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Zhang B, Zou Y, Yuan Z, Jiang K, Zhang Z, Chen S, Zhou X, Wu Q, Zhang X. Efferocytosis: the resolution of inflammation in cardiovascular and cerebrovascular disease. Front Immunol 2024; 15:1485222. [PMID: 39660125 PMCID: PMC11628373 DOI: 10.3389/fimmu.2024.1485222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024] Open
Abstract
Cardiovascular and cerebrovascular diseases have surpassed cancer as significant global health challenges, which mainly include atherosclerosis, myocardial infarction, hemorrhagic stroke and ischemia stroke. The inflammatory response immediately following these diseases profoundly impacts patient prognosis and recovery. Efficient resolution of inflammation is crucial not only for halting the inflammatory process but also for restoring tissue homeostasis. Efferocytosis, the phagocytic clearance of dying cells by phagocytes, especially microglia and macrophages, plays a critical role in this resolution process. Upon tissue injury, phagocytes are recruited to the site of damage where they engulf and clear dying cells through efferocytosis. Efferocytosis suppresses the secretion of pro-inflammatory cytokines, stimulates the production of anti-inflammatory cytokines, modulates the phenotype of microglia and macrophages, accelerates the resolution of inflammation, and promotes tissue repair. It involves three main stages: recognition, engulfment, and degradation of dying cells. Optimal removal of apoptotic cargo by phagocytes requires finely tuned machinery and associated modifications. Key molecules in efferocytosis, such as 'Find-me signals', 'Eat-me signals', and 'Don't eat-me signals', have been shown to enhance efferocytosis following cardiovascular and cerebrovascular diseases. Moreover, various additional molecules, pathways, and mitochondrial metabolic processes have been identified to enhance prognosis and outcomes via efferocytosis in diverse experimental models. Impaired efferocytosis can lead to inflammation-associated pathologies and prolonged recovery periods. Therefore, this review consolidates current understanding of efferocytosis mechanisms and its application in cardiovascular and cerebrovascular diseases, proposing future research directions.
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Affiliation(s)
- Bingtao Zhang
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yan Zou
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Zixuan Yuan
- Department of Neurosurgery, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Kun Jiang
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Zhaoxiang Zhang
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Shujuan Chen
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xiaoming Zhou
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Qi Wu
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xin Zhang
- Department of Neurosurgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
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Alam J, Yaman E, de Paiva CS, Li DQ, Villalba Silva GC, Zuo Z, Pflugfelder SC. Changes in conjunctival mononuclear phagocytes and suppressive activity of regulatory macrophages in desiccation induced dry eye. Ocul Surf 2024; 34:348-362. [PMID: 39306240 PMCID: PMC11984642 DOI: 10.1016/j.jtos.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 09/07/2024] [Accepted: 09/10/2024] [Indexed: 09/27/2024]
Abstract
PURPOSE To evaluate the effects of dry eye on conjunctival immune cell number and transcriptional profiles with attention to mononuclear phagocytes. METHODS Expression profiling was performed by single-cell RNA sequencing on sorted conjunctival immune cells from non-stressed and C57BL/6 mice subjected to desiccating stress (DS). Monocle 3 modeled cell trajectory, scATAC-seq assessed chromatin accessibility and IPA identified canonical pathways. Inflammation and goblet cells were measured after depletion of MRC1+ MΦs with mannosylated clodronate liposomes. RESULTS Mononuclear phagocytes (monocytes, MΦs, DCs) comprised 72 % of immune cells and showed the greatest changes with DS. Distinct DS induced gene expression patterns were seen in phagocytes classified by expression of Ccr2 and [Timd4, Lyve1, Folr2 (TLR)]. Expression of phagocytosis/efferocytosis genes increased in TLF+CCR2- MΦs. Monocytes showed the highest expression of Ace, Cx3cr1, Vegfa, Ifngr1,2, and Stat1 and TLF-CCR2+ cells expressed higher levels of inflammatory mediators (Il1a, Il1b, Il1rn, Nfkb1, Ccl5, MHCII, Cd80, Cxcl10, Icam1). A trajectory from monocyte precursors branched to terminate in regulatory MΦs or in mDCs via transitional MΦ and cDC clusters. Activated pathways in TLF+ cells include phagocytosis, PPAR/RXRα activation, IL-10 signaling, alternate MΦ activation, while inflammatory pathways were suppressed. Depletion of MRC1+ MΦs increased IL-17 and IFN-γ expression and cytokine-expressing T cells, reduced IL-10 and worsened goblet loss. CONCLUSIONS Dryness stimulates distinct gene expression patterns in conjunctival phagocytes, increasing expression of regulatory genes in TLF+ cells regulated in part by RXRα, and inflammatory genes in CCR2+ cells. Regulatory MΦs depletion worsens DS induced inflammation and goblet cell loss.
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Affiliation(s)
- Jehan Alam
- Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - Ebru Yaman
- Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - Cintia S de Paiva
- Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - De-Quan Li
- Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
| | - Gerda Cristal Villalba Silva
- Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Zhen Zuo
- Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Stephen C Pflugfelder
- Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA.
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Yuan S, Chai Y, Xu J, Wang Y, Jiang L, Lu N, Jiang H, Wang J, Pan X, Deng J. Engineering Efferocytosis-Mimicking Nanovesicles to Regulate Joint Anti-Inflammation and Peripheral Immunosuppression for Rheumatoid Arthritis Therapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2404198. [PMID: 38810118 PMCID: PMC11267389 DOI: 10.1002/advs.202404198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 05/16/2024] [Indexed: 05/31/2024]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of the synovial joints and the dysfunction of regulatory T cells (Tregs) in the peripheral blood. Therefore, an optimal treatment strategy should aim to eliminate the inflammatory response in the joints and simultaneously restore the immune tolerance of Tregs in peripheral blood. Accordingly, we developed an efferocytosis-mimicking nanovesicle that contains three functional factors for immunomodulating of efferocytosis, including "find me" and "eat me" signals for professional (macrophage) or non-professional phagocytes (T lymphocyte), and "apoptotic metabolite" for metabolite digestion. We showed that efferocytosis-mimicking nanovesicles targeted the inflamed joints and spleen of mice with collagen-induced arthritis, further recruiting and selectively binding to macrophages and T lymphocytes to induce M2 macrophage polarization and Treg differentiation and T helper cell 17 (Th17) recession. Under systemic administration, the efferocytosis-mimicking nanovesicles effectively maintained the pro-inflammatory M1/anti-inflammatory M2 macrophage balance in joints and the Treg/Th17 imbalance in peripheral blood to prevent RA progression. This study demonstrates the potential of efferocytosis-mimicking nanovesicles for RA immunotherapy.
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Affiliation(s)
- Shanshan Yuan
- Joint Centre of Translational MedicineThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000China
- Joint Centre of Translational MedicineWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
- Zhejiang Engineering Research Center for Tissue Repair MaterialsWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
| | - Yingqian Chai
- Joint Centre of Translational MedicineThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000China
- Joint Centre of Translational MedicineWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
- Zhejiang Engineering Research Center for Tissue Repair MaterialsWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
| | - Jianghua Xu
- Joint Centre of Translational MedicineThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000China
- Joint Centre of Translational MedicineWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
- Zhejiang Engineering Research Center for Tissue Repair MaterialsWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
| | - Youchao Wang
- Chimie ParisTechPSL UniversityCNRSInstitute of Chemistry for Life and Health SciencesLaboratory for Inorganic Chemical BiologyParis75005France
| | - Lihua Jiang
- Joint Centre of Translational MedicineThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000China
- Joint Centre of Translational MedicineWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
- Zhejiang Engineering Research Center for Tissue Repair MaterialsWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
| | - Ning Lu
- Joint Centre of Translational MedicineThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000China
- Joint Centre of Translational MedicineWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
- Zhejiang Engineering Research Center for Tissue Repair MaterialsWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
| | - Hongyi Jiang
- Department of OrthopaedicsThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou325000China
| | - Jilong Wang
- Joint Centre of Translational MedicineThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000China
- Joint Centre of Translational MedicineWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
- Zhejiang Engineering Research Center for Tissue Repair MaterialsWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
| | - Xiaoyun Pan
- Department of OrthopaedicsThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhou325000China
| | - Junjie Deng
- Joint Centre of Translational MedicineThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouZhejiang325000China
- Joint Centre of Translational MedicineWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
- Zhejiang Engineering Research Center for Tissue Repair MaterialsWenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China
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Ohno R, Mainka M, Kirchhoff R, Hartung NM, Schebb NH. Sterol Derivatives Specifically Increase Anti-Inflammatory Oxylipin Formation in M2-like Macrophages by LXR-Mediated Induction of 15-LOX. Molecules 2024; 29:1745. [PMID: 38675565 PMCID: PMC11052137 DOI: 10.3390/molecules29081745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/29/2024] [Accepted: 04/07/2024] [Indexed: 04/28/2024] Open
Abstract
The understanding of the role of LXR in the regulation of macrophages during inflammation is emerging. Here, we show that LXR agonist T09 specifically increases 15-LOX abundance in primary human M2 macrophages. In time- and dose-dependent incubations with T09, an increase of 3-fold for ALOX15 and up to 15-fold for 15-LOX-derived oxylipins was observed. In addition, LXR activation has no or moderate effects on the abundance of macrophage marker proteins such as TLR2, TLR4, PPARγ, and IL-1RII, as well as surface markers (CD14, CD86, and CD163). Stimulation of M2-like macrophages with FXR and RXR agonists leads to moderate ALOX15 induction, probably due to side activity on LXR. Finally, desmosterol, 24(S),25-Ep cholesterol and 22(R)-OH cholesterol were identified as potent endogenous LXR ligands leading to an ALOX15 induction. LXR-mediated ALOX15 regulation is a new link between the two lipid mediator classes sterols, and oxylipins, possibly being an important tool in inflammatory regulation through anti-inflammatory oxylipins.
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Affiliation(s)
| | | | | | | | - Nils Helge Schebb
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Gaußstr. 20, 42119 Wuppertal, Germany
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Wang X, Du W, Li Y, Yang HH, Zhang Y, Akbar R, Morgan H, Peng T, Chen J, Sadayappan S, Hu YC, Fan Y, Huang W, Fan GC. Macrophage-enriched Sectm1a promotes efficient efferocytosis to attenuate ischemia/reperfusion-induced cardiac injury. JCI Insight 2024; 9:e173832. [PMID: 38456501 PMCID: PMC10972593 DOI: 10.1172/jci.insight.173832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 01/23/2024] [Indexed: 03/09/2024] Open
Abstract
Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and restoration of cardiac function after myocardial ischemia/reperfusion (I/R). Here, we define secreted and transmembrane protein 1a (Sectm1a), a cardiac macrophage-enriched gene, as a modulator of macrophage efferocytosis in I/R-injured hearts. Upon myocardial I/R, Sectm1a-KO mice exhibited impaired macrophage efferocytosis, leading to massive accumulation of apoptotic cardiomyocytes, cardiac inflammation, fibrosis, and consequently, exaggerated cardiac dysfunction. By contrast, therapeutic administration of recombinant SECTM1A protein significantly enhanced macrophage efferocytosis and improved cardiac function. Mechanistically, SECTM1A could elicit autocrine effects on the activation of glucocorticoid-induced TNF receptor (GITR) at the surface of macrophages, leading to the upregulation of liver X receptor α (LXRα) and its downstream efferocytosis-related genes and lysosomal enzyme genes. Our study suggests that Sectm1a-mediated activation of the Gitr/LXRα axis could be a promising approach to enhance macrophage efferocytosis for the treatment of myocardial I/R injury.
