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1
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Pantarelli C, Welch HCE. Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment. Eur J Clin Invest 2018; 48 Suppl 2:e12939. [PMID: 29682742 PMCID: PMC6321979 DOI: 10.1111/eci.12939] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/17/2018] [Indexed: 12/15/2022]
Abstract
Rac-GTPases and their Rac-GEF activators play important roles in the recruitment and host defence functions of neutrophils. These proteins control the activation of adhesion molecules and the cytoskeletal dynamics that enable the adhesion, migration and tissue recruitment of neutrophils. They also regulate the effector functions that allow neutrophils to kill bacterial and fungal pathogens, and to clear debris. This review focuses on the roles of Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment.
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2
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Hepatic Rac1 GTPase contributes to liver-mediated basal immune homeostasis and LPS-induced endotoxemia. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2018; 1865:1277-1292. [DOI: 10.1016/j.bbamcr.2018.06.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 05/30/2018] [Accepted: 06/17/2018] [Indexed: 12/16/2022]
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3
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Kragstrup TW, Andersen MN, Schiøttz-Christensen B, Jurik AG, Hvid M, Deleuran B. Increased interleukin (IL)-20 and IL-24 target osteoblasts and synovial monocytes in spondyloarthritis. Clin Exp Immunol 2017; 189:342-351. [PMID: 28369789 DOI: 10.1111/cei.12973] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2017] [Indexed: 12/12/2022] Open
Abstract
The pathogenesis of spondyloarthritis (SpA) involves activation of the innate immune system, inflammation and new bone formation. The two cytokines interleukin (IL)-20 and IL-24 have been shown to link innate immune activation and tissue homeostasis. We hypothesized that these two cytokines are secreted as part of activation of the innate immune system and affect bone homeostasis in SpA. IL-20 and IL-24 were measured in plasma from axial SpA patients (n = 83). Peripheral SpA patients (n = 16) were included for in-vitro cell culture studies. The plasma IL-20 and IL-24 levels were increased in SpA patients compared with healthy controls (HCs) by 57 and 83%, respectively (both P < 0·0001). The Toll-like receptor 4-induced secretion of the two cytokines was greater in SpA peripheral blood mononuclear cells (PBMCs) compared with HC PBMCs. IL-20 and IL-24 increased the production of monocyte chemoattractant protein-1 by activated SpA synovial fluid monocytes, decreased the production of Dickkopf-1 by SpA fibroblast-like synovial cells and induced mineralization in human osteoblasts. Taken together, our findings indicate disease-aggravating functions of IL-20 and IL-24 in SpA.
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Affiliation(s)
- T W Kragstrup
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.,Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
| | - M N Andersen
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - B Schiøttz-Christensen
- Spine Centre of Southern Denmark, Hospital Lillebaelt, Middelfart, Denmark.,Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark
| | - A G Jurik
- Department of Radiology, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - M Hvid
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - B Deleuran
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.,Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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4
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Nosratababadi R, Bagheri V, Zare-Bidaki M, Hakimi H, Zainodini N, Kazemi Arababadi M. Toll like receptor 4: an important molecule in recognition and induction of appropriate immune responses against Chlamydia infection. Comp Immunol Microbiol Infect Dis 2017; 51:27-33. [PMID: 28504091 DOI: 10.1016/j.cimid.2017.03.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 02/06/2017] [Accepted: 03/12/2017] [Indexed: 01/09/2023]
Abstract
Chlamydia species are obligate intracellular pathogens causing different infectious diseases particularly asymptomatic genital infections and are also responsible for a wide range of complications. Previous studies showed that there are different immune responses to Chlamydia species and their infections are limited to some cases. Moreover, Chlamydia species are able to alter immune responses through modulating the expression of some immune system related molecules including cytokines. Toll like receptors (TLRs) belonge to pathogen recognition receptors (PRRs) and play vital roles in recognition of microbes and stimulation of appropriate immune responses. Therefore, it appears that TLRs may be considered as important sensors for recognition of Chlamydia and promotion of immune responses against these bacterial infections. Accordingly, TLR4 detects several microbial PAMPs such as bacterial lipopolysacharide (LPS) and subsequently activates transcription from pro-inflammatory cytokines in both MYD88 and TRIF pathways dependent manner. The purpose of this review is to provide the recent data about the status and major roles played by TLR4 in Chlamydia species recognition and promotion of immune responses against these infections and also the relationship between TLR4 activities and pathogenesis of Chlamydia infections.
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Affiliation(s)
- Reza Nosratababadi
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Vahid Bagheri
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Zare-Bidaki
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Microbiology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hamid Hakimi
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Microbiology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Nahid Zainodini
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Microbiology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Kazemi Arababadi
- Immunology of Infectious Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Immunology, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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5
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Small GTPases and their guanine-nucleotide exchange factors and GTPase-activating proteins in neutrophil recruitment. Curr Opin Hematol 2016; 23:44-54. [PMID: 26619317 DOI: 10.1097/moh.0000000000000199] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW The review describes the roles of Rho- and Rap-guanosine triphosphatases (GTPases) and of their activators, guanine-nucleotide exchange factors (GEFs), and inhibitors, GTPase activating proteins (GAPs), in neutrophil recruitment from the blood stream into inflamed tissues, with a focus on recently identified roles in neutrophils, endothelial cells, and platelets. RECENT FINDINGS Recent studies have identified important roles of Rho- and Rap-GTPases, and of their GEFs and GAPs, in the neutrophil recruitment cascade. These proteins control the upregulation and/or activation of adhesion molecules on the surface of neutrophils, endothelial cells, and platelets, and they alter cell/cell adhesion in the vascular endothelium. This enables the capture of neutrophils from the blood stream, their migration along and through the vessel wall, and their passage into the inflamed tissue. In particular, it has recently become clear that P-Rex and Vav family Rac-GEFs in platelets are crucial for neutrophil recruitment. SUMMARY These recent findings have contributed greatly to our understanding of the signalling pathways that control neutrophil recruitment to sites of inflammation and have opened up new avenues of research in this field.
