The innate immune sensing of pathogens is important for host to mount defensive responses. STING has emerged in recent years as a critical signaling adaptor in the immune response to cytosolic DNA and RNA derived from pathogens. Liu et al. (2016) demonstrate that the RIG-I-dependent RNA sensing signaling induces STING expression via a TNF-α and IFN-α synergy. The up-regulation of STING is vital for 5′pppRNA restriction of HSV, a DNA virus that infects humans and causes herpes, in vitro and in vivo. This study provides new insights into the cross talk between DNA and RNA pathogen-sensing systems via the control of STING.
{"title":"RIGulation of STING expression: at the crossroads of viral RNA and DNA sensing pathways","authors":"Yiliu Liu, R. Lin, D. Olagnier","doi":"10.14800/ics.1491","DOIUrl":"https://doi.org/10.14800/ics.1491","url":null,"abstract":"The innate immune sensing of pathogens is important for host to mount defensive responses. STING has emerged in recent years as a critical signaling adaptor in the immune response to cytosolic DNA and RNA derived from pathogens. Liu et al. (2016) demonstrate that the RIG-I-dependent RNA sensing signaling induces STING expression via a TNF-α and IFN-α synergy. The up-regulation of STING is vital for 5′pppRNA restriction of HSV, a DNA virus that infects humans and causes herpes, in vitro and in vivo. This study provides new insights into the cross talk between DNA and RNA pathogen-sensing systems via the control of STING.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78730495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Behcet's disease (BD), a systemic vasculitis disorder is associated with the Silk Road. Oral aphthous and genital ulcers, skin lesions and ocular lesions are the most common manifestations. These manifestations are frequently associated with neurological symptoms, pulmonary involvement and arthritis. The etiology remains uncertain and the most fashionable hypothesis is immunological. BD disease is thought to be caused by pathogenic helper T (Th) cells. Th1, Th2, Th17 and Treg cells have been implicated in its pathogenesis. Recently spotlight has been drawn to novel cytokine of the IL-1 family: interleukin-37. Since its discovery, IL-37 has been studied extensively in immunological field. It has been established that IL-37 possesses anti-inflammatory property both in innate immune response as well as in acquired immune responses by suppressing pro-inflammatory molecules. This review will discuss the role of IL-37 in BD
{"title":"The anti-Inflammatory activity of Interleukin-37 in Behçet’s disease","authors":"K. Hamzaoui, A. Hamzaoui","doi":"10.14800/ICS.1452","DOIUrl":"https://doi.org/10.14800/ICS.1452","url":null,"abstract":"Behcet's disease (BD), a systemic vasculitis disorder is associated with the Silk Road. Oral aphthous and genital ulcers, skin lesions and ocular lesions are the most common manifestations. These manifestations are frequently associated with neurological symptoms, pulmonary involvement and arthritis. The etiology remains uncertain and the most fashionable hypothesis is immunological. BD disease is thought to be caused by pathogenic helper T (Th) cells. Th1, Th2, Th17 and Treg cells have been implicated in its pathogenesis. Recently spotlight has been drawn to novel cytokine of the IL-1 family: interleukin-37. Since its discovery, IL-37 has been studied extensively in immunological field. It has been established that IL-37 possesses anti-inflammatory property both in innate immune response as well as in acquired immune responses by suppressing pro-inflammatory molecules. This review will discuss the role of IL-37 in BD","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86580421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The participation of C-reactive protein (CRP) in host defense against microorganisms has been well described. More controversial has been its role in chronic conditions such as cardiovascular disease. Our recent publications explain the reasons for some of the confusion concerning CRP as a risk factor for disease and whether it is pro-inflammatory or anti-inflammatory. We found that two isoforms of CRP, pentameric (pCRP) and monomeric (mCRP), on microparticles (MPs), were not measureable by standard clinical assays. When we investigated MPs by imaging cytometry in plasma from controls versus patients with peripheral artery disease, we found that MPs from endothelial cells bearing mCRP were elevated. This elevation did not correlate with the soluble pCRP measured by high-sensitivity CRP assays. The data suggest that detection of mCRP on MPs may be a more specific marker in diagnosis, measurement of progression, and risk sensitivity in chronic disease. In an in vitro model of vascular inflammation, pCRP was anti-inflammatory and mCRP was pro-inflammatory for macrophage and T cell polarization. When we further investigated pCRP under defined conditions, we found that pCRP in the absence of a phosphocholine ligand had no inflammatory consequences. When combined with phosphocholine ligands, pCRP signaled through two Fcγ receptors (FcγRI and FcγRII) via phosphorylation of spleen tyrosine kinase (pSYK) to activate monocytes. Phosphocholine itself, when bound to