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Affiliation(s)
| | - Wa Du
- Department of Cancer Biology, and
| | - Yutian Li
- Department of Pharmacology and Systems Physiology
| | - Hui-Hui Yang
- Department of Pharmacology and Systems Physiology
| | - Yu Zhang
- Department of Pharmacology and Systems Physiology
| | - Rubab Akbar
- Department of Pharmacology and Systems Physiology
| | - Hannah Morgan
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Tianqing Peng
- Centre for Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada
| | - Jing Chen
- Division of Biomedical Informatics and
| | - Sakthivel Sadayappan
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Yueh-Chiang Hu
- Transgenic Animal and Genome Editing Facility, Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | | | - Wei Huang
- Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Fontaine V, Boumedine T, Monteiro E, Fournié M, Gersende G, Sahel JA, Picaud S, Veillet S, Lafont R, Latil M, Dilda PJ, Camelo S. RAR Inhibitors Display Photo-Protective and Anti-Inflammatory Effects in A2E Stimulated RPE Cells In Vitro through Non-Specific Modulation of PPAR or RXR Transactivation. Int J Mol Sci 2024; 25:3037. [PMID: 38474284 PMCID: PMC10932305 DOI: 10.3390/ijms25053037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/23/2024] [Accepted: 03/02/2024] [Indexed: 03/14/2024] Open
Abstract
N-retinylidene-N-retinylethanolamine (A2E) has been associated with age-related macular degeneration (AMD) physiopathology by inducing cell death, angiogenesis and inflammation in retinal pigmented epithelial (RPE) cells. It was previously thought that the A2E effects were solely mediated via the retinoic acid receptor (RAR)-α activation. However, this conclusion was based on experiments using the RAR "specific" antagonist RO-41-5253, which was found to also be a ligand and partial agonist of the peroxisome proliferator-activated receptor (PPAR)-γ. Moreover, we previously reported that inhibiting PPAR and retinoid X receptor (RXR) transactivation with norbixin also modulated inflammation and angiogenesis in RPE cells challenged in the presence of A2E. Here, using several RAR inhibitors, we deciphered the respective roles of RAR, PPAR and RXR transactivations in an in vitro model of AMD. We showed that BMS 195614 (a selective RAR-α antagonist) displayed photoprotective properties against toxic blue light exposure in the presence of A2E. BMS 195614 also significantly reduced the AP-1 transactivation and mRNA expression of the inflammatory interleukin (IL)-6 and vascular endothelial growth factor (VEGF) induced by A2E in RPE cells in vitro, suggesting a major role of RAR in these processes. Surprisingly, however, we showed that (1) Norbixin increased the RAR transactivation and (2) AGN 193109 (a high affinity pan-RAR antagonist) and BMS 493 (a pan-RAR inverse agonist), which are photoprotective against toxic blue light exposure in the presence of A2E, also inhibited PPARs transactivation and RXR transactivation, respectively. Therefore, in our in vitro model of AMD, several commercialized RAR inhibitors appear to be non-specific, and we propose that the phototoxicity and expression of IL-6 and VEGF induced by A2E in RPE cells operates through the activation of PPAR or RXR rather than by RAR transactivation.
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Affiliation(s)
- Valérie Fontaine
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, 75012 Paris, France; (V.F.); (T.B.); (M.F.); (J.-A.S.); (S.P.)
| | - Thinhinane Boumedine
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, 75012 Paris, France; (V.F.); (T.B.); (M.F.); (J.-A.S.); (S.P.)
| | - Elodie Monteiro
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, 75012 Paris, France; (V.F.); (T.B.); (M.F.); (J.-A.S.); (S.P.)
| | - Mylène Fournié
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, 75012 Paris, France; (V.F.); (T.B.); (M.F.); (J.-A.S.); (S.P.)
| | - Gendre Gersende
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, 75012 Paris, France; (V.F.); (T.B.); (M.F.); (J.-A.S.); (S.P.)
| | - José-Alain Sahel
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, 75012 Paris, France; (V.F.); (T.B.); (M.F.); (J.-A.S.); (S.P.)
- Fondation Ophtalmologique Rothschild, 29 rue Manin, 75019 Paris, France
- Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Serge Picaud
- Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, 75012 Paris, France; (V.F.); (T.B.); (M.F.); (J.-A.S.); (S.P.)
| | - Stanislas Veillet
- Biophytis, Sorbonne Université, BC9, 4 place Jussieu, 75005 Paris, France (M.L.); (P.J.D.)
| | - René Lafont
- Biophytis, Sorbonne Université, BC9, 4 place Jussieu, 75005 Paris, France (M.L.); (P.J.D.)
| | - Mathilde Latil
- Biophytis, Sorbonne Université, BC9, 4 place Jussieu, 75005 Paris, France (M.L.); (P.J.D.)
| | - Pierre J. Dilda
- Biophytis, Sorbonne Université, BC9, 4 place Jussieu, 75005 Paris, France (M.L.); (P.J.D.)
| | - Serge Camelo
- Biophytis, Sorbonne Université, BC9, 4 place Jussieu, 75005 Paris, France (M.L.); (P.J.D.)
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Almhanna H, Kumar AHS, Kilroy D, Duggan G, Irwin JA, Hogg B, Reid C. Comparison of Siglec-1 protein networks and expression patterns in sperm and male reproductive tracts of mice, rats, and humans. Vet World 2024; 17:645-657. [PMID: 38680147 PMCID: PMC11045525 DOI: 10.14202/vetworld.2024.645-657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 02/23/2024] [Indexed: 05/01/2024] Open
Abstract
Background Sialic acid-binding immunoglobulin-like lectin 1 (Siglec-1) is a transmembrane glycoprotein involved in the sialic acid (Sia)-dependent regulation of the immune system. Siglec-1 expression has recently been identified in the male reproductive tract (MRT) of several species, including humans, cattle, horses, and sheep, and may play a role in modulating fertility in a Sia-dependent manner. Materials and Methods In this study, protein-protein interaction (PPI) analysis of Siglec-1 was conducted to identify associated network protein conservation, and the expression of Siglec-1 in the MRT of mice and rats, including their accessory sex glands and spermatozoa was determined by immunostaining. Results Network analysis of proteins with Siglec-1 in mice and rats demonstrated significant similarity to human Siglec-1 networks, suggesting a similar conservation of network proteins between these species and, hence, a potential conservation role in immune modulation and function. Specific immunostaining patterns of mouse and rat testes, epididymis, ductus deferens, accessory sex gland tissues, and sperm were detected using human Siglec-1. These results confirmed that the human Siglec-1 antibody could cross-react with mouse and rat Siglec-1, suggesting that the specific expression patterns of Siglec-1 in the MRT and sperm of both mice and rats are similar to those observed in other species. Conclusions The conservation of Siglec-1 expression patterns in sperm and within the MRT and the similarity of protein networks for Siglec-1 across species suggest that Siglec-1 may function in a similar manner across species. These results also suggest that rodents may serve as a valuable model system for exploring the function of Siglecs in the reproductive system across species and their potential role in modulating fertility in a Sia-dependent manner.
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Affiliation(s)
- Hazem Almhanna
- Department of Anatomy and Histology, College of Veterinary Medicine, University of Al-Qadisiyah, Iraq
- School of Veterinary Medicine, University College Dublin, Belfield, Dublin-04, Ireland
| | - Arun HS Kumar
- School of Veterinary Medicine, University College Dublin, Belfield, Dublin-04, Ireland
| | - David Kilroy
- School of Veterinary Medicine, University College Dublin, Belfield, Dublin-04, Ireland
| | - Gina Duggan
- School of Veterinary Medicine, University College Dublin, Belfield, Dublin-04, Ireland
| | - Jane A. Irwin
- School of Veterinary Medicine, University College Dublin, Belfield, Dublin-04, Ireland
| | - Bridget Hogg
- School of Veterinary Medicine, University College Dublin, Belfield, Dublin-04, Ireland
| | - Colm Reid
- School of Veterinary Medicine, University College Dublin, Belfield, Dublin-04, Ireland
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Adil Ali M, Garabuczi É, Tarban N, Sarang Z. All-trans retinoic acid and dexamethasone regulate phagocytosis-related gene expression and enhance dead cell uptake in C2C12 myoblast cells. Sci Rep 2023; 13:21001. [PMID: 38017321 PMCID: PMC10684882 DOI: 10.1038/s41598-023-48492-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 11/27/2023] [Indexed: 11/30/2023] Open
Abstract
Extensive mechanical stress frequently causes micro-traumas in skeletal muscle, followed by a regeneration period. The effective removal of dead myofibers is a prerequisite for proper regeneration, and several cell types, including professional phagocytes, were reported to be active in this process. Myoblasts express several molecules of the phagocytic machinery, such as BAI1, stabilin-2, and TAM (Tyro3, Axl, Mertk) tyrosine kinase receptors, but these molecules were reported to serve primarily cell fusion and survival, and their role in the phagocytosis was not investigated. Therefore, we aimed to investigate the in vitro phagocytic capacity of the C2C12 mouse myoblast cell line. RNA sequencing data were analyzed to determine the level and changes of phagocytosis-related gene expression during the differentiation process of C2C12 cells. To study the phagocytic capacity of myoblasts and the effect of dexamethasone, all-trans retinoic acid, hemin, and TAM kinase inhibitor treatments on phagocytosis, C2C12 cells were fed dead thymocytes, and their phagocytic capacity was determined by flow cytometry. The effect of dexamethasone and all-trans retinoic acid on phagocytosis-related gene expression was determined by quantitative PCR. Both undifferentiated and differentiated cells engulfed dead cells being the undifferentiated cells more effective. In line with this, we observed that the expression of several phagocytosis-related genes was downregulated during the differentiation process. The phagocytosis could be increased by dexamethasone and all-trans retinoic acid and decreased by hemin and TAM kinase inhibitor treatments. Our results indicate that myoblasts not only express phagocytic machinery genes but are capable of efficient dead cell clearance as well, and this is regulated similarly, as reported in professional phagocytes.
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Affiliation(s)
- Maysaa Adil Ali
- Faculty of Medicine, Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, Hungary
| | - Éva Garabuczi
- Department of Integrative Health Science, Faculty of Health Science, Institute of Health Science, University of Debrecen, Debrecen, Hungary
| | - Nastaran Tarban
- Faculty of Medicine, Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, Hungary
| | - Zsolt Sarang
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
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Vellozo NS, Matos-Silva TC, Lopes MF. Immunopathogenesis in Trypanosoma cruzi infection: a role for suppressed macrophages and apoptotic cells. Front Immunol 2023; 14:1244071. [PMID: 37662946 PMCID: PMC10469960 DOI: 10.3389/fimmu.2023.1244071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 08/04/2023] [Indexed: 09/05/2023] Open
Abstract
During Trypanosoma cruzi infection, macrophages phagocytose parasites and remove apoptotic cells through efferocytosis. While macrophage 1 (M1) produces proinflammatory cytokines and NO and fights infection, M2 macrophages are permissive host cells that express arginase 1 and play a role in tissue repair. The regulation of M1 and M2 phenotypes might either induce or impair macrophage-mediated immunity towards parasite control or persistence in chronic Chagas disease. Here, we highlight a key role of macrophage activation in early immune responses to T. cruzi that prevent escalating parasitemia, heart parasitism, and mortality during acute infection. We will discuss the mechanisms of macrophage activation and deactivation, such as T cell cytokines and efferocytosis, and how to improve macrophage-mediated immunity to prevent parasite persistence, inflammation, and the development of chagasic cardiomyopathy. Potential vaccines or therapy must enhance early T cell-macrophage crosstalk and parasite control to restrain the pathogenic outcomes of parasite-induced inflammation in the heart.
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Affiliation(s)
| | | | - Marcela F. Lopes
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Smith LC, Gow AJ, Abramova E, Vayas K, Guo C, Noto J, Lyman J, Rodriquez J, Gelfand-Titiyevskiy B, Malcolm C, Laskin JD, Laskin DL. Role of PPARγ in dyslipidemia and altered pulmonary functioning in mice following ozone exposure. Toxicol Sci 2023; 194:109-119. [PMID: 37202362 PMCID: PMC10306402 DOI: 10.1093/toxsci/kfad048] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2023] Open
Abstract
Exposure to ozone causes decrements in pulmonary function, a response associated with alterations in lung lipids. Pulmonary lipid homeostasis is dependent on the activity of peroxisome proliferator activated receptor gamma (PPARγ), a nuclear receptor that regulates lipid uptake and catabolism by alveolar macrophages (AMs). Herein, we assessed the role of PPARγ in ozone-induced dyslipidemia and aberrant lung function in mice. Exposure of mice to ozone (0.8 ppm, 3 h) resulted in a significant reduction in lung hysteresivity at 72 h post exposure; this correlated with increases in levels of total phospholipids, specifically cholesteryl esters, ceramides, phosphatidylcholines, phosphorylethanolamines, sphingomyelins, and di- and triacylglycerols in lung lining fluid. This was accompanied by a reduction in relative surfactant protein-B (SP-B) content, consistent with surfactant dysfunction. Administration of the PPARγ agonist, rosiglitazone (5 mg/kg/day, i.p.) reduced total lung lipids, increased relative amounts of SP-B, and normalized pulmonary function in ozone-exposed mice. This was associated with increases in lung macrophage expression of CD36, a scavenger receptor important in lipid uptake and a transcriptional target of PPARγ. These findings highlight the role of alveolar lipids as regulators of surfactant activity and pulmonary function following ozone exposure and suggest that targeting lipid uptake by lung macrophages may be an efficacious approach for treating altered respiratory mechanics.