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6
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Pietrosimone KM, Liu P. Contributions of neutrophils to the adaptive immune response in autoimmune disease. World J Transl Med 2015; 4:60-68. [PMID: 27042404 PMCID: PMC4816207 DOI: 10.5528/wjtm.v4.i3.60] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 10/01/2015] [Accepted: 11/25/2015] [Indexed: 02/05/2023] Open
Abstract
Neutrophils are granulocytic cytotoxic leukocytes of the innate immune system that activate during acute inflammation. Neutrophils can also persist beyond the acute phase of inflammation to impact the adaptive immune response during chronic inflammation. In the context of the autoimmune disease, neutrophils modulating T and B cell functions by producing cytokines and chemokines, forming neutrophil extracellular traps, and acting as or priming antigen presentation cells. Thus, neutrophils are actively involved in chronic inflammation and tissue damage in autoimmune disease. Using rheumatoid arthritis as an example, this review focuses on functions of neutrophils in adaptive immunity and the therapeutic potential of these cells in the treatment of autoimmune disease and chronic inflammation.
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7
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The Role of the Transcriptional Regulation of Stromal Cells in Chronic Inflammation. Biomolecules 2015; 5:2723-57. [PMID: 26501341 PMCID: PMC4693255 DOI: 10.3390/biom5042723] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Revised: 09/23/2015] [Accepted: 10/09/2015] [Indexed: 01/02/2023] Open
Abstract
Chronic inflammation is a common process connecting pathologies that vary in their etiology and pathogenesis such as cancer, autoimmune diseases, and infections. The response of the immune system to tissue damage involves a carefully choreographed series of cellular interactions between immune and non-immune cells. In recent years, it has become clear that stromal resident cells have an essential role perpetuating the inflammatory environment and dictating in many cases the outcome of inflammatory based pathologies. Signal transduction pathways remain the main focus of study to understand how stimuli contribute to perpetuating the inflammatory response, mainly due to their potential role as therapeutic targets. However, molecular events orchestrated in the nucleus by transcription factors add additional levels of complexity and may be equally important for understanding the phenotypic differences of activated stromal components during the chronic inflammatory process. In this review, we focus on the contribution of transcription factors to the selective regulation of inducible proinflammatory genes, with special attention given to the regulation of the stromal fibroblastic cell function and response.
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Franca RFO, Vieira SM, Talbot J, Peres RS, Pinto LG, Zamboni DS, Louzada-Junior P, Cunha FQ, Cunha TM. Expression and activity ofNOD1andNOD2/RIPK2signalling in mononuclear cells from patients with rheumatoid arthritis. Scand J Rheumatol 2015. [DOI: 10.3109/03009742.2015.1047403] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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9
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Kragstrup TW, Andersen T, Holm C, Schiøttz-Christensen B, Jurik AG, Hvid M, Deleuran B. Toll-like receptor 2 and 4 induced interleukin-19 dampens immune reactions and associates inversely with spondyloarthritis disease activity. Clin Exp Immunol 2015; 180:233-42. [PMID: 25639337 DOI: 10.1111/cei.12577] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2014] [Indexed: 12/27/2022] Open
Abstract
Spondyloarthritis (SpA) is a group of immune mediated inflammatory diseases affecting joints, gut, skin and entheses. The inflammatory process involves activation of Toll-like receptor (TLR)-2 and TLR-4 and production of cytokines and chemokines such as monocyte chemoattractant protein 1 (CCL2/MCP-1). This proinflammatory chemokine recruits monocytes to sites of inflammation and is central in the development of several immune-mediated inflammatory diseases. Interleukin (IL)-19 is a member of the IL-10 family of cytokines. IL-19-deficient mice are more susceptible to innate-mediated colitis and develop more severe inflammation in response to injury. In this work, we studied inducers of IL-19 production and effect of IL-19 on the production of CCL2/MCP-1 and proinflammatory cytokines in peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) and in PBMCs and synovial fluid mononuclear cells (SFMCs) from SpA patients. Further, we measured IL-19 in plasma from HCs and in plasma and synovial fluid from SpA patients. Constitutive IL-19 expression was present in both PBMCs and SFMCs and the secretion of IL-19 was increased by TLR-2 and TLR-4 ligands. Neutralizing IL-19 in HC PBMCs and SpA SFMCs resulted in increased production of CCL-2/MCP-1. IL-19 concentrations were decreased in synovial fluid compared with plasma and associated inversely with disease activity in SpA. SpA SFMCs produced less IL-19 in response to LPS compared with HC PBMCs. These findings indicate that IL-19 production is diminished in SpA. Taken together, impaired IL-19 control of the innate immune system might be involved in the pathogenesis of SpA.
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Affiliation(s)
- T W Kragstrup
- Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
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10
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Quintero CA, Tudela JG, Damiani MT. Rho GTPases as pathogen targets: Focus on curable sexually transmitted infections. Small GTPases 2015; 6:108-18. [PMID: 26023809 DOI: 10.4161/21541248.2014.991233] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Pathogens have evolved highly specialized mechanisms to infect hosts. Several microorganisms modulate the eukaryotic cell surface to facilitate their engulfment. Once internalized, they hijack the molecular machinery of the infected cell for their own benefit. At different stages of phagocytosis, particularly during invasion, certain pathogens manipulate pathways governed by small GTPases. In this review, we focus on the role of Rho proteins on curable, sexually transmitted infections caused by Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and Treponema pallidum. Despite the high, worldwide frequencies of these sexually-transmitted diseases, very little is known about the strategies developed by these microorganisms to usurp key eukaryotic proteins that control intracellular signaling and actin dynamics. Improved knowledge of these molecular mechanisms will contribute to the elucidation of how these clinically important pathogens manipulate intracellular processes and parasitize their hosts.