pCRP, induced a congruent M2 macrophage and Th2 response. Phosphocholine is also the head group on the lipid phosphatidylcholine, which can become oxidized. Liposomes bearing oxidized phosphatidylcholine without pCRP promoted a uniform M1 macrophage and Th1 pro-inflammatory response. When oxidized liposomes were bound to pCRP, there was a disjunction in the macrophage and T cell response: monocytes matured into M2 macrophages, but the T cells polarized into a Th1 phenotype. The CRP-bound liposomes signaled monocytes via FcγRII to promote an anti-inflammatory M2 macrophage state, whereas the lack of FcγR on T cells allowed their liposome-induced polarization to a pro-inflammatory Th1 phenotype unopposed by the contribution of the pCRP/FcγR interaction. Different isoforms of CRP and its binding to complex ligands may determine its biological activities and their contribution to inflammatory states.
{"title":"The role of C-reactive protein in innate and acquired inflammation: new perspectives","authors":"J. Trial, L. Potempa, M. Entman","doi":"10.14800/ICS.1409","DOIUrl":"https://doi.org/10.14800/ICS.1409","url":null,"abstract":"The participation of C-reactive protein (CRP) in host defense against microorganisms has been well described. More controversial has been its role in chronic conditions such as cardiovascular disease. Our recent publications explain the reasons for some of the confusion concerning CRP as a risk factor for disease and whether it is pro-inflammatory or anti-inflammatory. We found that two isoforms of CRP, pentameric (pCRP) and monomeric (mCRP), on microparticles (MPs), were not measureable by standard clinical assays. When we investigated MPs by imaging cytometry in plasma from controls versus patients with peripheral artery disease, we found that MPs from endothelial cells bearing mCRP were elevated. This elevation did not correlate with the soluble pCRP measured by high-sensitivity CRP assays. The data suggest that detection of mCRP on MPs may be a more specific marker in diagnosis, measurement of progression, and risk sensitivity in chronic disease. In an in vitro model of vascular inflammation, pCRP was anti-inflammatory and mCRP was pro-inflammatory for macrophage and T cell polarization. When we further investigated pCRP under defined conditions, we found that pCRP in the absence of a phosphocholine ligand had no inflammatory consequences. When combined with phosphocholine ligands, pCRP signaled through two Fcγ receptors (FcγRI and FcγRII) via phosphorylation of spleen tyrosine kinase (pSYK) to activate monocytes. Phosphocholine itself, when bound to pCRP, induced a congruent M2 macrophage and Th2 response. Phosphocholine is also the head group on the lipid phosphatidylcholine, which can become oxidized. Liposomes bearing oxidized phosphatidylcholine without pCRP promoted a uniform M1 macrophage and Th1 pro-inflammatory response. When oxidized liposomes were bound to pCRP, there was a disjunction in the macrophage and T cell response: monocytes matured into M2 macrophages, but the T cells polarized into a Th1 phenotype. The CRP-bound liposomes signaled monocytes via FcγRII to promote an anti-inflammatory M2 macrophage state, whereas the lack of FcγR on T cells allowed their liposome-induced polarization to a pro-inflammatory Th1 phenotype unopposed by the contribution of the pCRP/FcγR interaction. Different isoforms of CRP and its binding to complex ligands may determine its biological activities and their contribution to inflammatory states.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83222665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chien-Wei Chen, Sindy Hu, Paulus S. Wang, Shyi-Wu Wang
There is a growing body of evidence supporting the immunomodulation effects of testosterone. Previous researches have focused on its direct blunt inflammatory effect on mediation of cytokines secretion through down-regulated expression of toll-like receptor 4 (TLR4). However, how testosterone modulates immune responses via mechanisms of TLR4 downstream molecules has not yet been elucidated. Recently, we have firstly confirmed that testosterone deficiency is the main reason that caused the exacerbate inflammation status in rat spleen. Orchidectomy in rats resulted in a markedly enhance of spleen weight ( splenomegaly ) and basal production of nitric oxide (NO) from splenocytes. Moreover, lipopolysaccharide (LPS) amplified proliferation rate of splenocytes and the production of tumor necrosis factor-alpha (TNF-α) following castration. Extracellular signal-regulated kinase (ERK) is a critical mediator of TLR4 cascades, and we further examined whether absence of endogenous testosterone affects ERK expression. As anticipated, orchidectomized rats manifested an increased phosphorylation of ERK. Furthermore, testosterone administration was demonstrated to be associated with a diminished LPS-evoked TNF-α and NO secretion in a dose-dependent manner. In the present study, we answered how testosterone withdrawal affects downstream signaling cascades of TLR4 and supports that testosterone might potentially ameliorate inflammatory responses. Our findings mention the possibility that testosterone functions might serve as a useful endogenous regulator of immune responses.