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Affiliation(s)
- Ley Cody Smith
- Department of Pharmaceutical Sciences, University of Connecticut School of Pharmacy, Storrs, Connecticut 06269, USA
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Andrew J Gow
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Elena Abramova
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Kinal Vayas
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Changjiang Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Jack Noto
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Jack Lyman
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Jessica Rodriquez
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Benjamin Gelfand-Titiyevskiy
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Callum Malcolm
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Jeffrey D Laskin
- Department of Environmental and Occupational Health and Justice, School of Public Health, Rutgers University, Piscataway, New Jersey 08854, USA
| | - Debra L Laskin
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, USA
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11
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Xin S, Liu X, Li Z, Sun X, Wang R, Zhang Z, Feng X, Jin L, Li W, Tang C, Mei W, Cao Q, Wang H, Zhang J, Feng L, Ye L. ScRNA-seq revealed an immunosuppression state and tumor microenvironment heterogeneity related to lymph node metastasis in prostate cancer. Exp Hematol Oncol 2023; 12:49. [PMID: 37221625 PMCID: PMC10204220 DOI: 10.1186/s40164-023-00407-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 04/25/2023] [Indexed: 05/25/2023] Open
Abstract
BACKGROUND Metastasis is a crucial aspect of disease progression leading to death in patients with prostate cancer (PCa). However, its mechanism remains unclear. We aimed to explore the mechanism of lymph node metastasis (LNM) by analyzing the heterogeneity of tumor microenvironment (TME) in PCa using scRNA-seq. METHODS A total of 32,766 cells were obtained from four PCa tissue samples for scRNA-seq, annotated, and grouped. InferCNV, GSVA, DEG functional enrichment analysis, trajectory analysis, intercellular network evaluation, and transcription factor analysis were carried out for each cell subgroup. Furthermore, validation experiments targeting luminal cell subgroups and CXCR4 + fibroblast subgroup were performed. RESULTS The results showed that only EEF2 + and FOLH1 + luminal subgroups were present in LNM, and they appeared at the initial stage of luminal cell differentiation, which were comfirmed by verification experiments. The MYC pathway was enriched in the EEF2 + and FOLH1 + luminal subgroups, and MYC was associated with PCa LNM. Moreover, MYC did not only promote the progression of PCa, but also led to immunosuppression in TME by regulating PDL1 and CD47. The proportion of CD8 + T cells in TME and among NK cells and monocytes was lower in LNM than in the primary lesion, while the opposite was true for Th and Treg cells. Furthermore, these immune cells in TME underwent transcriptional reprogramming, including CD8 + T subgroups of CCR7 + and IL7R+, as well as M2-like monocyte subgroups expressing tumor-associated signature genes, like CCR7, SGKI, and RPL31. Furthermore, STEAP4+, ADGRF5 + and CXCR4+, and SRGNC + fibroblast subgroups were closely related to tumor progression, tumor metabolism, and immunosuppression, indicating their contributions in PCa metastasis. Meanwhile, The presence of CXCR4 + Fibroblasts in PCa was confirmed by polychromatic immunofluorescence. CONCLUSIONS The significant heterogeneity of luminal, immune, and interstitial cells in PCa LNM may not only directly contribute to tumor progression, but also indirectly result in TME immunosuppression, which may be the cause of metastasis in PCa and in which MYC played an role.
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Affiliation(s)
- Shiyong Xin
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, Shanghai, 200120, China
- Department of Urology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Xiang Liu
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, Shanghai, 200120, China
- Department of Urology, Putuo People's Hospital, School of Medicine, Shanghai, China
| | - Ziyao Li
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, Shanghai, 200120, China
| | - Xianchao Sun
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, Shanghai, 200120, China
| | - Rong Wang
- School of Pharmacy, Inner Mongolia Medical University, Hohhot, 010000, China
| | - Zhenhua Zhang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Xinwei Feng
- School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, China
| | - Liang Jin
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, Shanghai, 200120, China
| | - Weiyi Li
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, Shanghai, 200120, China
| | - Chaozhi Tang
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, Shanghai, 200120, China
| | - Wangli Mei
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, Shanghai, 200120, China
| | - Qiong Cao
- Department of Pathology, The Third Affiliated Hospital of Henan University of Science and Technology, Henan, 471003, China
| | - Haojie Wang
- Department of Central Laboratory, Zhengzhou University, Luoyang Central Hospital, Luoyang, 471003, China
| | - Jianguo Zhang
- Department of Urology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China
| | - Lijin Feng
- Department of Pathology, Jing'an District Zhabei Central Hospital, No.619, Zhonghuaxin Road, Shanghai, 200070, China.
| | - Lin Ye
- Department of Urology, Shanghai East Hospital, School of Medicine, Tongji University, No.150, Ji-mo Rd, Pu-dong new District, Shanghai, 200120, China.
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12
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Gao Y, Jiao Y, Gong X, Liu J, Xiao H, Zheng Q. Role of transcription factors in apoptotic cells clearance. Front Cell Dev Biol 2023; 11:1110225. [PMID: 36743409 PMCID: PMC9892555 DOI: 10.3389/fcell.2023.1110225] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 01/09/2023] [Indexed: 01/20/2023] Open
Abstract
The human body generates 10-100 billion cells every day, and the same number of cells die to maintain homeostasis. The genetically controlled, autonomously ordered cell death mainly proceeds by apoptosis. Apoptosis is an important way of programmed cell death in multicellular organisms, timely and effective elimination of apoptotic cells plays a key role in the growth and development of organisms and the maintenance of homeostasis. During the clearance of apoptotic cells, transcription factors bind to specific target promoters and act as activators or repressors to regulate multiple genes expression, how transcription factors regulate apoptosis is an important and poorly understood aspect of normal development. This paper summarizes the regulatory mechanisms of transcription factors in the clearance of apoptotic cells to date.
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Affiliation(s)
| | | | | | | | - Hui Xiao
- *Correspondence: Hui Xiao, ; Qian Zheng,
| | - Qian Zheng
- *Correspondence: Hui Xiao, ; Qian Zheng,
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Zhang H, Ni M, Wang H, Zhang J, Jin D, Busuttil RW, Kupiec-Weglinski JW, Li W, Wang X, Zhai Y. Gsk3β regulates the resolution of liver ischemia/reperfusion injury via MerTK. JCI Insight 2023; 8:e151819. [PMID: 36422999 PMCID: PMC9870084 DOI: 10.1172/jci.insight.151819] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 11/21/2022] [Indexed: 11/27/2022] Open
Abstract
Although glycogen synthase kinase β (Gsk3β) has been shown to regulate tissue inflammation, whether and how it regulates inflammation resolution versus inflammation activation is unclear. In a murine liver, partial warm ischemia/reperfusion injury (IRI) model, we found that Gsk3β inhibitory phosphorylation increased at both the early-activation and late-resolution stages of the disease. Myeloid Gsk3β deficiency not only alleviated liver injuries, it also facilitated the restoration of liver homeostasis. Depletion of Kupffer cells prior to the onset of liver ischemia diminished the differences between the WT and Gsk3β-KO mice in the activation of liver IRI. However, the resolution of liver IRI remained accelerated in Gsk3β-KO mice. In CD11b-DTR mice, Gsk3β-deficient BM-derived macrophages (BMMs) facilitated the resolution of liver IRI as compared with WT cells. Furthermore, Gsk3β deficiency promoted the reparative phenotype differentiation in vivo in liver-infiltrating macrophages and in vitro in BMMs. Gsk3 pharmacological inhibition promoted the resolution of liver IRI in WT, but not myeloid MerTK-deficient, mice. Thus, Gsk3β regulates liver IRI at both activation and resolution stages of the disease. Gsk3 inactivation enhances the proresolving function of liver-infiltrating macrophages in an MerTK-dependent manner.
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Affiliation(s)
- Hanwen Zhang
- Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Ming Ni
- Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
- Hepatobiliary Center, Key Laboratory of Liver Transplantation of Chinese Academy of Medical Sciences, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Han Wang
- Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
- Hepatobiliary Center, Key Laboratory of Liver Transplantation of Chinese Academy of Medical Sciences, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jing Zhang
- Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
| | - Dan Jin
- Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ronald W. Busuttil
- Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
| | - Jerzy W. Kupiec-Weglinski
- Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
| | - Wei Li
- Department of Hepatobiliary-Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xuehao Wang
- Hepatobiliary Center, Key Laboratory of Liver Transplantation of Chinese Academy of Medical Sciences, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yuan Zhai
- Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
- Transplant Surgery, College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
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14
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Zhang M, Johnson-Stephenson TK, Wang W, Wang Y, Li J, Li L, Zen K, Chen X, Zhu D. Mesenchymal stem cell-derived exosome-educated macrophages alleviate systemic lupus erythematosus by promoting efferocytosis and recruitment of IL-17+ regulatory T cell. STEM CELL RESEARCH & THERAPY 2022; 13:484. [PMID: 36153633 PMCID: PMC9509559 DOI: 10.1186/s13287-022-03174-7] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 09/11/2022] [Indexed: 11/21/2022]
Abstract
Background Anti-inflammatory polarized macrophages are reported to alleviate systemic lupus erythematosus (SLE). Our previous studies have demonstrated that exosomes from adipose-derived stem cells promote the anti-inflammatory polarization of macrophages. However, the possible therapeutic effect of exosomes from stem cells on SLE remains unexplored.
Methods Exosomes were isolated from the conditioned medium of bone marrow-derived mesenchymal stem cells using ultrafiltration and size-exclusion chromatography and were identified by nanoparticle tracking analysis and immunoblotting of exosomal-specific markers. Macrophages were collected from the MRL/lpr mouse kidney. The phenotype of macrophages was identified by immunoblotting for intracellular markers-inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1), and flow cytometry for macrophage markers F4/80, CD86, CD206, B7H4, and CD138. Pristane-induced murine lupus nephritis models were employed for in vivo study. Results When macrophages from the kidney of the MRL/lpr mice were treated with exosomes from bone marrow-derived mesenchymal stem cells (BM-MSCs), the upregulation of CD206, B7H4, CD138, Arg-1, CCL20, and anti-inflammatory cytokines was observed, which suggested that the macrophages were polarized to a specific anti-inflammatory phenotype. These anti-inflammatory macrophages produced low levels of reactive oxygen species (ROS) but had a high efferocytosis activity and promoted regulatory T (Treg) cell recruitment. Moreover, exosome injection stimulated the anti-inflammatory polarization of macrophages and increased the production of IL-17+ Treg cells in a pristane-induced murine lupus nephritis model. We observed that exosomes from BMMSCs depleted of microRNA-16 (miR-16) and microRNA-21 (miR-21) failed to downregulate PDCD4 and PTEN in macrophages, respectively, and attenuated exosome-induced anti-inflammatory polarization. Conclusion Our findings provide evidence that exosomes from BMMSCs promote the anti-inflammatory polarization of macrophages. These macrophages alleviate SLE nephritis in lupus mice by consuming apoptotic debris and inducing the recruitment of Treg cells. We identify that exosomal delivery of miR-16 and miR-21 is a significant contributor to the polarization of macrophages. Graphical abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03174-7.
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15
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Madalena KM, Brennan FH, Popovich PG. Genetic deletion of the glucocorticoid receptor in Cx 3cr1 + myeloid cells is neuroprotective and improves motor recovery after spinal cord injury. Exp Neurol 2022; 355:114114. [PMID: 35568187 PMCID: PMC10034962 DOI: 10.1016/j.expneurol.2022.114114] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/29/2022] [Accepted: 05/08/2022] [Indexed: 11/23/2022]
Abstract
Glucocorticoid receptors (GRs), part of the nuclear receptor superfamily of transcription factors (TFs), are ubiquitously expressed in all cell types and regulate cellular responses to glucocorticoids (e.g., cortisol in humans; corticosterone in rodents). In myeloid cells, glucocorticoids binding to GRs can enhance or repress gene transcription, thereby imparting distinct and context-dependent functions in macrophages at sites of inflammation. In experimental models and in humans, glucocorticoids are widely used as anti-inflammatory treatments to promote recovery of function after SCI. Thus, we predicted that deleting GR in mouse myeloid lineage cells (i.e., microglia and monocyte-derived macrophages) would enhance inflammation at the site of injury and worsen functional recovery after traumatic spinal cord injury (SCI). Contrary to our prediction, the intraspinal macrophage response to a moderate (75 kdyne) spinal contusion SCI was reduced in Cx3cr1-Cre;GRf/f conditional knockout mice (with GR specifically deleted in myeloid cells). This phenotype was associated with improvements in hindlimb motor recovery, myelin sparing, axon sparing/regeneration, and microvascular protection/plasticity relative to SCI mice with normal myeloid cell GR expression. Further analysis revealed that macrophage GR deletion impaired lipid and myelin phagocytosis and foamy macrophage formation. Together, these data reveal endogenous GR signaling as a key pathway that normally inhibits mechanisms of macrophage-mediated repair after SCI.
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Affiliation(s)
- Kathryn M Madalena
- Neuroscience Graduate Program, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Belford Center for Spinal Cord Injury, Center for Brain and Spinal Cord Repair, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Faith H Brennan
- Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Belford Center for Spinal Cord Injury, Center for Brain and Spinal Cord Repair, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Phillip G Popovich
- Neuroscience Graduate Program, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Belford Center for Spinal Cord Injury, Center for Brain and Spinal Cord Repair, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
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16
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Zhang J, Ding W, Zhao M, Liu J, Xu Y, Wan J, Wang M. Mechanisms of efferocytosis in determining inflammation resolution: Therapeutic potential and the association with cardiovascular disease. Br J Pharmacol 2022; 179:5151-5171. [PMID: 36028471 DOI: 10.1111/bph.15939] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/16/2022] [Accepted: 08/19/2022] [Indexed: 11/29/2022] Open
Abstract
Efferocytosis is defined as the clearance of apoptotic cells (ACs) in physiological and pathological states and is performed by efferocytes, such as macrophages. Efferocytosis can lead to the resolution of inflammation and restore tissue homoeostasis; however, the mechanisms of efferocytosis in determining inflammation resolution are still not completely understood, and the effects of efferocytosis on other proresolving properties need to be explored and explained. In this review, the process of efferocytosis will be summarized briefly, and then these mechanisms and effects will be thoroughly discussed. In addition, the association between the mechanisms of efferocytosis in determining inflammation resolution and cardiovascular diseases will also be reviewed, as an understanding of this association may provide information on novel treatment targets.