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Affiliation(s)
- Cristián A Quintero
- a Laboratory of Phagocytosis and Intracellular Trafficking; IHEM-CONICET; School of Medicine; University of Cuyo ; Mendoza , Argentina
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11
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Inman RD. Reactive arthritis. Rheumatology (Oxford) 2015. [DOI: 10.1016/b978-0-323-09138-1.00112-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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12
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P-Rex and Vav Rac-GEFs in platelets control leukocyte recruitment to sites of inflammation. Blood 2014; 125:1146-58. [PMID: 25538043 DOI: 10.1182/blood-2014-07-591040] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
The small GTPase Rac is required for neutrophil recruitment during inflammation, but its guanine-nucleotide exchange factor (GEF) activators seem dispensable for this process, which led us to investigate the possibility of cooperation between Rac-GEF families. Thioglycollate-induced neutrophil recruitment into the peritoneum was more severely impaired in P-Rex1(-/-) Vav1(-/-) (P1V1) or P-Rex1(-/-) Vav3(-/-) (P1V3) mice than in P-Rex null or Vav null mice, suggesting cooperation between P-Rex and Vav Rac-GEFs in this process. Neutrophil transmigration and airway infiltration were all but lost in P1V1 and P1V3 mice during lipopolysaccharide (LPS)-induced pulmonary inflammation, with altered intercellular adhesion molecule 1-dependent slow neutrophil rolling and strongly reduced L- and E-selectin-dependent adhesion in airway postcapillary venules. Analysis of adhesion molecule expression, neutrophil adhesion, spreading, and migration suggested that these defects were only partially neutrophil-intrinsic and were not obviously involving vascular endothelial cells. Instead, P1V1 and P1V3 platelets recapitulated the impairment of LPS-induced intravascular neutrophil adhesion and recruitment, showing P-Rex and Vav expression in platelets to be crucial. Similarly, during ovalbumin-induced allergic inflammation, pulmonary recruitment of P1V1 and P1V3 eosinophils, monocytes, and lymphocytes was compromised in a platelet-dependent manner, and airway inflammation was essentially abolished, resulting in improved airway responsiveness. Therefore, platelet P-Rex and Vav family Rac-GEFs play important proinflammatory roles in leukocyte recruitment.
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13
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Stavropoulos PG, Soura E, Kanelleas A, Katsambas A, Antoniou C. Reactive arthritis. J Eur Acad Dermatol Venereol 2014; 29:415-24. [PMID: 25199646 DOI: 10.1111/jdv.12741] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Accepted: 08/08/2014] [Indexed: 01/20/2023]
Abstract
Reactive arthritis (ReA) is an immune-mediated seronegative arthritis that belongs to the group of spondyloarthropathies and develops after a gastrointestinal or genitourinary system infection. The condition is considered to be characterized by a triad of symptoms (conjunctivitis, arthritis and urethritis) although a constellation of other manifestations may also be present. ReA is characterized by psoriasiform dermatological manifestations that may resemble those of pustular psoriasis and, similar to guttate psoriasis, is a post-infectious entity. Also, the articular manifestations of the disorder are similar to those of psoriatic arthritis and both conditions show a correlation with HLA-B27. These facts have led several authors to suggest that there is a connection between ReA and psoriasis, listing ReA among the disorders related to psoriasis. However, the pathogenetic mechanism behind the condition is complex and poorly understood. Bacterial antigenicity, the type of host response (i.e. Th1/Th2 imbalance) and various genetic factors (i.e. HLA-B27 etc.) play an important role in the development of the disorder. It is unknown whether all the aforementioned factors are part of a mechanism that could be similar to, or share basic aspects with known psoriasis pathogenesis mechanisms.
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Affiliation(s)
- P G Stavropoulos
- 1st Department of Dermatology/University Clinic, 'Andreas Syggros' Hospital, Athens, Greece
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14
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Shelef MA, Tauzin S, Huttenlocher A. Neutrophil migration: moving from zebrafish models to human autoimmunity. Immunol Rev 2013; 256:269-81. [PMID: 24117827 PMCID: PMC4117680 DOI: 10.1111/imr.12124] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
There has been a resurgence of interest in the neutrophil's role in autoimmune disease. Classically considered an early responder that dies at the site of inflammation, new findings using live imaging of embryonic zebrafish and other modalities suggest that neutrophils can reverse migrate away from sites of inflammation. These 'inflammation-sensitized' neutrophils, as well as the neutrophil extracellular traps and other products made by neutrophils in general, may have many implications for autoimmunity. Here, we review what is known about the role of neutrophils in three different autoimmune diseases: rheumatoid arthritis, systemic lupus erythematosus, and small vessel vasculitis. We then highlight recent findings related to several cytoskeletal regulators that guide neutrophil recruitment including Lyn, Rac2, and SHIP. Finally, we discuss how our improved understanding of the molecules that control neutrophil chemotaxis may impact our knowledge of autoimmunity.
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Affiliation(s)
- Miriam A. Shelef
- Division of Rheumatology, Department of Medicine, University of Wisconsin – Madison, Madison, WI
| | - Sebastien Tauzin
- Departments of Pediatrics and Medical Microbiology and Immunology, University of Wisconsin – Madison, Madison, WI
| | - Anna Huttenlocher
- Departments of Pediatrics and Medical Microbiology and Immunology, University of Wisconsin – Madison, Madison, WI
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15
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Reedquist KA, Tak PP. Signal transduction pathways in chronic inflammatory autoimmune disease: small GTPases. Open Rheumatol J 2012; 6:259-72. [PMID: 23028410 PMCID: PMC3460313 DOI: 10.2174/1874312901206010259] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Revised: 06/19/2012] [Accepted: 06/21/2012] [Indexed: 01/28/2023] Open
Abstract
Ras superfamily small GTPases represent a wide and diverse class of intracellular signaling proteins that are highly conserved during evolution. These enzymes serve as key checkpoints in coupling antigen receptor, growth factor, cytokine and chemokine stimulation to cellular responses. Once activated, via their ability to regulate multiple downstream signaling pathways, small GTPases amplify and diversify signaling cascades which regulate cellular proliferation, survival, cytokine expression, trafficking and retention. Small GTPases, particularly members of the Ras, Rap, and Rho family, critically coordinate the function and interplay of immune and stromal cells during inflammatory respones, and increasing evidence indicates that alterations in small GTPase signaling contribute to the pathological behavior of these cell populations in human chronic inflammatory diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Here, we review how Ras, Rap, and Rho family GTPases contribute to the biology of cell populations relevant to human chronic inflammatory disease, highlight recent advances in understanding how alterations in these pathways contribute to pathology in RA and SLE, and discuss new therapeutic strategies that may allow specific targeting of small GTPases in the clinic.