{"title":"Testosterone as a regulator of immune system via modulation of toll-like receptor 4/extracellular signal-regulated kinase signaling pathway","authors":"Chien-Wei Chen, Sindy Hu, Paulus S. Wang, Shyi-Wu Wang","doi":"10.14800/ICS.1407","DOIUrl":"https://doi.org/10.14800/ICS.1407","url":null,"abstract":"There is a growing body of evidence supporting the immunomodulation effects of testosterone. Previous researches have focused on its direct blunt inflammatory effect on mediation of cytokines secretion through down-regulated expression of toll-like receptor 4 (TLR4). However, how testosterone modulates immune responses via mechanisms of TLR4 downstream molecules has not yet been elucidated. Recently, we have firstly confirmed that testosterone deficiency is the main reason that caused the exacerbate inflammation status in rat spleen. Orchidectomy in rats resulted in a markedly enhance of spleen weight ( splenomegaly ) and basal production of nitric oxide (NO) from splenocytes. Moreover, lipopolysaccharide (LPS) amplified proliferation rate of splenocytes and the production of tumor necrosis factor-alpha (TNF-α) following castration. Extracellular signal-regulated kinase (ERK) is a critical mediator of TLR4 cascades, and we further examined whether absence of endogenous testosterone affects ERK expression. As anticipated, orchidectomized rats manifested an increased phosphorylation of ERK. Furthermore, testosterone administration was demonstrated to be associated with a diminished LPS-evoked TNF-α and NO secretion in a dose-dependent manner. In the present study, we answered how testosterone withdrawal affects downstream signaling cascades of TLR4 and supports that testosterone might potentially ameliorate inflammatory responses. Our findings mention the possibility that testosterone functions might serve as a useful endogenous regulator of immune responses.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84190354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CASPASE-12 (CASP12) has an anti-inflammatory function during infection, and is a risk factor for sepsis in African-Americans (AA). To determine if CASP12 could be protective for systemic lupus erythematosus (SLE) in AA, we genotyped AA SLE patients and controls. We found that, at best, there was a weak association between CASP12 genotype with the absence of anti-dsDNA autoantibodies in SLE patients. No effect was seen upon serum interleukin-1 beta levels, nor was any other protective effect noted for the CASP12 genotype, whether upon association with SLE, or any of the 11 American College of Rheumatology classification criteria. We concluded that CASP12 genotype thus does not influence the phenotype of SLE in AA. This raises the issue as to why this protein would not play a more significant role in a chronic inflammatory disease process.