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Affiliation(s)
- Jishou Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Wen Ding
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China.,department of radiology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Mengmeng Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jianfang Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Yao Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Jun Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Menglong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.,Cardiovascular Research Institute, Wuhan University, Wuhan, China.,Hubei Key Laboratory of Cardiology, Wuhan, China
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17
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Chen B, Li R, Hernandez SC, Hanna A, Su K, Shinde AV, Frangogiannis NG. Differential effects of Smad2 and Smad3 in regulation of macrophage phenotype and function in the infarcted myocardium. J Mol Cell Cardiol 2022; 171:1-15. [PMID: 35780861 DOI: 10.1016/j.yjmcc.2022.06.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 06/22/2022] [Accepted: 06/25/2022] [Indexed: 02/08/2023]
Abstract
TGF-βs regulate macrophage responses, by activating Smad2/3. We have previously demonstrated that macrophage-specific Smad3 stimulates phagocytosis and mediates anti-inflammatory macrophage transition in the infarcted heart. However, the role of macrophage Smad2 signaling in myocardial infarction remains unknown. We studied the role of macrophage-specific Smad2 signaling in healing mouse infarcts, and we explored the basis for the distinct effects of Smad2 and Smad3. In infarct macrophages, Smad3 activation preceded Smad2 activation. In contrast to the effects of Smad3 loss, myeloid cell-specific Smad2 disruption had no effects on mortality, ventricular dysfunction and adverse remodeling, after myocardial infarction. Macrophage Smad2 loss modestly, but transiently increased myofibroblast density in the infarct, but did not affect phagocytic removal of dead cells, macrophage infiltration, collagen deposition, and scar remodeling. In isolated macrophages, TGF-β1, -β2 and -β3, activated both Smad2 and Smad3, whereas BMP6 triggered only Smad3 activation. Smad2 and Smad3 had similar patterns of nuclear translocation in response to TGF-β1. RNA-sequencing showed that Smad3, and not Smad2, was the main mediator of transcriptional effects of TGF-β on macrophages. Smad3 loss resulted in differential expression of genes associated with RAR/RXR signaling, cholesterol biosynthesis and lipid metabolism. In both isolated bone marrow-derived macrophages and in infarct macrophages, Smad3 mediated synthesis of Nr1d2 and Rara, two genes encoding nuclear receptors, that may be involved in regulation of their phagocytic and anti-inflammatory properties. In conclusion, the in vivo and in vitro effects of TGF-β on macrophage function involve Smad3, and not Smad2.
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Affiliation(s)
- Bijun Chen
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States of America
| | - Ruoshui Li
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States of America
| | - Silvia C Hernandez
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States of America
| | - Anis Hanna
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States of America
| | - Kai Su
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States of America
| | - Arti V Shinde
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States of America
| | - Nikolaos G Frangogiannis
- The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, NY, United States of America.
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18
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Liu J, Zhu Z, Leung GKK. Erythrophagocytosis by Microglia/Macrophage in Intracerebral Hemorrhage: From Mechanisms to Translation. Front Cell Neurosci 2022; 16:818602. [PMID: 35237132 PMCID: PMC8882619 DOI: 10.3389/fncel.2022.818602] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 01/10/2022] [Indexed: 12/17/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is a devastating condition characterized by hematoma related mass effect. Microglia/macrophage (M φ) are rapidly recruited in order to remove the red blood cells through erythrophagocytosis. Efficient erythrophagocytosis can detoxify hemolytic products and facilitate neurological recovery after ICH. The underlying mechanisms include modulation of inflammatory response and oxidative stress, among others. It is a dynamic process mediated by a cascade of signal transduction, including “find-me” signals, “eat-me” signals and a set of phagocytotic receptors-ligand pairs that may be exploited as therapeutic targets. This review summarizes mechanistic signaling pathways of erythrophagocytosis and highlights the potential of harnessing M φ-mediated phagocytosis for ICH treatment.
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Affiliation(s)
- Jiaxin Liu
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong SAR, China
| | - Zhiyuan Zhu
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong SAR, China
- Department of Functional Neurosurgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Guangzhou, China
- Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Gilberto Ka-Kit Leung
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong SAR, China
- *Correspondence: Gilberto Ka-Kit Leung,
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19
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A novel therapeutic strategy for atherosclerosis: autophagy-dependent cholesterol efflux. J Physiol Biochem 2022; 78:557-572. [DOI: 10.1007/s13105-021-00870-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 12/25/2021] [Indexed: 10/19/2022]
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Shishkina GT, Gulyaeva NV, Lanshakov DA, Kalinina TS, Onufriev MV, Moiseeva YV, Sukhareva EV, Babenko VN, Dygalo NN. Identifying the Involvement of Pro-Inflammatory Signal in Hippocampal Gene Expression Changes after Experimental Ischemia: Transcriptome-Wide Analysis. Biomedicines 2021; 9:1840. [PMID: 34944656 PMCID: PMC8698395 DOI: 10.3390/biomedicines9121840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 11/27/2021] [Accepted: 12/02/2021] [Indexed: 12/26/2022] Open
Abstract
Acute cerebral ischemia induces distant inflammation in the hippocampus; however, molecular mechanisms of this phenomenon remain obscure. Here, hippocampal gene expression profiles were compared in two experimental paradigms in rats: middle cerebral artery occlusion (MCAO) and intracerebral administration of lipopolysaccharide (LPS). The main finding is that 10 genes (Clec5a, CD14, Fgr, Hck, Anxa1, Lgals3, Irf1, Lbp, Ptx3, Serping1) may represent key molecular links underlying acute activation of immune cells in the hippocampus in response to experimental ischemia. Functional annotation clustering revealed that these genes built the same clusters related to innate immunity/immunity/innate immune response in all MCAO differentially expressed genes and responded to the direct pro-inflammatory stimulus group. The gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses also indicate that LPS-responding genes were the most abundant among the genes related to "positive regulation of tumor necrosis factor biosynthetic process", "cell adhesion", "TNF signaling pathway", and "phagosome" as compared with non-responding ones. In contrast, positive and negative "regulation of cell proliferation" and "HIF-1 signaling pathway" mostly enriched with genes that did not respond to LPS. These results contribute to understanding genomic mechanisms of the impact of immune/inflammatory activation on expression of hippocampal genes after focal brain ischemia.
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Affiliation(s)
- Galina T. Shishkina
- Laboratory of Functional Neurogenomics, Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Science, 630090 Novosibirsk, Russia; (D.A.L.); (T.S.K.); (E.V.S.); (V.N.B.); (N.N.D.)
| | - Natalia V. Gulyaeva
- Laboratory of Functional Biochemistry of the Nervous System, Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485 Moscow, Russia; (N.V.G.); (M.V.O.); (Y.V.M.)
- Research and Clinical Center for Neuropsychiatry of Moscow Healthcare Department, 115419 Moscow, Russia
| | - Dmitriy A. Lanshakov
- Laboratory of Functional Neurogenomics, Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Science, 630090 Novosibirsk, Russia; (D.A.L.); (T.S.K.); (E.V.S.); (V.N.B.); (N.N.D.)
| | - Tatyana S. Kalinina
- Laboratory of Functional Neurogenomics, Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Science, 630090 Novosibirsk, Russia; (D.A.L.); (T.S.K.); (E.V.S.); (V.N.B.); (N.N.D.)
| | - Mikhail V. Onufriev
- Laboratory of Functional Biochemistry of the Nervous System, Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485 Moscow, Russia; (N.V.G.); (M.V.O.); (Y.V.M.)
- Research and Clinical Center for Neuropsychiatry of Moscow Healthcare Department, 115419 Moscow, Russia
| | - Yulia V. Moiseeva
- Laboratory of Functional Biochemistry of the Nervous System, Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, 117485 Moscow, Russia; (N.V.G.); (M.V.O.); (Y.V.M.)
| | - Ekaterina V. Sukhareva
- Laboratory of Functional Neurogenomics, Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Science, 630090 Novosibirsk, Russia; (D.A.L.); (T.S.K.); (E.V.S.); (V.N.B.); (N.N.D.)
| | - Vladimir N. Babenko
- Laboratory of Functional Neurogenomics, Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Science, 630090 Novosibirsk, Russia; (D.A.L.); (T.S.K.); (E.V.S.); (V.N.B.); (N.N.D.)
| | - Nikolay N. Dygalo
- Laboratory of Functional Neurogenomics, Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Science, 630090 Novosibirsk, Russia; (D.A.L.); (T.S.K.); (E.V.S.); (V.N.B.); (N.N.D.)
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21
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Cappelli K, Ferlisi F, Mecocci S, Maranesi M, Trabalza-Marinucci M, Zerani M, Dal Bosco A, Acuti G. Dietary Supplementation of Olive Mill Waste Water Polyphenols in Rabbits: Evaluation of the Potential Effects on Hepatic Apoptosis, Inflammation and Metabolism through RT-qPCR Approach. Animals (Basel) 2021; 11:2932. [PMID: 34679953 PMCID: PMC8532769 DOI: 10.3390/ani11102932] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/27/2021] [Accepted: 10/09/2021] [Indexed: 12/24/2022] Open
Abstract
Agro-industrial processing for the production of food or non-food products generates a wide range of by-products and residues rich in bioactive compounds including polyphenols. The concentration of these by-products is sometimes higher than in the original raw material as in the case of olive mill waste water (OMWW), one of the main by-products of olive oil extraction. Polyphenols are secondary plant metabolites that regulate the expression of specific inflammatory genes, transcriptional factors and pro/anti-apoptotic molecules, thus modulating the signaling pathways essential for cell health and homeostasis. The liver plays a key role in regulating homeostasis by responding to dietary changes in order to maintain nutritional and physiological states. In this study a nutrigenomic approach was adopted, which focuses on the effects of diet-health-gene interactions and the modulation of cellular processes, in order to evaluate the expression of the genes (AGER, BAX, COX2, IL1B, PPARA, PPARG, SIRT1, TNFA) involved in these interactions in the livers of rabbits fed with a diet supplemented with OMWW (POL) or without supplements (control, CTR). The RT-qPCR analysis showed the down-regulation of SIRT1, TNFA, AGER, BAX and PPARA transcripts in the POL group compared to the CTR group. These results show that OMWW dietary supplementation prevents cell death and tissue deterioration in rabbits.
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Affiliation(s)
- Katia Cappelli
- Department of Veterinary Medicine, University of Perugia, Via San Costanzo, 4, 06126 Perugia, Italy; (K.C.); (F.F.); (S.M.); (M.Z.); (G.A.)
| | - Flavia Ferlisi
- Department of Veterinary Medicine, University of Perugia, Via San Costanzo, 4, 06126 Perugia, Italy; (K.C.); (F.F.); (S.M.); (M.Z.); (G.A.)
| | - Samanta Mecocci
- Department of Veterinary Medicine, University of Perugia, Via San Costanzo, 4, 06126 Perugia, Italy; (K.C.); (F.F.); (S.M.); (M.Z.); (G.A.)
| | - Margherita Maranesi
- Department of Veterinary Medicine, University of Perugia, Via San Costanzo, 4, 06126 Perugia, Italy; (K.C.); (F.F.); (S.M.); (M.Z.); (G.A.)
| | - Massimo Trabalza-Marinucci
- Department of Veterinary Medicine, University of Perugia, Via San Costanzo, 4, 06126 Perugia, Italy; (K.C.); (F.F.); (S.M.); (M.Z.); (G.A.)
| | - Massimo Zerani
- Department of Veterinary Medicine, University of Perugia, Via San Costanzo, 4, 06126 Perugia, Italy; (K.C.); (F.F.); (S.M.); (M.Z.); (G.A.)
| | - Alessandro Dal Bosco
- Department of Agricultural, Food and Environmental Science, University of Perugia, Borgo XX Giugno, 74, 06100 Perugia, Italy;
| | - Gabriele Acuti
- Department of Veterinary Medicine, University of Perugia, Via San Costanzo, 4, 06126 Perugia, Italy; (K.C.); (F.F.); (S.M.); (M.Z.); (G.A.)
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22
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Adipose Tissue Immunometabolism and Apoptotic Cell Clearance. Cells 2021; 10:cells10092288. [PMID: 34571937 PMCID: PMC8470283 DOI: 10.3390/cells10092288] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 08/26/2021] [Accepted: 08/30/2021] [Indexed: 12/19/2022] Open
Abstract
The safe removal of apoptotic debris by macrophages—often referred to as efferocytosis—is crucial for maintaining tissue integrity and preventing self-immunity or tissue damaging inflammation. Macrophages clear tissues of hazardous materials from dying cells and ultimately adopt a pro-resolving activation state. However, adipocyte apoptosis is an inflammation-generating process, and the removal of apoptotic adipocytes by so-called adipose tissue macrophages triggers a sequence of events that lead to meta-inflammation and obesity-associated metabolic diseases. Signals that allow apoptotic cells to control macrophage immune functions are complex and involve metabolites released by the apoptotic cells and also metabolites produced by the macrophages during the digestion of apoptotic cell contents. This review provides a concise summary of the adipocyte-derived metabolites that potentially control adipose tissue macrophage immune functions and, hence, may induce or alleviate adipose tissue inflammation.