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Affiliation(s)
- Kris A Reedquist
- Division of Clinical Immunology and Rheumatology, Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, The Netherlands
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16
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Yokota K, Miyazaki T, Hemmatazad H, Gay RE, Kolling C, Fearon U, Suzuki H, Mimura T, Gay S, Ospelt C. The pattern-recognition receptor nucleotide-binding oligomerization domain-containing protein 1 promotes production of inflammatory mediators in rheumatoid arthritis synovial fibroblasts. ACTA ACUST UNITED AC 2012; 64:1329-37. [DOI: 10.1002/art.34318] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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17
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Rizzo A, Domenico MD, Carratelli CR, Paolillo R. The role of Chlamydia and Chlamydophila infections in reactive arthritis. Intern Med 2012; 51:113-7. [PMID: 22214635 DOI: 10.2169/internalmedicine.51.6228] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Chlamydia trachomatis and Chlamydophila pneumoniae are human pathogens; the former being the etiologic agent for trachoma as well as a prevalent sexually transmitted bacterium, while C. pneumoniae is a respiratory pathogen responsible for community-acquired pneumonia. Patients with reactive arthritis show evidence of present or past Chlamydial infection. Chlamydia spp., has been strongly implicated as a triggering factor for reactive arthritis. We describe the simultaneous occurrence of C. pneumoniae and C. trachomatis infections in a subject with reactive arthritis. We suggest treatment for a patient with Chlamydia-associated arthritis to define a means by which persistent organisms can be induced to return to the active developmental cycle, thereby making them more accessible to antibiotic activity.
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Affiliation(s)
- Antonietta Rizzo
- Department of Experimental Medicine, Section of Microbiology and Clinical Microbiology, Faculty of Medicine and Surgery-Second University of Naples, Italy.
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18
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Abstract
Reactive arthritis (ReA), an inflammatory arthritic condition that is commonly associated with Chlamydia infections, represents a significant health burden, yet is poorly understood. The enigma of this disease is reflected in its problematic name and in its ill-defined pathogenesis. The existence of persistent pathogens in the arthritic joint is acknowledged, but their relevance remains elusive. Progress is being made in understanding the underlying mechanisms of ReA, whereby an imbalance between type 1 and type 2 immune responses seems to be critical in determining susceptibility to disease. Such an imbalance occurs prior to the initiation of an adaptive immune response, suggesting that innate cellular and molecular mechanisms in ReA should be prioritized as fruitful areas for investigation.
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Lawson CD, Donald S, Anderson KE, Patton DT, Welch HCE. P-Rex1 and Vav1 cooperate in the regulation of formyl-methionyl-leucyl-phenylalanine-dependent neutrophil responses. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2011; 186:1467-76. [PMID: 21178006 DOI: 10.4049/jimmunol.1002738] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
G protein-coupled receptor (GPCR) activation elicits neutrophil responses such as chemotaxis and reactive oxygen species (ROS) formation, which depend on the small G protein Rac and are essential for host defense. P-Rex and Vav are two families of guanine-nucleotide exchange factors (GEFs) for Rac, which are activated through distinct mechanisms but can both control GPCR-dependent neutrophil responses. It is currently unknown whether they play specific roles or whether they can compensate for each other in controlling these responses. In this study, we have assessed the function of neutrophils from mice deficient in P-Rex and/or Vav family GEFs. We found that both the P-Rex and the Vav family are important for LPS priming of ROS formation, whereas particle-induced ROS responses and cell spreading are controlled by the Vav family alone. Surprisingly, fMLF-stimulated ROS formation, adhesion, and chemotaxis were synergistically controlled by P-Rex1 and Vav1. These responses were more severely impaired in neutrophils lacking both P-Rex1 and Vav1 than those lacking the entire P-Rex family, the entire Vav family, or both P-Rex1 and Vav3. P-Rex1/Vav1 (P1V1) double-deficient cells also showed the strongest reduction in fMLF-stimulated activation of Rac1 and Rac2. This reduction in Rac activity may be sufficient to cause the defects observed in fMLF-stimulated P1V1 neutrophil responses. Additionally, Mac-1 surface expression was reduced in P1V1 cells, which might contribute further to defects in responses involving integrins, such as GPCR-stimulated adhesion and chemotaxis. We conclude that P-Rex1 and Vav1 together are the major fMLFR-dependent Dbl family Rac-GEFs in neutrophils and cooperate in the control of fMLF-stimulated neutrophil responses.
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Affiliation(s)
- Campbell D Lawson
- Inositide Laboratory, Babraham Research Campus, Babraham Institute, Cambridge CB22 3AT, United Kingdom
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EVANS DAVIDM, REVEILLE JOHND, BROWN MATTHEWA, CHANDRAN VINOD, GLADMAN DAFNAD, MARTIN TAMMYM, McGOVERN DERMOT, WORDSWORTH PAUL, INMAN ROBERTD. The Genetic Basis of Spondyloarthritis: SPARTAN/IGAS 2009. J Rheumatol 2010; 37:2626-31. [DOI: 10.3899/jrheum.100892] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
A joint meeting was held in July 2009 in Houston, Texas, of members of the Spondyloarthritis Research and Therapy Network (SPARTAN), founded in 2003 to promote research, education, and treatment of ankylosing spondylitis (AS) and related forms of spondyloarthritis (SpA), and members of International Genetics of AS (IGAS), founded in 2003 to encourage and coordinate studies internationally in the genetics of AS. The general topic was the genetic basis of SpA, with presentations on the future of human genetic studies; microbes, SpA, and innate immunity; susceptibility of AS to the major histocompatibility complex (MHC) and non-MHC; and individual discussions of the genetics of psoriasis and psoriatic arthritis, uveitis, inflammatory bowel disease, and enteropathic arthritis. Summaries of those discussions are presented.