{"title":"Caspase-12 and lupus: the curious case of the dog that didn't bark","authors":"E. Hermel","doi":"10.14800/ICS.1383","DOIUrl":"https://doi.org/10.14800/ICS.1383","url":null,"abstract":"CASPASE-12 (CASP12) has an anti-inflammatory function during infection, and is a risk factor for sepsis in African-Americans (AA). To determine if CASP12 could be protective for systemic lupus erythematosus (SLE) in AA, we genotyped AA SLE patients and controls. We found that, at best, there was a weak association between CASP12 genotype with the absence of anti-dsDNA autoantibodies in SLE patients. No effect was seen upon serum interleukin-1 beta levels, nor was any other protective effect noted for the CASP12 genotype, whether upon association with SLE, or any of the 11 American College of Rheumatology classification criteria. We concluded that CASP12 genotype thus does not influence the phenotype of SLE in AA. This raises the issue as to why this protein would not play a more significant role in a chronic inflammatory disease process.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78160512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Iron-based nanomaterials are thought to be cytotoxic in recent researches due to the mechanism that they can produce hydroxyl radical (•OH) in cells via Fenton reaction. However, we found Prussian blue nanoparticles (PBNPs) possess reactive oxygen species (ROS) scavenging ability due to their peroxidase (POD), catalase (CAT), super-oxide dismutase (SOD)-like activities and affinity for •OH. We theorized the multienzyme-like activities of PBNPs were caused by their abundant redox potentials in different forms: Prussian White (PW), Prussian blue (PB), Berlin Green (BG) and Prussian Yellow (PY), what makes them admirable electron transporters. The reported PBNPs show anti-inflammation ability in lipopolysaccharide (LPS)-induced cell and animal inflammation research endeavors.
{"title":"Prussian blue nanoparticles possess potential anti-inflammatory properties via scavenging reactive oxygen species","authors":"Wei Zhang, N. Gu, Yu Zhang","doi":"10.14800/ICS.1342","DOIUrl":"https://doi.org/10.14800/ICS.1342","url":null,"abstract":"Iron-based nanomaterials are thought to be cytotoxic in recent researches due to the mechanism that they can produce hydroxyl radical (•OH) in cells via Fenton reaction. However, we found Prussian blue nanoparticles (PBNPs) possess reactive oxygen species (ROS) scavenging ability due to their peroxidase (POD), catalase (CAT), super-oxide dismutase (SOD)-like activities and affinity for •OH. We theorized the multienzyme-like activities of PBNPs were caused by their abundant redox potentials in different forms: Prussian White (PW), Prussian blue (PB), Berlin Green (BG) and Prussian Yellow (PY), what makes them admirable electron transporters. The reported PBNPs show anti-inflammation ability in lipopolysaccharide (LPS)-induced cell and animal inflammation research endeavors.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82210191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Clathrin-dependent endocytic pathway is crucial for cell entry of extracellular pathogens and their components. The innate immune system utilizes this pathway to detect pathogen-associated molecular patterns (PAMPs) within endosomes. In the clathrin-mediated endocytosis, cargo selection depends on AP-2 adaptor and its accessory proteins, but the molecular mechanism of PAMP selection to be internalized is largely unknown. The endosomal Toll-like receptors (TLRs) 3, 7, 8, and 9 recognize viral or bacterial nucleic acids, as well as host-derived nucleic acids incorporated into the endosomal compartments, where type I interferon (IFN)-producing signals are arisen. In addition, lipopolysaccharide (LPS) receptor TLR4 transmits signals to produce IFN-b from endosomes after the clathrin-dependent endocytosis of LPS-TLR4. The cytosolic protein Raftlin that possesses membrane-anchoring motif mediates cellular uptake of TLR3/4 ligands in human cells through association with clathrin-AP-2 complex. Raftlin was first identified as a major raft protein in B cells that modulates B-cell or T-cell receptor-mediated signaling. In this review, we will focus on the Raftlin function in innate immunity and discuss the molecular mechanisms of cellular uptake and delivery of TLR ligands.