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23
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Xu C, Chen H, Zhou S, Sun C, Xia X, Peng Y, Zhuang J, Fu X, Zeng H, Zhou H, Cao Y, Yu Q, Li Y, Hu L, Zhou G, Yan F, Chen G, Li J. Pharmacological Activation of RXR-α Promotes Hematoma Absorption via a PPAR-γ-dependent Pathway After Intracerebral Hemorrhage. Neurosci Bull 2021; 37:1412-1426. [PMID: 34142331 DOI: 10.1007/s12264-021-00735-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 02/16/2021] [Indexed: 12/26/2022] Open
Abstract
Endogenously eliminating the hematoma is a favorable strategy in addressing intracerebral hemorrhage (ICH). This study sought to determine the role of retinoid X receptor-α (RXR-α) in the context of hematoma absorption after ICH. Our results showed that pharmacologically activating RXR-α with bexarotene significantly accelerated hematoma clearance and alleviated neurological dysfunction after ICH. RXR-α was expressed in microglia/macrophages, neurons, and astrocytes. Mechanistically, bexarotene promoted the nuclear translocation of RXR-α and PPAR-γ, as well as reducing neuroinflammation by modulating microglia/macrophage reprograming from the M1 into the M2 phenotype. Furthermore, all the beneficial effects of RXR-α in ICH were reversed by the PPAR-γ inhibitor GW9662. In conclusion, the pharmacological activation of RXR-α confers robust neuroprotection against ICH by accelerating hematoma clearance and repolarizing microglia/macrophages towards the M2 phenotype through PPAR-γ-related mechanisms. Our data support the notion that RXR-α might be a promising therapeutic target for ICH.
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Affiliation(s)
- Chaoran Xu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Huaijun Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Shengjun Zhou
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Chenjun Sun
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Xiaolong Xia
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Yucong Peng
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Jianfeng Zhuang
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Xiongjie Fu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Hanhai Zeng
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Hang Zhou
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Yang Cao
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Qian Yu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Yin Li
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Libin Hu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Guoyang Zhou
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Feng Yan
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Gao Chen
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China.
| | - Jianru Li
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China.
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24
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Discovery of new chalone adamantyl arotinoids having RXRα-modulating and anticancer activities. Bioorg Chem 2021; 113:104961. [PMID: 34023650 DOI: 10.1016/j.bioorg.2021.104961] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 04/21/2021] [Accepted: 05/01/2021] [Indexed: 11/23/2022]
Abstract
In the present study, a new series of chalcone adamantly arotinoids (chalcone AdArs) derived from RAR antagonist MX781, are synthesized, characterized, and evaluated for the biological activities in vitro. The studies of antiproliferative activity and RXRα-binding affinity of target compounds result in the discovery of a lead candidate (WA15), which is a good RXRα binder (Kd = 2.89 × 10-6 M) with potent antiproliferative activity against human cancer cell lines (IC50 ≈ 10 μM) and low toxic to normal LO2 and MRC-5 cells (IC50 > 50 μM). Different from MX781, WA15 eliminates RARα antagonist activity but inhibits 9-cis-RA-induced RXRα transactivation activity in a dose-dependent manner. Compound WA15 is found to be a good apoptosis inducer in various cancer cells and promotes cell apoptosis in an RXRα-independent manner. Besides, WA15 shows the induction of proteasome-dependent RXRα degradation which might enhance the WA15-induced apoptosis. Finally, the immunoblotting indicates that WA15 can inhibit the TNFα-induced IKK activation and IκBα degradation, suggesting that the anticancer activity of WA15 might be related to the inhibition of IKK/NF-κB signal pathway.
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25
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Chen W, Li L, Wang J, Zhang R, Zhang T, Wu Y, Wang S, Xing D. The ABCA1-efferocytosis axis: A new strategy to protect against atherosclerosis. Clin Chim Acta 2021; 518:1-8. [PMID: 33741356 DOI: 10.1016/j.cca.2021.02.025] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/24/2021] [Accepted: 02/26/2021] [Indexed: 12/13/2022]
Abstract
Atherosclerosis, a disease process characterized by lipid accumulation and inflammation, is the main cause of coronary heart disease (CHD) and myocardial infarction (MI). Efferocytosis involves the clearance of apoptotic cells by phagocytes. Successful engulfment triggers the release of anti-inflammatory cytokines to suppress atherosclerosis. ABCA1 is a key mediator of cholesterol efflux to apoA-I for the generation of HDL-C in reverse cholesterol transport (RCT). Intriguingly, ABCA1 promotes not only cholesterol efflux but also efferocytosis. ABCA1 promotes efferocytosis by regulating the release of "find-me" ligands, including LPC, and the exposure, release, and expression of "eat-me" ligands, including PtdSer, ANXA1, ANXA5, MEGF10, and GULP1. ABCA1 has a pathway similar to TG2, which is an "eat-me" ligand. ABCA1 has the highest known homology to ABCA7, which controls efferocytosis as the engulfment and processing ligand. In addition, ABCA1 can form several regulatory feedback axes with ANXA1, MEGF10, GULP1, TNFα, and IL-6. Therefore, ABCA1 is the central factor that links cholesterol efflux and apoptotic cell clearance. Several drugs have been studied or approved for apoptotic cell clearance, such as CD47 antibody and PD1-/PD-L1 antibody. In this article, we review the role and mechanism of action of ABCA1 in efferocytosis and focus on new insights into the ABCA1-efferocytosis axis and its potential as a novel therapeutic target in atherosclerosis.
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Affiliation(s)
- Wujun Chen
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China
| | - Lu Li
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China
| | - Jie Wang
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China
| | - Renshuai Zhang
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China
| | - Tingting Zhang
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China
| | - Yudong Wu
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China.
| | - Shuai Wang
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China; School of Medical Imaging, Radiotherapy Department of Affiliated Hospital, Weifang Medical University, Weifang, Shandong 261053, China.
| | - Dongming Xing
- Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao Cancer Institute, Qingdao, Shandong 266071, China; School of Life Sciences, Tsinghua University, Beijing 100084, China.
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26
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Fige É, Szendrei J, Sós L, Kraszewska I, Potor L, Balla J, Szondy Z. Heme Oxygenase-1 Contributes to Both the Engulfment and the Anti-Inflammatory Program of Macrophages during Efferocytosis. Cells 2021; 10:652. [PMID: 33804125 PMCID: PMC8001822 DOI: 10.3390/cells10030652] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 11/23/2022] Open
Abstract
Heme oxygenase-1 (HO-1) plays a vital role in the catabolism of heme and yields equimolar amounts of biliverdin, carbon monoxide, and free iron. We report that macrophages engulfing either the low amount of heme-containing apoptotic thymocytes or the high amount of heme-containing eryptotic red blood cells (eRBCs) strongly upregulate HO-1. The induction by apoptotic thymocytes is dependent on soluble signals, which do not include adenylate cyclase activators but induce the p38 mitogen-activated protein (MAP) kinase pathway, while in the case of eRBCs, it is cell uptake-dependent. Both pathways might involve the regulation of BTB and CNC homology 1 (BACH1), which is the repressor transcription regulator factor of the HO-1 gene. Long-term continuous efferocytosis of apoptotic thymocytes is not affected by the loss of HO-1, but that of eRBCs is inhibited. This latter is related to an internal signaling pathway that prevents the efferocytosis-induced increase in Rac1 activity. While the uptake of apoptotic cells suppressed the basal pro-inflammatory cytokine production in wild-type macrophages, in the absence of HO-1, engulfing macrophages produced enhanced amounts of pro-inflammatory cytokines. Our data demonstrate that HO-1 is required for both the engulfment and the anti-inflammatory response parts of the efferocytosis program.
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Affiliation(s)
- Éva Fige
- Section of Dental Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Dentistry, University of Debrecen, 4012 Debrecen, Hungary; (É.F.); (J.S.); (L.S.)
| | - Judit Szendrei
- Section of Dental Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Dentistry, University of Debrecen, 4012 Debrecen, Hungary; (É.F.); (J.S.); (L.S.)
| | - László Sós
- Section of Dental Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Dentistry, University of Debrecen, 4012 Debrecen, Hungary; (É.F.); (J.S.); (L.S.)
| | - Izabela Kraszewska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland;
| | - László Potor
- HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, 4012 Debrecen, Hungary; (L.P.); (J.B.)
- Department of Pediatrics, Faculty of Medicine, University of Debrecen, 4012 Debrecen, Hungary
- Division of Nephrology, Department of Medicine, Faculty of Medicine, University of Debrecen, 4012 Debrecen, Hungary
| | - József Balla
- HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, University of Debrecen, 4012 Debrecen, Hungary; (L.P.); (J.B.)
- Division of Nephrology, Department of Medicine, Faculty of Medicine, University of Debrecen, 4012 Debrecen, Hungary
| | - Zsuzsa Szondy
- Section of Dental Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Dentistry, University of Debrecen, 4012 Debrecen, Hungary; (É.F.); (J.S.); (L.S.)
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27
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Snodgrass RG, Benatzy Y, Schmid T, Namgaladze D, Mainka M, Schebb NH, Lütjohann D, Brüne B. Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation. Cell Death Differ 2020; 28:1301-1316. [PMID: 33177619 PMCID: PMC8027700 DOI: 10.1038/s41418-020-00652-4] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 10/09/2020] [Accepted: 10/15/2020] [Indexed: 12/31/2022] Open
Abstract
Macrophages acquire anti-inflammatory and proresolving functions to facilitate resolution of inflammation and promote tissue repair. While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression of inflammatory responses and play a pivotal role in wound healing, contemporaneous exposure to apoptotic cells (ACs) potentiates the expression of anti-inflammatory and tissue repair genes. Given that liver X receptors (LXRs), which coordinate sterol metabolism and immune cell function, play an essential role in the clearance of ACs, we investigated whether LXR activation following engulfment of ACs selectively potentiates the expression of Th2 cytokine-dependent genes in primary human AAMs. We show that AC uptake simultaneously upregulates LXR-dependent, but suppresses SREBP-2-dependent gene expression in macrophages, which are both prevented by inhibiting Niemann–Pick C1 (NPC1)-mediated sterol transport from lysosomes. Concurrently, macrophages accumulate sterol biosynthetic intermediates desmosterol, lathosterol, lanosterol, and dihydrolanosterol but not cholesterol-derived oxysterols. Using global transcriptome analysis, we identify anti-inflammatory and proresolving genes including interleukin-1 receptor antagonist (IL1RN) and arachidonate 15-lipoxygenase (ALOX15) whose expression are selectively potentiated in macrophages upon concomitant exposure to ACs or LXR agonist T0901317 (T09) and Th2 cytokines. We show priming macrophages via LXR activation enhances the cellular capacity to synthesize inflammation-suppressing specialized proresolving mediator (SPM) precursors 15-HETE and 17-HDHA as well as resolvin D5. Silencing LXRα and LXRβ in macrophages attenuates the potentiation of ALOX15 expression by concomitant stimulation of ACs or T09 and IL-13. Collectively, we identify a previously unrecognized mechanism of regulation whereby LXR integrates AC uptake to selectively shape Th2-dependent gene expression in AAMs.
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Affiliation(s)
- Ryan G Snodgrass
- Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
| | - Yvonne Benatzy
- Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
| | - Tobias Schmid
- Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
| | - Dmitry Namgaladze
- Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany
| | - Malwina Mainka
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
| | - Nils Helge Schebb
- Chair of Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany
| | - Dieter Lütjohann
- Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
| | - Bernhard Brüne
- Faculty of Medicine, Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany.
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28
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Wu S, Romero-Ramírez L, Mey J. Retinoic acid increases phagocytosis of myelin by macrophages. J Cell Physiol 2020; 236:3929-3945. [PMID: 33165955 PMCID: PMC7984038 DOI: 10.1002/jcp.30137] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/21/2020] [Accepted: 10/23/2020] [Indexed: 12/28/2022]
Abstract
Traumatic injuries of the central nervous system (CNS) are followed by the accumulation of cellular debris including proteins and lipids from myelinated fiber tracts. Insufficient phagocytic clearance of myelin debris influences the pathological process because it induces inflammation and blocks axonal regeneration. We investigated whether ligands of nuclear receptor families retinoic acid receptors (RARs), retinoid X receptors, peroxisome proliferator-activated receptors, lipid X receptors, and farnesoid X receptors increase myelin phagocytosis by murine bone marrow-derived macrophages and Raw264.7 cells. Using in vitro assays with 3,3'-dioctadecyloxacarbocyanine perchlorate- and pHrodo-labeled myelin we found that the transcriptional activator all-trans retinoic acid (RA)enhanced endocytosis of myelin involving the induction of tissue transglutaminase-2. The RAR-dependent increase of phagocytosis was not associated with changes in gene expression of receptors FcγR1, FcγR2b, FcγR3, TREM2, DAP12, CR3, or MerTK. The combination of RA and myelin exposure significantly reduced the expression of M1 marker genes inducible nitric oxide synthase and interleukin-1β and increased expression of transmembrane proteins CD36 and ABC-A1, which are involved in lipid transport and metabolism. The present results suggest an additional mechanism for therapeutic applications of RA after CNS trauma. It remains to be studied whether endogenous RA-signaling regulates phagocytosis in vivo.