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Detection of Chlamydophila pneumoniae in patients with arthritis: significance and diagnostic value. Rheumatol Int 2010; 31:1307-13. [PMID: 20383512 DOI: 10.1007/s00296-010-1460-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2009] [Accepted: 03/12/2010] [Indexed: 10/19/2022]
Abstract
The aim of this study was to assess the potential clinical implications of Chlamydophila pneumoniae in patients with acute and chronic arthritic diseases and to investigate whether blood monocytes might reflect a concomitant synovial or persistent systemic infection. C. pneumoniae was investigated with advanced PCR and reverse transcriptase (RT) PCR techniques targeting different genes and combined with cell line cultures, in synovial fluid (SF) and peripheral blood mononuclear cell (PBMC) specimens collected from 28 patients with arthritis. Five out of twenty-eight patients (17.8%) were found to have C. pneumoniae DNA in either SF or PBMC specimens. Their diagnosis was reactive arthritis (ReA), S.A.P.H.O syndrome, psoriatic arthritis, undifferentiated oligoarthritis (UOA) and ankylosing spondylitis (AS). Specimens from patients with UOA and AS had also mRNA transcripts but those from AS yielded C. pneumoniae growth after co-culture. Moreover, C. pneumoniae DNA levels measured by Real-Time PCR (LightCycler) were higher in PBMC specimens compared to those found in SF at the end of antibiotic treatment. C. pneumoniae may have a role as triggering factor also in chronic arthritides including AS. The combined use of culture and molecular tools increases detection rates and improves the overall sensitivity, suggesting their potential use to detect C. pneumoniae. The different kinetics of bacterial DNA at both peripheral and synovial levels should be taken into consideration when monitoring and evaluating the effectiveness of antibiotic treatment.
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Abreu JR, Dontje W, Krausz S, de Launay D, van Hennik PB, van Stalborch AM, Ten Klooster JP, Sanders ME, Reedquist KA, Vervoordeldonk MJ, Hordijk PL, Tak PP. A Rac1 inhibitory peptide suppresses antibody production and paw swelling in the murine collagen-induced arthritis model of rheumatoid arthritis. Arthritis Res Ther 2010; 12:R2. [PMID: 20053277 PMCID: PMC2875627 DOI: 10.1186/ar2900] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2009] [Revised: 11/13/2009] [Accepted: 01/06/2010] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION The Rho family GTPase Rac1 regulates cytoskeletal rearrangements crucial for the recruitment, extravasation and activation of leukocytes at sites of inflammation. Rac1 signaling also promotes the activation and survival of lymphocytes and osteoclasts. Therefore, we assessed the ability of a cell-permeable Rac1 carboxy-terminal inhibitory peptide to modulate disease in mice with collagen-induced arthritis (CIA). METHODS CIA was induced in DBA/1 mice, and in either early or chronic disease, mice were treated three times per week by intraperitoneal injection with control peptide or Rac1 inhibitory peptide. Effects on disease progression were assessed by measurement of paw swelling. Inflammation and joint destruction were examined by histology and radiology. Serum levels of anti-collagen type II antibodies were measured by enzyme-linked immunosorbent assay. T-cell phenotypes and activation were assessed by fluorescence-activated cell sorting analysis. Results were analyzed using Mann-Whitney U and unpaired Student t tests. RESULTS Treatment of mice with Rac1 inhibitory peptide resulted in a decrease in paw swelling in early disease and to a lesser extent in more chronic arthritis. Of interest, while joint destruction was unaffected by Rac1 inhibitory peptide, anti-collagen type II antibody production was significantly diminished in treated mice, in both early and chronic arthritis. Ex vivo, Rac1 inhibitory peptide suppressed T-cell receptor/CD28-dependent production of tumor necrosis factor alpha, interferon gamma and interleukin-17 by T cells from collagen-primed mice, and reduced induction of ICOS and CD154, T-cell costimulatory proteins important for B-cell help. CONCLUSIONS The data suggest that targeting of Rac1 with the Rac1 carboxy-terminal inhibitory peptide may suppress T-cell activation and autoantibody production in autoimmune disease. Whether this could translate into clinically meaningful improvement remains to be shown.
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Affiliation(s)
- Joana Rf Abreu
- Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands.
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Carter JD, Hudson AP. Reactive arthritis: clinical aspects and medical management. Rheum Dis Clin North Am 2009; 35:21-44. [PMID: 19480995 DOI: 10.1016/j.rdc.2009.03.010] [Citation(s) in RCA: 123] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Reactive arthritis (ReA) is an inflammatory arthritis that arises after certain gastrointestinal or genitourinary infections, representing a classic interplay between host and environment. It belongs to the group of arthritidies known as the spondyloarthropathies. The classic syndrome is a triad of symptoms, including the urethra, conjunctiva, and synovium; however, the majority of patients do not present with this triad. Diagnostic criteria for ReA exist, but data suggest new criteria are needed. Epidemiologic and prospective studies have been difficult to perform because of over-reliance on the complete classic triad of symptoms and the different terms and eponyms used. Studies assessing various treatment strategies are ongoing.
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Affiliation(s)
- John D Carter
- Department of Internal Medicine, Division of Rheumatology, University of South Florida, 12901 Bruce B. Downs Boulevard, MDC 81, Tampa, FL 33612, USA.
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25
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Bharhani MS, Chiu B, Na KS, Inman RD. Activation of invariant NKT cells confers protection against Chlamydia trachomatis-induced arthritis. Int Immunol 2009; 21:859-70. [DOI: 10.1093/intimm/dxp052] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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26
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Inman RD. Innate Immunity of Spondyloarthritis: The Role of Toll-Like Receptors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2009; 649:300-9. [DOI: 10.1007/978-1-4419-0298-6_23] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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27
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Abdollahi-Roodsaz S, Joosten LAB, Helsen MM, Walgreen B, van Lent PL, van den Bersselaar LA, Koenders MI, van den Berg WB. Shift from toll-like receptor 2 (TLR-2) toward TLR-4 dependency in the erosive stage of chronic streptococcal cell wall arthritis coincident with TLR-4-mediated interleukin-17 production. ACTA ACUST UNITED AC 2008; 58:3753-64. [DOI: 10.1002/art.24127] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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28
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Schäppi MG, Jaquet V, Belli DC, Krause KH. Hyperinflammation in chronic granulomatous disease and anti-inflammatory role of the phagocyte NADPH oxidase. Semin Immunopathol 2008; 30:255-71. [PMID: 18509648 DOI: 10.1007/s00281-008-0119-2] [Citation(s) in RCA: 122] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2008] [Accepted: 04/15/2008] [Indexed: 10/22/2022]
Abstract
Chronic granulomatous disease (CGD) is an immunodeficiency caused by the lack of the superoxide-producing phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. However, CGD patients not only suffer from recurrent infections, but also present with inflammatory, non-infectious conditions. Among the latter, granulomas figure prominently, which gave the name to the disease, and colitis, which is frequent and leads to a substantial morbidity. In this paper, we systematically review the inflammatory lesions in different organs of CGD patients and compare them to observations in CGD mouse models. In addition to the more classical inflammatory lesions, CGD patients and their relatives have increased frequency of autoimmune diseases, and CGD mice are arthritis-prone. Possible mechanisms involved in CGD hyperinflammation include decreased degradation of phagocytosed material, redox-dependent termination of proinflammatory mediators and/or signaling, as well as redox-dependent cross-talk between phagocytes and lymphocytes (e.g. defective tryptophan catabolism). As a conclusion from this review, we propose the existence of ROS high and ROS low inflammatory responses, which are triggered as a function of the level of reactive oxygen species and have specific characteristics in terms of physiology and pathophysiology.
