/j.prostaglandins.2017.06.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 05/05/2017] [Accepted: 06/01/2017] [Indexed: 10/19/2022]
Abstract
The CD200/CD200R signalling pathway downregulates the synthesis of proinflammatory mediators and induces the synthesis of antiinflammatory mediators in macrophages and microglia. However, very little is known about the effect of this immunosuppressive pathway on the synthesis of lipid mediators. Therefore, we determined the synthesis of 35 lipids spanning 5 different lipid families in bone marrow-derived macrophages, which were treated with interleukin (IL) 4, IL10, lipopolysaccharide (LPS), or interferon γ (IFNγ) in absence and presence of CD200. Out of these conditions the only significant effect of CD200 was an increased synthesis of prostaglandin (PG) E2 and D2 in the presence of LPS. Accordingly, mRNA levels of cyclooxygenase-2, microsomal PGE2 synthase-1 and hematopoietic PGD synthase were upregulated by CD200 in presence of LPS. During Complete Freund's Adjuvant (CFA-) induced inflammation mPGES-1 was expressed in monocyte-derived macrophages and its expression was stronger in CD200R-positive than in CD200R-negative macrophages.
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Affiliation(s)
- Katharina Kern
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, Germany
| | - Sandra Pierre
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, Germany
| | - Yannick Schreiber
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, Germany
| | - Carlo Angioni
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, Germany
| | - Dominique Thomas
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, Germany
| | - Nerea Ferreirós
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, Germany
| | - Gerd Geisslinger
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, Germany
| | - Klaus Scholich
- Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, Germany.
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50
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Rackov G, Shokri R, De Mon MÁ, Martínez-A C, Balomenos D. The Role of IFN-β during the Course of Sepsis Progression and Its Therapeutic Potential. Front Immunol 2017; 8:493. [PMID: 28533774 PMCID: PMC5420561 DOI: 10.3389/fimmu.2017.00493] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 04/10/2017] [Indexed: 12/17/2022] Open
Abstract
Sepsis is a complex biphasic syndrome characterized by both pro- and anti-inflammatory immune states. Whereas early sepsis mortality is caused by an acute, deleterious pro-inflammatory response, the second sepsis phase is governed by acute immunosuppression, which predisposes patients to long-term risk for life-threatening secondary infections. Despite extensive basic research and clinical trials, there is to date no specific therapy for sepsis, and mortality rates are on the rise. Although IFN-β is one of the most-studied cytokines, its diverse effects are not fully understood. Depending on the disease or type of infection, it can have beneficial or detrimental effects. As IFN-β has been used successfully to treat diverse diseases, emphasis has been placed on understanding the role of IFN-β in sepsis. Analyses of mouse models of septic shock attribute a pro-inflammatory role to IFN-β in sepsis development. As anti-inflammatory treatments in humans with antibodies to TNF-α or IL1-β resulted disappointing, cytokine modulation approaches were discouraged and neutralization of IFN-β has not been pursued for sepsis treatment. In the case of patients with delayed sepsis and immunosuppression, there is a debate as to whether the use of specific cytokines would restore the deactivated immune response. Recent reports show an association of low IFN-β levels with the hyporesponsive state of monocytes from sepsis patients and after endotoxin tolerance induction. These data, discussed here, project a role for IFN-β in restoring monocyte function and reversing immunosuppression, and suggest IFN-β-based additive immunomodulatory therapy. The dichotomy in putative therapeutic approaches, involving reduction or an increase in IFN-β levels, mirrors the contrasting nature of the early hyperinflammatory state and the delayed immunosuppression phase.
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Affiliation(s)
- Gorjana Rackov
- Department of Immunology and Oncology, Universidad Autónoma de Madrid, Centro Nacional de Biotecnología - CSIC, Madrid, Spain.,IMDEA Nanoscience, Universidad Autónoma de Madrid, Madrid, Spain
| | - Rahman Shokri
- Department of Immunology and Oncology, Universidad Autónoma de Madrid, Centro Nacional de Biotecnología - CSIC, Madrid, Spain
| | - Melchor Álvarez De Mon
- Immune System Diseases-Rheumatology and Oncology Service, University Hospital Principe de Asturias, Alcalá de Henares, Spain
| | - Carlos Martínez-A
- Department of Immunology and Oncology, Universidad Autónoma de Madrid, Centro Nacional de Biotecnología - CSIC, Madrid, Spain
| | - Dimitrios Balomenos
- Department of Immunology and Oncology, Universidad Autónoma de Madrid, Centro Nacional de Biotecnología - CSIC, Madrid, Spain
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