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Affiliation(s)
- Siyu Wu
- Laboratorio Regeneración Neuronal e Inmunidad Innata, Hospital Nacional de Parapléjicos, Toledo, Spain.,School of Mental Health and Neuroscience and EURON Graduate School of Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Lorenzo Romero-Ramírez
- Laboratorio Regeneración Neuronal e Inmunidad Innata, Hospital Nacional de Parapléjicos, Toledo, Spain
| | - Jörg Mey
- Laboratorio Regeneración Neuronal e Inmunidad Innata, Hospital Nacional de Parapléjicos, Toledo, Spain.,School of Mental Health and Neuroscience and EURON Graduate School of Neuroscience, Maastricht University, Maastricht, The Netherlands
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Röszer T. Editorial overview: Immunomodulation 2020 - nuclear receptors. Curr Opin Pharmacol 2020; 53:vi-viii. [PMID: 33183678 PMCID: PMC7832667 DOI: 10.1016/j.coph.2020.10.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Tamás Röszer
- Institute of Neurobiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
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30
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Lightbody RJ, Taylor JMW, Dempsie Y, Graham A. MicroRNA sequences modulating inflammation and lipid accumulation in macrophage “foam” cells: Implications for atherosclerosis. World J Cardiol 2020; 12:303-333. [PMID: 32843934 PMCID: PMC7415235 DOI: 10.4330/wjc.v12.i7.303] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 06/03/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Accumulation of macrophage “foam” cells, laden with cholesterol and cholesteryl ester, within the intima of large arteries, is a hallmark of early “fatty streak” lesions which can progress to complex, multicellular atheromatous plaques, involving lipoproteins from the bloodstream and cells of the innate and adaptive immune response. Sterol accumulation triggers induction of genes encoding proteins mediating the atheroprotective cholesterol efflux pathway. Within the arterial intima, however, this mechanism is overwhelmed, leading to distinct changes in macrophage phenotype and inflammatory status. Over the last decade marked gains have been made in understanding of the epigenetic landscape which influence macrophage function, and in particular the importance of small non-coding micro-RNA (miRNA) sequences in this context. This review identifies some of the miRNA sequences which play a key role in regulating “foam” cell formation and atherogenesis, highlighting sequences involved in cholesterol accumulation, those influencing inflammation in sterol-loaded cells, and novel sequences and pathways which may offer new strategies to influence macrophage function within atherosclerotic lesions.
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Affiliation(s)
- Richard James Lightbody
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Janice Marie Walsh Taylor
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Yvonne Dempsie
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
| | - Annette Graham
- Department of Biological and Biomedical Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, United Kingdom
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31
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Liao J, Xie Y, Lin Q, Yang X, An X, Xia Y, Du J, Wang F, Li HH. Immunoproteasome subunit β5i regulates diet-induced atherosclerosis through altering MERTK-mediated efferocytosis in Apoe knockout mice. J Pathol 2020; 250:275-287. [PMID: 31758542 DOI: 10.1002/path.5368] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 11/01/2019] [Accepted: 11/20/2019] [Indexed: 12/29/2022]
Abstract
The immunoproteasome contains three catalytic subunits (β1i, β2i and β5i) that are important modulators of immune cell homeostasis. A previous study showed a correlation between β5i and human atherosclerotic plaque instability; however, the causative role of β5i in atherosclerosis and the underlying mechanisms remain unknown. Here we explored this issue in apolipoprotein E (Apoe) knockout (eKO) mice with genetic deletion or pharmacological inhibition of β5i. We found that β5i expression was upregulated in lesional macrophages after an atherogenic diet (ATD). β5i/Apoe double KO (dKO) mice fed on the ATD had a significant decrease in both lesion area and necrotic core area, compared with eKO controls. Moreover, dKO mice had less caspase-3+ apoptotic cell accumulation but enhanced efferocytosis of apoptotic cells and increased expression of Mer receptor tyrosine kinase (MERTK). Consistently, similar phenotypes were observed in eKO mice transplanted with dKO bone marrow or treated with β5i-specific inhibitor PR-957. Mechanistic studies in vitro revealed that β5i deletion reduced IκBα degradation and inhibited NF-κB activation, promoting Mertk transcription and efferocytosis, thereby attenuating apoptotic cell accumulation. In conclusion, we demonstrate that β5i plays an important role in diet-induced atherosclerosis by altering MERTK-mediated efferocytosis. β5i might be a potential pharmaceutical target against atherosclerosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Jiawei Liao
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Yunpeng Xie
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Qiuyue Lin
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Xiaolei Yang
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Xiangbo An
- Department of Interventional Therapy, First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Yunlong Xia
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Jie Du
- Beijing AnZhen Hospital, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, School of Basic Medical Sciences, Capital Medical University, Beijing, PR China
| | - Feng Wang
- Department of Interventional Therapy, First Affiliated Hospital of Dalian Medical University, Dalian, PR China
| | - Hui-Hua Li
- Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, PR China
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32
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Röszer T. Signal Mechanisms of M2 Macrophage Activation. PROGRESS IN INFLAMMATION RESEARCH 2020:73-97. [DOI: 10.1007/978-3-030-50480-9_4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Horst AK, Tiegs G, Diehl L. Contribution of Macrophage Efferocytosis to Liver Homeostasis and Disease. Front Immunol 2019; 10:2670. [PMID: 31798592 PMCID: PMC6868070 DOI: 10.3389/fimmu.2019.02670] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 10/29/2019] [Indexed: 12/21/2022] Open
Abstract
The clearance of apoptotic cells is pivotal for both maintaining tissue homeostasis and returning to homeostasis after tissue injury as part of the regenerative resolution response. The liver is known for its capacity to remove aged and damaged cells from the circulation and can serve as a graveyard for effector T cells. In particular Kupffer cells are active phagocytic cells, but during hepatic inflammatory responses incoming neutrophils and monocytes may contribute to pro-inflammatory damage. To stimulate resolution of such inflammation, myeloid cell function can change, via sensing of environmental changes in the inflammatory milieu. Also, the removal of apoptotic cells via efferocytosis and the signaling pathways that are activated in macrophages/phagocytes upon their engulfment of apoptotic cells are important for a return to tissue homeostasis. Here, we will discuss, how efferocytosis mechanisms in hepatic macrophages/phagocytes may regulate tissue homeostasis and be involved in tissue regeneration in liver disease.
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Affiliation(s)
- Andrea Kristina Horst
- Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Gisa Tiegs
- Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Linda Diehl
- Institute for Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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34
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Wei Y, Corbalán-Campos J, Gurung R, Natarelli L, Zhu M, Exner N, Erhard F, Greulich F, Geißler C, Uhlenhaut NH, Zimmer R, Schober A. Dicer in Macrophages Prevents Atherosclerosis by Promoting Mitochondrial Oxidative Metabolism. Circulation 2019; 138:2007-2020. [PMID: 29748186 DOI: 10.1161/circulationaha.117.031589] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Alternative macrophage activation, which relies on mitochondrial oxidative metabolism, plays a central role in the resolution of inflammation and prevents atherosclerosis. Moreover, macrophages handle large amounts of cholesterol and triglycerides derived from the engulfed modified lipoproteins during atherosclerosis. Although several microRNAs regulate macrophage polarization, the role of the microRNA-generating enzyme Dicer in macrophage activation during atherosclerosis is unknown. METHODS To evaluate the role of Dicer in atherosclerosis, Apoe-/- mice with or without macrophage-specific Dicer deletion were fed a high-fat diet for 12 weeks. Anti-argonaute 2 RNA immunoprecipitation chip and RNA deep sequencing combined with microRNA functional screening were performed in the Dicer wild-type and knockout bone marrow-derived macrophages to identify the individual microRNAs and the mRNA targets mediating the phenotypic effects of Dicer. The role of the identified individual microRNA and its target in atherosclerosis was determined by tail vein injection of the target site blockers in atherosclerotic Apoe-/- mice. RESULTS We show that Dicer deletion in macrophages accelerated atherosclerosis in mice, along with enhanced inflammatory response and increased lipid accumulation in lesional macrophages. In vitro, alternative activation was limited whereas lipid-filled foam cell formation was exacerbated in Dicer-deficient macrophages as a result of impaired mitochondrial fatty acid oxidative metabolism. Rescue of microRNA (miR)-10a, let-7b, and miR-195a expression restored the oxidative metabolism in alternatively activated Dicer-deficient macrophages. Suppression of ligand-dependent nuclear receptor corepressor by miR-10a promoted fatty acid oxidation, which mediated the lipolytic and anti-inflammatory effect of Dicer. miR-10a expression was negatively correlated to the progression of atherosclerosis in humans. Blocking the interaction between ligand-dependent nuclear receptor corepressor and miR-10a by target site blockers aggravated atherosclerosis development in mice. CONCLUSIONS Dicer plays an atheroprotective role by coordinately regulating the inflammatory response and lipid metabolism in macrophages through enhancing fatty acid-fueled mitochondrial respiration, suggesting that promoting Dicer/miR-10a-dependent metabolic reprogramming in macrophages has potential therapeutic implications to prevent atherosclerosis.
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Affiliation(s)
- Yuanyuan Wei
- Experimental Vascular Medicine, Institute for Cardiovascular Prevention (Y.W., J.C.-C., R.G., L.N., M.Z., C.G., A.S.), Ludwig-Maximilians-University Munich, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Germany (Y.W., A.S.)
| | - Judit Corbalán-Campos
- Experimental Vascular Medicine, Institute for Cardiovascular Prevention (Y.W., J.C.-C., R.G., L.N., M.Z., C.G., A.S.), Ludwig-Maximilians-University Munich, Germany
| | - Rashmi Gurung
- Experimental Vascular Medicine, Institute for Cardiovascular Prevention (Y.W., J.C.-C., R.G., L.N., M.Z., C.G., A.S.), Ludwig-Maximilians-University Munich, Germany
| | - Lucia Natarelli
- Experimental Vascular Medicine, Institute for Cardiovascular Prevention (Y.W., J.C.-C., R.G., L.N., M.Z., C.G., A.S.), Ludwig-Maximilians-University Munich, Germany
| | - Mengyu Zhu
- Experimental Vascular Medicine, Institute for Cardiovascular Prevention (Y.W., J.C.-C., R.G., L.N., M.Z., C.G., A.S.), Ludwig-Maximilians-University Munich, Germany
| | - Nicole Exner
- Biomedical Research Center, Biochemistry (N.E.), Ludwig-Maximilians-University Munich, Germany
| | - Florian Erhard
- Institut für Informatik (F.E., R.Z.), Ludwig-Maximilians-University Munich, Germany.,Dr Erhard is currently at the Institut für Virologie, Julius-Maximilians-Universität Würzburg, Germany
| | - Franziska Greulich
- Helmholtz Diabetes Center and German Center for Diabetes Research, IDO, Munich, Germany (F.G., N.H.U.)
| | - Claudia Geißler
- Experimental Vascular Medicine, Institute for Cardiovascular Prevention (Y.W., J.C.-C., R.G., L.N., M.Z., C.G., A.S.), Ludwig-Maximilians-University Munich, Germany
| | - N Henriette Uhlenhaut
- Helmholtz Diabetes Center and German Center for Diabetes Research, IDO, Munich, Germany (F.G., N.H.U.)
| | - Ralf Zimmer
- Institut für Informatik (F.E., R.Z.), Ludwig-Maximilians-University Munich, Germany
| | - Andreas Schober
- Experimental Vascular Medicine, Institute for Cardiovascular Prevention (Y.W., J.C.-C., R.G., L.N., M.Z., C.G., A.S.), Ludwig-Maximilians-University Munich, Germany.,DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Germany (Y.W., A.S.)