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Affiliation(s)
- Michela G Schäppi
- Gastroenterology and Hepatology Unit, Department of Paediatrics, University Hospitals of Geneva, Geneva 4, Switzerland.
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29
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Leech M, Xue JR, Dacumos A, Hall P, Santos L, Yang Y, Li M, Kitching AR, Morand EF. The tumour suppressor gene p53 modulates the severity of antigen-induced arthritis and the systemic immune response. Clin Exp Immunol 2008; 152:345-53. [PMID: 18341615 PMCID: PMC2384110 DOI: 10.1111/j.1365-2249.2008.03629.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/05/2008] [Indexed: 11/30/2022] Open
Abstract
p53 is a transcription factor with a well-described role in the induction of apoptosis and cell cycle arrest as part of a protective response to a variety of stressful stimuli. Expansion of inflamed tissue in rheumatoid arthritis has been related to the loss of functioning p53, and the severity of collagen-induced arthritis is increased in p53-/- mice. Our objective was to assess the role of p53 in a model of adaptive immunity, antigen-induced arthritis (AIA). AIA was induced in p53-/- and wild-type mice by priming with methylated bovine serum albumin followed by intra-articular challenge. Severity of arthritis was assessed using a standardized scoring system and synovial apoptosis was detected by TdT-mediated biotin-dUTP nick-end labelling. Splenocyte proliferation was measured by [H(3)] incorporation and interferon (IFN)-gamma release. Splenocyte viability was assessed using Titreglow. Splenic T cell activation status was assessed by flow cytometry. Serum cytokines were measured using enzyme-linked immunosorbent assay. Increased severity of AIA in p53-/- mice was associated with decreased synovial apoptosis and with increased delayed-type hypersensitivity response, increased mitogen and antigen-induced splenocyte proliferation and increased IFN-gamma release in p53-/- mice compared with wild-type mice. Antigen-specific immunoglobulin responses were equivalent in both groups. Splenocyte viability was increased in p53-/- mice but T cell apoptosis was equivalent. T cell activation markers were increased in p53-/- mice compared with wild-type mice. Lipopolysaccharide-induced tumour necrosis factor release was increased in p53-/- mice with a trend to increased interleukin-6 in p53-/- mice compared with littermates. p53 is involved in the modulation of adaptive and innate immune responses relevant to arthritis models and is also involved in the modulation of severity of AIA by both cell-cycle dependent and cell-cycle-independent mechanisms.
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MESH Headings
- Animals
- Apoptosis/genetics
- Apoptosis/immunology
- Arthritis, Experimental/genetics
- Arthritis, Experimental/immunology
- Arthritis, Rheumatoid/genetics
- Arthritis, Rheumatoid/immunology
- CD4-Positive T-Lymphocytes/immunology
- Disease Models, Animal
- Genes, p53/immunology
- Hypersensitivity, Delayed/genetics
- Hypersensitivity, Delayed/immunology
- Immunoglobulin G/biosynthesis
- Interferon-gamma/biosynthesis
- Lipopolysaccharides/immunology
- Lymphocyte Activation/genetics
- Lymphocyte Activation/immunology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Phytohemagglutinins/immunology
- Serum Albumin, Bovine/immunology
- Severity of Illness Index
- Spleen/immunology
- T-Lymphocytes/immunology
- Tumor Suppressor Protein p53/immunology
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Affiliation(s)
- M Leech
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Melbourne, Australia.
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30
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Cantaert T, Stone MA, ter Borg M, Mogg R, De Vries N, Wilson AG, Tak PP, Baeten D. A functional polymorphism of TIR-domain-containing adaptor protein is not associated with axial spondyloarthritis. Ann Rheum Dis 2008; 67:720-2. [PMID: 18073264 DOI: 10.1136/ard.2007.082784] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVE A genetic variant of the toll-like receptor (TLR)2/4 adaptor protein TIRAP (single nucleotide polymorphism (SNP) C539T) was identified in a UK and in several African populations. The heterozygous genotype of this SNP has been associated with protection from severe infections. This allele results in an attenuated response to bacterial pathogens. As an exaggerated innate immune response to pathogens has been implicated in spondyloarthritis (SpA) pathogenesis, we analysed if the heterozygous C/T genotype was underrepresented in axial SpA compared with healthy controls. METHODS 204 patients with axial SpA and 175 population-matched controls were included. SNP C539T was determined with a sequence-specific polymerase chain reaction and direct sequencing. RESULTS The frequency of the haplotypes was similar in cases and controls (87% for C and 13% for T in both groups). The C/T genotype, which attenuates TLR signalling, was not underrepresented in cases versus controls (19% in controls vs 24% in cases, p = 0.44). The T/T genotype, was slightly lower in cases than in controls, although this was not significant (3.4% in controls vs 1% in cases, p = 0.15). Within the cases, there were no differences in disease phenotype or activity between patients with the C/C or C/T genotype. CONCLUSIONS This study did not show significant associations of SNP S180L of the TLR2/4 adaptor protein TIRAP with axial SpA.
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Affiliation(s)
- T Cantaert
- Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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31
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Abstract
The course of every infection is different. The same pathogen can lead to subclinical, mild, severe or lethal infections in individuals. But is this just chance or determined by individual differences--on the side of the host as well as on the side of the pathogen? If so, we might need to consider these variations for treatment decisions. Indeed, we now understand that genetic polymorphisms and health status represent inborn and acquired risk factors. Similarly, pathogens impress with an increasing number of already identified virulence factors and host response modifiers. The emerging, more complex, view of the factors determining course and outcome of infections promises to enable more tailored and thus, hopefully, more effective treatment decisions.