依赖网格蛋白的胞内吞途径是胞外病原体及其组分进入细胞的关键途径。先天免疫系统利用该途径检测内体内的病原体相关分子模式(PAMPs)。在网格蛋白介导的胞吞作用中，载物选择依赖于AP-2接头及其附属蛋白，但内化PAMP选择的分子机制在很大程度上尚不清楚。内体toll样受体(TLRs) 3、7、8和9识别病毒或细菌核酸，以及纳入I型干扰素(IFN)产生信号的内体腔室的宿主来源的核酸。此外，脂多糖(LPS)受体TLR4在网状蛋白依赖的胞吞作用后，通过核内体传递信号产生IFN-b。具有膜锚定基序的胞质蛋白Raftlin通过与网格蛋白- ap -2复合物结合介导TLR3/4配体在人细胞中的细胞摄取。Raftlin最初被发现是B细胞中一个主要的raft蛋白，它调节B细胞或t细胞受体介导的信号传导。在这篇综述中，我们将重点关注Raftlin在先天免疫中的作用，并讨论TLR配体的细胞摄取和传递的分子机制。
{"title":"Cell type-specific role of Raftlin in the regulation of endosomal TLR signaling","authors":"M. Matsumoto, Megumi Tatematsu","doi":"10.14800/ICS.1326","DOIUrl":"https://doi.org/10.14800/ICS.1326","url":null,"abstract":"Clathrin-dependent endocytic pathway is crucial for cell entry of extracellular pathogens and their components. The innate immune system utilizes this pathway to detect pathogen-associated molecular patterns (PAMPs) within endosomes. In the clathrin-mediated endocytosis, cargo selection depends on AP-2 adaptor and its accessory proteins, but the molecular mechanism of PAMP selection to be internalized is largely unknown. The endosomal Toll-like receptors (TLRs) 3, 7, 8, and 9 recognize viral or bacterial nucleic acids, as well as host-derived nucleic acids incorporated into the endosomal compartments, where type I interferon (IFN)-producing signals are arisen. In addition, lipopolysaccharide (LPS) receptor TLR4 transmits signals to produce IFN-b from endosomes after the clathrin-dependent endocytosis of LPS-TLR4. The cytosolic protein Raftlin that possesses membrane-anchoring motif mediates cellular uptake of TLR3/4 ligands in human cells through association with clathrin-AP-2 complex. Raftlin was first identified as a major raft protein in B cells that modulates B-cell or T-cell receptor-mediated signaling. In this review, we will focus on the Raftlin function in innate immunity and discuss the molecular mechanisms of cellular uptake and delivery of TLR ligands.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84288557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
After a fruitless pursuit for suppressor cells spanning 1970s to mid-80s, the identification of CD4 + CD25 + T cells as a specific T-cell lineage with immune regulatory function in the 1990s has revived the theory of active immune tolerance and uncovered a brand-new avenue for immunologic research. Tregs have been shown to play a crucial role both in health and diseases. Whilst tremendous advance has been made in our understanding of the expanding varieties of effector mechanisms exploited by Tregs, the migration phenotypes as well as the anatomic sites where Tregs exert immune regulation are scarcely investigated. Migration of Tregs to either the lymph nodes or peripheral tissues has been shown to be exclusively indispensable in Treg-mediated immune regulation in various experimental models with specific gene-targeted mice. The once seemingly paradoxical findings were partly reconciled by later discovery of various Treg subsets with distinct migration/homing property as well as the inflammatory stage when Tregs came into play along an immune reaction. In our recent study, we investigated the migration characteristics of Treg cells by using the endothelial cell-based shear-stress flow assay that resembles the intravascular blood flow system. We found that both FoxP3-expressing Tregs and anergic T cells generated by blockage of costimulation factors, CD80 and CD86, exhibited a significantly decreased adhesion to endothelial cells as compared to antigen-activated effector T cells (66~88 % reduction). The less migration phenotype hinted inefficient tissue trafficking of the Tregs and suggested the lymph nodes as the anatomic site where Tregs optimally exert immune regulation. To this speculation, an essential role of lymph node positioning of Tregs in exerting immune suppression was demonstrated by the inability of adoptively transferred Tregs to prevent footpad inflammation after CCR7 or CD62L blockage that hindered lymph node entry of these Tregs. Therapeutic modality tageting leukocyte migration has been a mainstay alternative for immunologic diseses. Important messages for treatments of this kind and Treg-base cell therapy are that whilst inflammatory response can be harnessed by modulating the migration property of individual T-cell subsets, the relationship between Treg migration phenotypes and immune regulatory function should always be taken into account.