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da Rocha GHO, Loiola RA, Pantaleão LDN, Reutelingsperger C, Solito E, Farsky SHP. Control of expression and activity of peroxisome proliferated-activated receptor γ by Annexin A1 on microglia during efferocytosis. Cell Biochem Funct 2019; 37:560-568. [PMID: 31479167 DOI: 10.1002/cbf.3433] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 08/13/2019] [Accepted: 08/22/2019] [Indexed: 12/18/2022]
Abstract
Annexin A1 (AnxA1) is a protein secreted by phagocytic cells which plays a pivotal role on the resolution of inflammation by enhancing phagocytosis carried out by phagocytes. Which factors and intracellular mechanisms are linked to such actions exerted by AnxA1 are yet to be completely understood. In order to investigate such, BV2 microglial cells were transfected with plasmids aimed at down-modulating AnxA1 expression and also treated with exogenous recombinant rAnxA1; gene and protein expression of proliferated-activated receptor γ (PPARγ) and CD36, STAT6 phosphorylation and phagocytosis of apoptotic neurons were investigated. Down-modulating AnxA1 in BV2 cells impaired gene and protein expression of PPARγ, effects reversed by treatment with recombinant AnxA1 (rAnxA1). Lower levels of CD36 were also verified in AnxA1 down-modulated BV2 cells. AnxA1-mediated phagocytosis of apoptotic cells was abrogated due to blockade of PPARγ activation, and in AnxA1 down-modulated cells exogenous AnxA1 failed to exert any effects on phagocytosis. Lower levels of STAT6/pSTAT6 in AnxA1 down-modulated BV2 cells suggest the involvement of this transcription factor with PPARγ and CD36 synthesis and actions. Data here shown suggest that there is a probable connection between AnxA1, PPARγ, and CD36, which must all act in association in order for efferocytosis to occur properly. AnxA1-mediated phosphorylation of STAT6 is probably involved with intracellular pathways involving PPARγ and CD36 actions. These data evidence that PPARγ/CD36 play a role on AnxA1-mediated efferocytosis in microglial cells. SIGNIFICANCE OF THE STUDY: The findings of this work provide evidence that the glucocorticoid-mediated protein annexin A1 modulates PPARγ expression and that PPARγ is important for annexin A1-mediated efferocytosis. Only recently the interaction between these two factors has begun to be explored, and knowledge on associated cell mechanisms are still scarce. Elucidating how annexin A1 and PPARγ interact with one another provides basis for further research aimed at understanding molecular pathways and cell signaling events involved with these factors, expanding existing knowledge on the anti-inflammatory effects of such factors.
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Affiliation(s)
| | - Rodrigo Azevedo Loiola
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Lorena do Nascimento Pantaleão
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
| | - Chris Reutelingsperger
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
| | - Egle Solito
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University, London, United Kingdom
| | - Sandra Helena Poliselli Farsky
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
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36
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Arienti S, Barth ND, Dorward DA, Rossi AG, Dransfield I. Regulation of Apoptotic Cell Clearance During Resolution of Inflammation. Front Pharmacol 2019; 10:891. [PMID: 31456686 PMCID: PMC6701246 DOI: 10.3389/fphar.2019.00891] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 07/15/2019] [Indexed: 01/17/2023] Open
Abstract
Programmed cell death (apoptosis) has an important role in the maintenance of tissue homeostasis as well as the progression and ultimate resolution of inflammation. During apoptosis, the cell undergoes morphological and biochemical changes [e.g., phosphatidylserine (PtdSer) exposure, caspase activation, changes in mitochondrial membrane potential and DNA cleavage] that act to shut down cellular function and mark the cell for phagocytic clearance. Tissue phagocytes bind and internalize apoptotic cells, bodies, and vesicles, providing a mechanism for the safe disposal of apoptotic material. Phagocytic removal of apoptotic cells before they undergo secondary necrosis reduces the potential for bystander damage to adjacent tissue and importantly initiates signaling pathways within the phagocytic cell that act to dampen inflammation. In a pathological context, excessive apoptosis or failure to clear apoptotic material results in secondary necrosis with the release of pro-inflammatory intracellular contents. In this review, we consider some of the mechanisms by which phagocytosis of apoptotic cells can be controlled. We suggest that matching apoptotic cell load with the capacity for apoptotic cell clearance within tissues may be important for therapeutic strategies that target the apoptotic process for treatment of inflammatory disease.
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Affiliation(s)
- Simone Arienti
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Nicole D Barth
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - David A Dorward
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Adriano G Rossi
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Ian Dransfield
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
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37
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Arneth B. Systemic Lupus Erythematosus and DNA Degradation and Elimination Defects. Front Immunol 2019; 10:1697. [PMID: 31440232 PMCID: PMC6692764 DOI: 10.3389/fimmu.2019.01697] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 07/08/2019] [Indexed: 12/25/2022] Open
Abstract
Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by the production of autoantibodies specific for components of the cell nucleus and that causes damage to body tissues and organs. The pathogenesis of SLE remains unclear, with numerous studies pointing to a combination of genetic and environmental factors. A critical stage in SLE development is cell necrosis, in which undegraded chromatin and nucleoproteins are released into the blood, resulting in circulating cell-free DNA and serum nucleoproteins that trigger anti-dsDNA autoantibody production. This systematic literature review aimed to examine whether SLE stems from a DNA degradation and elimination defect. Materials and Methods: An advanced literature search was conducted in PubMed using the following keywords: [("SLE" OR "Systemic Lupus Erythematosus" OR "Lupus")] AND [("DNA" OR "DNA Degradation")] AND [("Defect Elimination")]. More articles were obtained from the references of the identified articles and basic Google searches. Twenty-five peer-reviewed articles published within the past 10 years (2007-2018) were included for review. Results: The findings of each study are summarized in Tables 1, 2. Discussion and Conclusion: The etiopathogenesis of SLE remains controversial, which limits therapeutic inventions for this disease. However, SLE is a DNA degradation and elimination disorder caused by uncleared histones and nuclear material that leak into the extracellular space and form cell-free DNA, triggering an immune response that destroys tissues and organs. Under normal conditions, apoptosis allows DNA and other nuclear material to be efficiently cleared through degradation and additional complex mechanisms such that this material does not trigger the immune system to produce nuclear autoantibodies.
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Affiliation(s)
- Borros Arneth
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, University Hospital of Giessen and Marburg, Justus Liebig University Giessen, Giessen, Germany
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38
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Voices from the dead: The complex vocabulary and intricate grammar of dead cells. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2019; 116:1-90. [PMID: 31036289 DOI: 10.1016/bs.apcsb.2019.02.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Of the roughly one million cells per second dying throughout the body, the vast majority dies by apoptosis, the predominant form of regulated cell death in higher organisms. Long regarded as mere waste, apoptotic cells are now recognized as playing a prominent and active role in homeostatic maintenance, especially resolution of inflammation, and in the sculpting of tissues during development. The activities associated with apoptotic cells are continually expanding, with more recent studies demonstrating their ability to modulate such vital functions as proliferation, survival, differentiation, metabolism, migration, and angiogenesis. In each case, the role of apoptotic cells is active, exerting their effects via new activities acquired during the apoptotic program. Moreover, the capacity to recognize and respond to apoptotic cells is not limited to professional phagocytes. Most, if not all, cells receive and integrate an array of signals from cells dying in their vicinity. These signals comprise a form of biochemical communication. As reviewed in this chapter, this communication is remarkably sophisticated; each of its three critical steps-encoding, transmission, and decoding of the apoptotic cell's "message"-is endowed with exquisite robustness. Together, the abundance and intricacy of the variables at each step comprise the vocabulary and grammar of the language by which dead cells achieve their post-mortem voice. The combinatorial complexity of the resulting communication network permits dying cells, through the signals they emit and the responses those signals elicit, to partake of an expanded role in homeostasis, acting as both sentinels of environmental change and agents of adaptation.
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Hu T, Wu Z, Bush SJ, Freem L, Vervelde L, Summers KM, Hume DA, Balic A, Kaiser P. Characterization of Subpopulations of Chicken Mononuclear Phagocytes That Express TIM4 and CSF1R. THE JOURNAL OF IMMUNOLOGY 2019; 202:1186-1199. [PMID: 30626692 DOI: 10.4049/jimmunol.1800504] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 12/03/2018] [Indexed: 01/08/2023]
Abstract
The phosphatidylserine receptor TIM4, encoded by TIMD4, mediates the phagocytic uptake of apoptotic cells. We applied anti-chicken TIM4 mAbs in combination with CSF1R reporter transgenes to dissect the function of TIM4 in the chick (Gallus gallus). During development in ovo, TIM4 was present on the large majority of macrophages, but expression became more heterogeneous posthatch. Blood monocytes expressed KUL01, class II MHC, and CSF1R-mApple uniformly. Around 50% of monocytes were positive for surface TIM4. They also expressed many other monocyte-specific transcripts at a higher level than TIM4- monocytes. In liver, highly phagocytic TIM4hi cells shared many transcripts with mammalian Kupffer cells and were associated with uptake of apoptotic cells. Although they expressed CSF1R mRNA, Kupffer cells did not express the CSF1R-mApple transgene, suggesting that additional CSF1R transcriptional regulatory elements are required by these cells. By contrast, CSF1R-mApple was detected in liver TIM4lo and TIM4- cells, which were not phagocytic and were more abundant than Kupffer cells. These cells expressed CSF1R alongside high levels of FLT3, MHCII, XCR1, and other markers associated with conventional dendritic cells in mice. In bursa, TIM4 was present on the cell surface of two populations. Like Kupffer cells, bursal TIM4hi phagocytes coexpressed many receptors involved in apoptotic cell recognition. TIM4lo cells appear to be a subpopulation of bursal B cells. In overview, TIM4 is associated with phagocytes that eliminate apoptotic cells in the chick. In the liver, TIM4 and CSF1R reporters distinguished Kupffer cells from an abundant population of dendritic cell-like cells.
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Affiliation(s)
- Tuanjun Hu
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom
| | - Zhiguang Wu
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom
| | - Stephen J Bush
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom
| | - Lucy Freem
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom
| | - Lonneke Vervelde
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom
| | - Kim M Summers
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom.,Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland 4102, Australia
| | - David A Hume
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom; .,Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland 4102, Australia
| | - Adam Balic
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom;
| | - Pete Kaiser
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom
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40
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Levy D, de Melo TC, Oliveira BA, Paz JL, de Freitas FA, Reichert CO, Rodrigues A, Bydlowski SP. 7-Ketocholesterol and cholestane-triol increase expression of SMO and LXRα signaling pathways in a human breast cancer cell line. Biochem Biophys Rep 2018; 19:100604. [PMID: 31463370 PMCID: PMC6709374 DOI: 10.1016/j.bbrep.2018.12.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 12/14/2018] [Accepted: 12/20/2018] [Indexed: 02/07/2023] Open
Abstract
Oxysterols are 27-carbon oxidation products of cholesterol metabolism. Oxysterols possess several biological actions, including the promotion of cell death. Here, we examined the ability of 7-ketocholesterol (7-KC), cholestane-3β-5α-6β-triol (triol), and a mixture of 5α-cholestane-3β,6β-diol and 5α-cholestane-3β,6α-diol (diol) to promote cell death in a human breast cancer cell line (MDA-MB-231). We determined cell viability, after 24-h incubation with oxysterols. These oxysterols promoted apoptosis. At least part of the observed effects promoted by 7-KC and triol arose from an increase in the expression of the sonic hedgehog pathway mediator, smoothened. However, this increased expression was apparently independent of sonic hedgehog expression, which did not change. Moreover, these oxysterols led to increased expression of LXRα, which is involved in cellular cholesterol efflux, and the ATP-binding cassette transporters, ABCA1 and ABCG1. Diols did not affect these pathways. These results suggested that the sonic hedgehog and LXRα pathways might be involved in the apoptotic process promoted by 7-KC and triol.
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Affiliation(s)
- Debora Levy
- Laboratory of Genetics and Molecular Hematology (LIM31), Department of Hematology, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil
| | - Thatiana Correa de Melo
- Laboratory of Genetics and Molecular Hematology (LIM31), Department of Hematology, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil
| | - Beatriz A. Oliveira
- Laboratory of Genetics and Molecular Hematology (LIM31), Department of Hematology, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil
| | - Jessica L. Paz
- Laboratory of Genetics and Molecular Hematology (LIM31), Department of Hematology, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil
| | - Fabio A. de Freitas
- Laboratory of Genetics and Molecular Hematology (LIM31), Department of Hematology, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil
| | - Cadiele O. Reichert
- Laboratory of Genetics and Molecular Hematology (LIM31), Department of Hematology, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil
| | | | - Sergio P. Bydlowski
- Laboratory of Genetics and Molecular Hematology (LIM31), Department of Hematology, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, SP, Brazil
- Instituto Nacional de Ciencia e Tecnologia em Medicina Regenerativa (INCT-Regenera), CNPq, Brazil
- Correspondence to: Department of Hematology, Faculdade de Medicina, Universidade de Sao Paulo, Av.Dr. Enéas de Carvalho Aguiar,155, 1st floor, room 43, 05403-000 São Paulo, SP, Brazil.