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Affiliation(s)
- Corinna Hermann
- Biochemical Pharmacology, University of Konstanz, Konstanz, Germany.
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32
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Song J, Bishop BL, Li G, Duncan MJ, Abraham SN. TLR4-initiated and cAMP-mediated abrogation of bacterial invasion of the bladder. Cell Host Microbe 2007; 1:287-98. [PMID: 17710226 PMCID: PMC1950120 DOI: 10.1016/j.chom.2007.05.007] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The remarkable resistance of the urinary tract to infection has been attributed to its physical properties and the innate immune responses triggered by pattern recognition receptors lining the tract. We report a distinct TLR4 mediated mechanism in bladder epithelial cells (BECs) that abrogates bacterial invasion, a necessary step for successful infection. Compared to controls, uropathogenic type 1 fimbriated Escherichia coli and Klebsiella pneumoniae invaded BECs of TLR4 mutant mice in 10-fold or greater numbers. TLR4 mediated suppression of bacterial invasion was linked to increased intracellular cAMP levels which negatively impacted Rac-1 mediated mobilization of the cytoskeleton. Artificially increasing intracellular cAMP levels in BECs of TLR4 mutant mice restored resistance to type 1 fimbriated bacterial invasion. This finding reveals a novel function for TLR4 and another facet of bladder innate defense.
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Affiliation(s)
- Jeongmin Song
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
| | - Brian L. Bishop
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
| | - Guojie Li
- Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
| | - Matthew J. Duncan
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
| | - Soman N. Abraham
- Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA
- Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
- Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA
- *Corresponding author, Mailing address; Department of Pathology, Duke University Medical Center, Campus Box 3020, Durham, NC 27710, USA; Phone: 919-684-6942; Fax: 919-684-2021; E-Mail:
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33
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Analysis of single nucleotide polymorphisms in Toll-like receptor 4 shows no association with ankylosing spondylitis in a Korean population. Rheumatol Int 2007; 28:627-30. [DOI: 10.1007/s00296-007-0490-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2007] [Accepted: 11/06/2007] [Indexed: 10/22/2022]
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Azim AC, Cao H, Gao X, Joo M, Malik AB, van Breemen RB, Sadikot RT, Park G, Christman JW. Regulation of cyclooxygenase-2 expression by small GTPase Rac2 in bone marrow macrophages. Am J Physiol Lung Cell Mol Physiol 2007; 293:L668-73. [PMID: 17575012 DOI: 10.1152/ajplung.00043.2007] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Cyclooxygenase 2 (COX-2) is induced by microbial products, proinflammatory cytokines, growth factors, and oncogenes. The Rho family includes RhoA, Rac1, Rac2, Rac3, and Cdc42 and is involved in regulation of the actin cytoskeleton organization, cell growth, vesicular cell trafficking, and transcriptional regulation. Rac2 binds to NADPH oxidase protein complex, and Rac2 null neutrophils are known to have poor phagocytic activity. We examined whether Rac2, the predominant small GTPase in hematopoietic cells, influences COX-2 expression in bone marrow-derived macrophages (BMDM). We showed that BMDM from Rac2(-/-) null mice have reduced COX-2 expression in response to treatment with endotoxin. Despite a compensatory increase in Rac1, BMDM from Rac2(-/-) null mice have less biologically active GTP-bound Rac in response to LPS stimulation. Signaling molecules (downstream of Rac2 and Toll-like receptor 4) such as p42/44, p38, and pAKT were also affected in BMDM from Rac2(-/-) null mouse macrophages. We also observed that BMDM from Rac2(-/-) null failed to degrade IkappaBalpha significantly and had less immunoreactive PU.1. We show that both NF-kappaB pathway and PU.1 are involved in normal macrophage function and play a role in macrophage COX-2 expression. In summary, these data indicate that Rac2 regulates COX-2 expression in BMDM.
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Affiliation(s)
- Anser C Azim
- Department of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois, Chicago, IL 60612, USA
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35
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Carter JD. Reactive arthritis: defined etiologies, emerging pathophysiology, and unresolved treatment. Infect Dis Clin North Am 2007; 20:827-47. [PMID: 17118292 DOI: 10.1016/j.idc.2006.09.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
ReA is unique in that it is one of the few disease states of which there is a known trigger. This insight into disease initiation has led to great advances in the pathophysiology. Despite this detailed knowledge, the proper treatment remains elusive. In the years to come it is possible that the specific treatment will be dictated by the triggering microbe.
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Affiliation(s)
- John D Carter
- Division of Rheumatology, University of South Florida, 12901 Bruce B. Downs Boulevard, MDC 81, Tampa, FL 33612, USA.
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36
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Düzgün N, Duman T, Haydardedeoğlu FE, Tutkak H. The lack of genetic association of the Toll-like receptor 2 (TLR2) Arg753Gln and Arg677Trp polymorphisms with rheumatic heart disease. Clin Rheumatol 2006; 26:915-9. [PMID: 17096074 DOI: 10.1007/s10067-006-0432-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2006] [Revised: 08/28/2006] [Accepted: 08/31/2006] [Indexed: 10/23/2022]
Abstract
UNLABELLED Acute rheumatic fever (ARF) is a non-suppurative inflammatory disease after group A, beta haemolytic streptococcal pharyngitis. Certain individuals can develop ARF. This finding implies variability in host predisposition to ARF. A variety of studies have linked specific genetic markers with ARF or rheumatic heart disease (RHD) as a sequelae of ARF. For this purpose, we aimed to search the role of polymorphisms in Toll-like receptor-2 and -4 (TLR2 and TLR4) gene in Turkish patients with RHD. This study included a total 84 patients with RHD, ages ranging between 18 and 65, 25 male and 59 female, fulfilling the revised classification criteria of Jones. One hundred forty healthy unrelated persons were selected as a control group. Genotype analysis: DNA was extracted from whole blood. TLR4 gene (Asp 299Gly and Thr399Ile) and TLR2 gene (Arg753Gln and Arg677Trp) polymorphisms were genotyped by the previously reported method. STATISTICAL ANALYSIS binary logistic regression models were used. Results were expressed as odds ratios (OR) with corresponding 95% confidence intervals (95% CI). Significant level was predefined at 0.05. There was a significant difference for carrying Ile allele in the 399 position in the patients compared to healthy controls (OR = 5.26, 95% CI, 1.40-19.73, p = 0.014). In the TLR4 gene, Asp 299Gly polymorphism did not reach to a statistically significant value (OR = 3.02). We found no Arg753Gln polymorphism of the TLR2 gene in the patient group. There were three heterozygote samples in the healthy group. We did not detect Arg677Trp polymorphism of the TLR2 gene in both patient and control groups.