{"title":"Location, Location, Location – Positioning Tregs to the right place at the right time","authors":"Miao‐Tzu Huang, Yi‐Lien Chen, B. Chiang","doi":"10.14800/ICS.1267","DOIUrl":"https://doi.org/10.14800/ICS.1267","url":null,"abstract":"After a fruitless pursuit for suppressor cells spanning 1970s to mid-80s, the identification of CD4 + CD25 + T cells as a specific T-cell lineage with immune regulatory function in the 1990s has revived the theory of active immune tolerance and uncovered a brand-new avenue for immunologic research. Tregs have been shown to play a crucial role both in health and diseases. Whilst tremendous advance has been made in our understanding of the expanding varieties of effector mechanisms exploited by Tregs, the migration phenotypes as well as the anatomic sites where Tregs exert immune regulation are scarcely investigated. Migration of Tregs to either the lymph nodes or peripheral tissues has been shown to be exclusively indispensable in Treg-mediated immune regulation in various experimental models with specific gene-targeted mice. The once seemingly paradoxical findings were partly reconciled by later discovery of various Treg subsets with distinct migration/homing property as well as the inflammatory stage when Tregs came into play along an immune reaction. In our recent study, we investigated the migration characteristics of Treg cells by using the endothelial cell-based shear-stress flow assay that resembles the intravascular blood flow system. We found that both FoxP3-expressing Tregs and anergic T cells generated by blockage of costimulation factors, CD80 and CD86, exhibited a significantly decreased adhesion to endothelial cells as compared to antigen-activated effector T cells (66~88 % reduction). The less migration phenotype hinted inefficient tissue trafficking of the Tregs and suggested the lymph nodes as the anatomic site where Tregs optimally exert immune regulation. To this speculation, an essential role of lymph node positioning of Tregs in exerting immune suppression was demonstrated by the inability of adoptively transferred Tregs to prevent footpad inflammation after CCR7 or CD62L blockage that hindered lymph node entry of these Tregs. Therapeutic modality tageting leukocyte migration has been a mainstay alternative for immunologic diseses. Important messages for treatments of this kind and Treg-base cell therapy are that whilst inflammatory response can be harnessed by modulating the migration property of individual T-cell subsets, the relationship between Treg migration phenotypes and immune regulatory function should always be taken into account.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83146563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glioblastoma Multiforme (GBM, Astrocytoma grade-IV) is the most common primary malignant brain tumour in adults and unfortunately the most deadly. Patients with GBM exhibit a deficient anti-tumor immune response. Immunotherapy is rapidly becoming one of the pillars of anti-cancer therapy. GBM has not received similar clinical successes as of yet, a fact which may be attributed to its relative inaccessibility,its poor immunogenicity, or any of the many other immune mechanisms known to be inactivated in these tumor cells. Focused Ultrasound (FUS) is emerging as a promising treatment approach. The effects of FUS on the tissue are not merely thermal. Reported FUS-induced acoustic cavitation which carries both mechanical and molecular implications as well as FUS induced immunomodulation play important roles. This is a concise research highlights on a comprehensive report by the same group. We separately discuss the different pertinent immunosuppressive mechanisms harnessed by GBM and the immunomodulatory effects of FUS. The three modes of FUS action can all be assigned a molecular final common pathway of immunomodulation. Thermal ablation induced immune effects, microbubbles effects in disrupting the BBB and introducing antigens and drugs to the tumor milieu as well as FUS induced molecular effects are discussed. The effect of FUS on the pro-inflammatory cytokines secretion profile, the stress response, the intra-tumoral immune-cellspopulations, dendritic cells activitymoderation and FUS induced increased cytotoxic cells potency are all discussed. A conceptual synopsis of the synergistic treatment of GBM utilizing FUS and immunotherapy is presented. The interaction of multiple approaches harnessing immune-components and circumventing immunosuppressing mechanisms may herald a new era in the fight against GBM.