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Leung DTH, Nguyen T, Oliver EM, Matti J, Alexiadis M, Silke J, Jobling TW, Fuller PJ, Chu S. Combined PPARγ Activation and XIAP Inhibition as a Potential Therapeutic Strategy for Ovarian Granulosa Cell Tumors. Mol Cancer Ther 2018; 18:364-375. [PMID: 30530769 DOI: 10.1158/1535-7163.mct-18-0078] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 06/25/2018] [Accepted: 12/04/2018] [Indexed: 11/16/2022]
Abstract
Ovarian granulosa cell tumors (GCT) are characterized by indolent growth and late relapse. No therapeutic modalities aside from surgery have proven effective. We previously reported overexpression of the nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPARγ), and constitutive activity of the NFκB and AP1 signaling pathways in GCT. PPARγ presents as a potential therapeutic target as it impedes proliferation and promotes terminal differentiation of granulosa cells. However, resistance to the actions of PPARγ is caused by NFκB transrepression in GCT-derived cell lines, KGN and COV434. We showed that abrogation of NFκB signaling in GCT cells enables PPARγ agonists to initiate apoptosis. In addition, we observed overexpression of an NFκB-induced gene, X-linked inhibitor of apoptosis protein (XIAP), in GCT and GCT-derived cells. XIAP is an attractive therapeutic target due to its role in inhibiting the apoptotic pathway. We investigated the antitumor effects of combined XIAP inhibition using Smac-mimetics and PPARγ activation using thiazolidinediones (TZD) in the GCT-derived cells. Transactivation assays revealed that NFκB transrepression of PPARγ can be relieved by NFκB or XIAP inhibition. Combined Smac-mimetic and TZD significantly induced apoptosis, reduced cell viability and proliferation in KGN cells in monolayer and 3D spheroid culture, and in GCT explant models. The Smac-mimetic and TZD cotreatment also delayed cell invasion, upregulated proapoptotic genes, and compromised cell metabolism in KGN cells. This study provides evidence that PPARγ and XIAP cotreatment has antineoplastic effects in GCT. As therapeutics that target these proteins are already in clinical or preclinical use, expedient translation to the clinic is possible.
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Affiliation(s)
- Dilys T H Leung
- Hudson Institute of Medical Research and the Monash University Department of Molecular and Translational Science, Clayton, Victoria, Australia
| | - Trang Nguyen
- Hudson Institute of Medical Research and the Monash University Department of Molecular and Translational Science, Clayton, Victoria, Australia
| | - Edwina May Oliver
- Hudson Institute of Medical Research and the Monash University Department of Molecular and Translational Science, Clayton, Victoria, Australia
| | - Juliana Matti
- Hudson Institute of Medical Research and the Monash University Department of Molecular and Translational Science, Clayton, Victoria, Australia
| | - Maria Alexiadis
- Hudson Institute of Medical Research and the Monash University Department of Molecular and Translational Science, Clayton, Victoria, Australia
| | - John Silke
- Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - Thomas W Jobling
- Department of Gynecology Oncology, Monash Health, Clayton, Victoria, Australia
| | - Peter J Fuller
- Hudson Institute of Medical Research and the Monash University Department of Molecular and Translational Science, Clayton, Victoria, Australia
| | - Simon Chu
- Hudson Institute of Medical Research and the Monash University Department of Molecular and Translational Science, Clayton, Victoria, Australia.
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Mohammadi S, Saghaeian-Jazi M, Sedighi S, Memarian A. Sodium valproate modulates immune response by alternative activation of monocyte-derived macrophages in systemic lupus erythematosus. Clin Rheumatol 2018; 37:719-727. [PMID: 29196891 DOI: 10.1007/s10067-017-3922-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 10/21/2017] [Accepted: 11/17/2017] [Indexed: 02/05/2023]
Abstract
The anti-inflammatory role of macrophages in apoptotic cells (ACs) clearance is involved in Systemic Lupus Erythematosus (SLE) pathogenesis. The efferocytic capability of macrophages is altered by M1/M2 polarization. Histone deacetylase inhibitors (HDACi) are proposed to enhance the expansion of M2 macrophages. Sodium valproate (VPA) is an HDACi with different anti-inflammatory properties. Here, we aimed to investigate the effects of HDACi by VPA on the polarization of monocyte-derived macrophages (MDMs) and regulating the expression of anti-inflammatory cytokines in SLE. We studied the ex vivo alterations of MDMs among 15 newly diagnosed SLE patients and 10 normal subjects followed by ACs and VPA treatments. M1/M2 polarization was assessed by expression of CD86/CD163, IL1-β, IDO-1, and MRC-1 among treated and non-treated MDMs. We also evaluated the production of IL-10, IL-12, TGF-β1, and TNF-α cytokines in the cell culture supernatants. CD163 was overexpressed upon VPA treatment, while CD86 showed no significant change. IL1-β and IDO-1 genes were significantly downregulated, and the mRNA expression of MRC-1 was increased among VPA-treated MDMs of SLE patients. The anti-inflammatory cytokines (IL-10 and TGF-β1) were overproduced while TNF-α level was decreased in response to VPA. The population of classically activated macrophages was more prevalent among SLE patients and efferocytosis was defected. VPA could successfully enhance the anti-inflammatory immune response through alternative activation of MDMs in SLE patients.
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Affiliation(s)
- Saeed Mohammadi
- Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Marie Saghaeian-Jazi
- Biochemistry and Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sima Sedighi
- Joint, Bone and Connective tissue Research Center (JBCRC), Golestan University of Medical Sciences, Gorgan, Iran.
| | - Ali Memarian
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran.
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Wallqvist A, Wang H, Zavaljevski N, Memišević V, Kwon K, Pieper R, Rajagopala SV, Reifman J. Mechanisms of action of Coxiella burnetii effectors inferred from host-pathogen protein interactions. PLoS One 2017; 12:e0188071. [PMID: 29176882 PMCID: PMC5703456 DOI: 10.1371/journal.pone.0188071] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 10/31/2017] [Indexed: 02/06/2023] Open
Abstract
Coxiella burnetii is an obligate Gram-negative intracellular pathogen and the etiological agent of Q fever. Successful infection requires a functional Type IV secretion system, which translocates more than 100 effector proteins into the host cytosol to establish the infection, restructure the intracellular host environment, and create a parasitophorous vacuole where the replicating bacteria reside. We used yeast two-hybrid (Y2H) screening of 33 selected C. burnetii effectors against whole genome human and murine proteome libraries to generate a map of potential host-pathogen protein-protein interactions (PPIs). We detected 273 unique interactions between 20 pathogen and 247 human proteins, and 157 between 17 pathogen and 137 murine proteins. We used orthology to combine the data and create a single host-pathogen interaction network containing 415 unique interactions between 25 C. burnetii and 363 human proteins. We further performed complementary pairwise Y2H testing of 43 out of 91 C. burnetii-human interactions involving five pathogen proteins. We used the combined data to 1) perform enrichment analyses of target host cellular processes and pathways, 2) examine effectors with known infection phenotypes, and 3) infer potential mechanisms of action for four effectors with uncharacterized functions. The host-pathogen interaction profiles supported known Coxiella phenotypes, such as adapting cell morphology through cytoskeletal re-arrangements, protein processing and trafficking, organelle generation, cholesterol processing, innate immune modulation, and interactions with the ubiquitin and proteasome pathways. The generated dataset of PPIs-the largest collection of unbiased Coxiella host-pathogen interactions to date-represents a rich source of information with respect to secreted pathogen effector proteins and their interactions with human host proteins.
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Affiliation(s)
- Anders Wallqvist
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, United States of America
| | - Hao Wang
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, United States of America
| | - Nela Zavaljevski
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, United States of America
| | - Vesna Memišević
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, United States of America
| | - Keehwan Kwon
- J. Craig Venter Institute, Rockville, Maryland, United States of America
| | - Rembert Pieper
- J. Craig Venter Institute, Rockville, Maryland, United States of America
| | | | - Jaques Reifman
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Maryland, United States of America
- * E-mail:
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Heckmann BL, Boada-Romero E, Cunha LD, Magne J, Green DR. LC3-Associated Phagocytosis and Inflammation. J Mol Biol 2017; 429:3561-3576. [PMID: 28847720 DOI: 10.1016/j.jmb.2017.08.012] [Citation(s) in RCA: 191] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 08/16/2017] [Accepted: 08/22/2017] [Indexed: 02/06/2023]
Abstract
LC3-associated phagocytosis (LAP) is a novel form of non-canonical autophagy where LC3 (microtubule-associated protein 1A/1B-light chain 3) is conjugated to phagosome membranes using a portion of the canonical autophagy machinery. The impact of LAP to immune regulation is best characterized in professional phagocytes, in particular macrophages, where LAP has instrumental roles in the clearance of extracellular particles including apoptotic cells and pathogens. Binding of dead cells via receptors present on the macrophage surface results in the translocation of the autophagy machinery to the phagosome and ultimately LC3 conjugation. These events promote a rapid form of phagocytosis that produces an "immunologically silent" clearance of the apoptotic cells. Consequences of LAP deficiency include a decreased capacity to clear dying cells and the establishment of a lupus-like autoimmune disease in mice. The ability of LAP to attenuate autoimmunity likely occurs through the dampening of pro-inflammatory signals upon engulfment of dying cells and prevention of autoantigen presentation to other immune cells. However, it remains unclear how LAP shapes both the activation and outcome of the immune response at the molecular level. Herein, we provide a detailed review of LAP and its known roles in the immune response and provide further speculation on the putative mechanisms by which LAP may regulate immune function, perhaps through the metabolic reprogramming and polarization of macrophages.
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Affiliation(s)
- Bradlee L Heckmann
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
| | - Emilio Boada-Romero
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
| | - Larissa D Cunha
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
| | - Joelle Magne
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States
| | - Douglas R Green
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, United States.
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Decote-Ricardo D, Nunes MP, Morrot A, Freire-de-Lima CG. Implication of Apoptosis for the Pathogenesis of Trypanosoma cruzi Infection. Front Immunol 2017; 8:518. [PMID: 28536576 PMCID: PMC5422484 DOI: 10.3389/fimmu.2017.00518] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 04/18/2017] [Indexed: 12/24/2022] Open
Abstract
Apoptosis is induced during the course of immune response to different infectious agents, and the ultimate fate is the recognition and uptake of apoptotic bodies by neighboring cells or by professional phagocytes. Apoptotic cells expose specific ligands to a set of conserved receptors expressed on macrophage cellular surface, which are the main cells involved in the clearance of the dying cells. These scavenger receptors, besides triggering the production of anti-inflammatory factors, also block the production of inflammatory mediators by phagocytes. Experimental infection of mice with the parasite Trypanosoma cruzi shows many pathological changes that parallels the evolution of human infection. Leukocytes undergoing intense apoptotic death are observed during the immune response to T. cruzi in the mouse model of the disease. T. cruzi replicate intensely and secrete molecules with immunomodulatory activities that interfere with T cell-mediated immune responses and secretion of pro-inflammatory cytokine secretion. This mechanism of immune evasion allows the infection to be established in the vertebrate host. Under inflammatory conditions, efferocytosis of apoptotic bodies generates an immune-regulatory phenotype in phagocytes, which is conducive to intracellular pathogen replication. However, the relevance of cellular apoptosis in the pathology of Chagas’ disease requires further studies. Here, we review the evidence of leukocyte apoptosis in T. cruzi infection and its immunomodulatory mechanism for disease progression.
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Affiliation(s)
- Débora Decote-Ricardo
- Instituto de Veterinária, Universidade Federal Rural do Rio de Janeiro, Seropédica, Brazil
| | - Marise P Nunes
- Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Alexandre Morrot
- Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Celio G Freire-de-Lima
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Brophy ML, Dong Y, Wu H, Rahman HNA, Song K, Chen H. Eating the Dead to Keep Atherosclerosis at Bay. Front Cardiovasc Med 2017; 4:2. [PMID: 28194400 PMCID: PMC5277199 DOI: 10.3389/fcvm.2017.00002] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 01/12/2017] [Indexed: 12/22/2022] Open
Abstract
Atherosclerosis is the primary cause of coronary heart disease (CHD), ischemic stroke, and peripheral arterial disease. Despite effective lipid-lowering therapies and prevention programs, atherosclerosis is still the leading cause of mortality in the United States. Moreover, the prevalence of CHD in developing countries worldwide is rapidly increasing at a rate expected to overtake those of cancer and diabetes. Prominent risk factors include the hardening of arteries and high levels of cholesterol, which lead to the initiation and progression of atherosclerosis. However, cell death and efferocytosis are critical components of both atherosclerotic plaque progression and regression, yet, few currently available therapies focus on these processes. Thus, understanding the causes of cell death within the atherosclerotic plaque, the consequences of cell death, and the mechanisms of apoptotic cell clearance may enable the development of new therapies to treat cardiovascular disease. Here, we review how endoplasmic reticulum stress and cholesterol metabolism lead to cell death and inflammation, how dying cells affect plaque progression, and how autophagy and the clearance of dead cells ameliorates the inflammatory environment of the plaque. In addition, we review current research aimed at alleviating these processes and specifically targeting therapeutics to the site of the plaque.
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Affiliation(s)
- Megan L Brophy
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Karp Family Research Laboratories, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Yunzhou Dong
- Karp Family Research Laboratories, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital , Boston, MA , USA
| | - Hao Wu
- Karp Family Research Laboratories, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital , Boston, MA , USA
| | - H N Ashiqur Rahman
- Karp Family Research Laboratories, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital , Boston, MA , USA
| | - Kai Song
- Karp Family Research Laboratories, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital , Boston, MA , USA
| | - Hong Chen
- Karp Family Research Laboratories, Vascular Biology Program, Harvard Medical School, Boston Children's Hospital , Boston, MA , USA
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