{"title":"Can High Intensity Focused Ultrasound Facilitate Immunomodulation in Glioblastoma Multiforme","authors":"O. Cohen-Inbar","doi":"10.14800/ICS.1228","DOIUrl":"https://doi.org/10.14800/ICS.1228","url":null,"abstract":"Glioblastoma Multiforme (GBM, Astrocytoma grade-IV) is the most common primary malignant brain tumour in adults and unfortunately the most deadly. Patients with GBM exhibit a deficient anti-tumor immune response. Immunotherapy is rapidly becoming one of the pillars of anti-cancer therapy. GBM has not received similar clinical successes as of yet, a fact which may be attributed to its relative inaccessibility,its poor immunogenicity, or any of the many other immune mechanisms known to be inactivated in these tumor cells. Focused Ultrasound (FUS) is emerging as a promising treatment approach. The effects of FUS on the tissue are not merely thermal. Reported FUS-induced acoustic cavitation which carries both mechanical and molecular implications as well as FUS induced immunomodulation play important roles. This is a concise research highlights on a comprehensive report by the same group. We separately discuss the different pertinent immunosuppressive mechanisms harnessed by GBM and the immunomodulatory effects of FUS. The three modes of FUS action can all be assigned a molecular final common pathway of immunomodulation. Thermal ablation induced immune effects, microbubbles effects in disrupting the BBB and introducing antigens and drugs to the tumor milieu as well as FUS induced molecular effects are discussed. The effect of FUS on the pro-inflammatory cytokines secretion profile, the stress response, the intra-tumoral immune-cellspopulations, dendritic cells activitymoderation and FUS induced increased cytotoxic cells potency are all discussed. A conceptual synopsis of the synergistic treatment of GBM utilizing FUS and immunotherapy is presented. The interaction of multiple approaches harnessing immune-components and circumventing immunosuppressing mechanisms may herald a new era in the fight against GBM.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78820979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cardiac transplantation (CTx) has improved survival in patients with advanced heart failure. Unfortunately, the conditional survival remains less than 15 years. The primary cause of mortality at 5 years following a CTx is the development of accelerated coronary atherosclerosis named coronary allograft vasculopathy (CAV). The neutrophils likely play an important role in this diffuse inflammatory process. Nevertheless, the contribution of the neutrophils on the pathogenesis of CAV is poorly understood. Regardless of their essential contribution for the prevention of graft rejection, immunosuppressive drugs (IDs) may have detrimental effects via some pro-inflammatory activities. This review presents the role of neutrophils on vascular inflammation and on the biologic effects of diverse immunosuppressive agents including mTOR inhibitors in the context of the pathophysiology of CAV. We investigated the impact of different IDs on the inflammatory responses of isolated human neutrophils harvested from healthy controls and herein, we reported on some novel characteristics of everolimus (EVE) on isolated neutrophils in comparison with other immunosuppressive agents. These biologic effects may contribute to their beneficial effects on the allograft vasculature and consequently on the prevention of CAV.
{"title":"Effects of immunosuppressive agents on neutrophils inflammatory response in humans: an inflammatory perspective on coronary allograft vasculopathy","authors":"M. White","doi":"10.14800/ICS.1181","DOIUrl":"https://doi.org/10.14800/ICS.1181","url":null,"abstract":"Cardiac transplantation (CTx) has improved survival in patients with advanced heart failure. Unfortunately, the conditional survival remains less than 15 years. The primary cause of mortality at 5 years following a CTx is the development of accelerated coronary atherosclerosis named coronary allograft vasculopathy (CAV). The neutrophils likely play an important role in this diffuse inflammatory process. Nevertheless, the contribution of the neutrophils on the pathogenesis of CAV is poorly understood. Regardless of their essential contribution for the prevention of graft rejection, immunosuppressive drugs (IDs) may have detrimental effects via some pro-inflammatory activities. This review presents the role of neutrophils on vascular inflammation and on the biologic effects of diverse immunosuppressive agents including mTOR inhibitors in the context of the pathophysiology of CAV. We investigated the impact of different IDs on the inflammatory responses of isolated human neutrophils harvested from healthy controls and herein, we reported on some novel characteristics of everolimus (EVE) on isolated neutrophils in comparison with other immunosuppressive agents. These biologic effects may contribute to their beneficial effects on the allograft vasculature and consequently on the prevention of CAV.","PeriodicalId":13679,"journal":{"name":"Inflammation and cell signaling","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75032935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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