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Affiliation(s)
- Nurşen Düzgün
- Department of Clinical Immunology and Rheumatology, Ankara University School of Medicine, Ankara, Turkey.
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37
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Ruse M, Knaus UG. New players in TLR-mediated innate immunity: PI3K and small Rho GTPases. Immunol Res 2006; 34:33-48. [PMID: 16720897 DOI: 10.1385/ir:34:1:33] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/1999] [Revised: 11/30/1999] [Accepted: 11/30/1999] [Indexed: 12/12/2022]
Abstract
Toll-like receptors (TLRs) play a crucial role in the innate immune system as a first line of defense against pathogens. TLR activation in phagocytes produces pro-inflammatory cytokines and chemokines that contribute directly to elimination of infectious agents and activation of adaptive immune responses. However, a sustained inflammatory response can result in tissue damage and generalized sepsis. This review summarizes the complex and sometimes conflicting links of TLR signaling with two important regulators of immune cells functions: phosphoinositide 3-kinases (PI3Ks) and small GTPases of the Rho family. A unified model of hierarchical organization of these signaling participants is still premature, given that the tools for delineating how control of TLRmediated pathways is achieved are just emerging. Critical progress in our understanding of spatial-temporal propagation of TLR signaling will certainly be provided in the near future by pharmacological targeting of PI3Ks using recently characterized, second-generation PI3K inhibitors in combination with gene-targeting strategies for PI3K subunits and Rho GTPases targeted to the murine myeloid compartment.
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Affiliation(s)
- Monica Ruse
- Department of Immunology, The Scripps Research Institute La Jolla, California.
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38
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Abstract
In spondyloarthritis, in particular ankylosing spondylitis (AS), a need exists for clinically meaningful biomarkers, both for diagnosis and prognosis. Earlier diagnosis has become an imperative since the advent of biologic therapy, which has proved effective in controlling axial inflammation. Presently, however, there are no biomarkers that reliably distinguish inflammatory back pain from the far more prevalent mechanical back pain. The target sites in AS--sacroiliac joints and the spine--are relatively inaccessible to the investigator and clinician, so defining markers associated with or predictive of axial inflammation remains an important goal. Cytokines, metalloproteinases, and cartilage catabolic products are all candidates for the important role of biomarker in spondyloarthritis.
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Affiliation(s)
- Kyoung-Sun Na
- The Arthritis Center of Excellence, Toronto Western Hospital, Toronto, Ontario, Canada M5T 2S8
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39
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Kim TH, Inman RD. Biomarkers in spondylarthritis: a peripheral vision. ARTHRITIS AND RHEUMATISM 2006; 54:1733-5. [PMID: 16729285 DOI: 10.1002/art.21916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
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40
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Rihl M, Köhler L, Klos A, Zeidler H. Persistent infection of Chlamydia in reactive arthritis. Ann Rheum Dis 2006; 65:281-4. [PMID: 16474031 PMCID: PMC1798068 DOI: 10.1136/ard.2005.044966] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2005] [Indexed: 01/15/2023]
Abstract
Unravelling the molecular mechanisms
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41
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Inman RD, Chiu B. Early cytokine profiles in the joint define pathogen clearance and severity of arthritis inChlamydia-induced arthritis in rats. ACTA ACUST UNITED AC 2006; 54:499-507. [PMID: 16447224 DOI: 10.1002/art.21643] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
OBJECTIVE Although Chlamydia trachomatis-induced arthritis is among the most common rheumatic diseases having an identified infectious trigger, the pathogenesis of this arthritis is not well defined. We sought to investigate the host-microbe interactions that contribute to the severity of arthritis initiated by chlamydial infection. METHODS We established an experimental rat model of C. trachomatis-induced arthritis that recapitulates many pathologic features of the clinical disease. The severity of the arthritis was defined using an established histopathologic scoring system. Host clearance of the pathogen and local cytokine production were examined by enzyme-linked immunosorbent assays. RESULTS Lewis rats were susceptible to C. trachomatis-induced arthritis, whereas BN rats were relatively resistant to this disease. Significant differences in the histopathologic severity of arthritis were originally observed on day 21, and this prompted an examination of the acute phase of the arthritis. As early as day 5 after the onset of the arthritis, pathologic changes in Lewis rats were more severe than those in BN rats. An evaluation of the role of complement using cobra venom factor treatment excluded complement as being the key to differential sensitivity, because decomplementation did not eliminate the differences in arthritis severity between Lewis and BN rats. Host clearance, in contrast, was significantly different between the rat strains, with BN rats showing more prompt and effective clearance of the pathogen from both synovial tissues and spleen compared with Lewis rats. Local cytokine profiles demonstrated that host resistance was characterized by enhanced synovial expression of tumor necrosis factor alpha, interferon-gamma (IFNgamma), and interleukin-4. CONCLUSION These studies demonstrated that cytokines thought to be proinflammatory in nature can play an important role in host defense in infection-triggered arthritis and serve to highlight the dynamic cytokine relationships that constitute effective host-pathogen interactions.
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Affiliation(s)
- Robert D Inman
- Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada.
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42
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Sun Y, Büki KG, Ettala O, Vääräniemi JP, Väänänen HK. Possible role of direct Rac1-Rab7 interaction in ruffled border formation of osteoclasts. J Biol Chem 2005; 280:32356-61. [PMID: 16040606 DOI: 10.1074/jbc.m414213200] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Rab7 has been shown to regulate the late steps of the endocytic pathway. In bone-resorbing osteoclasts, it is involved in formation of the ruffled border, which is a late endosomal-like compartment in the plasma membrane. Here we report a new Rab7-interacting protein, Rac1, another small GTPase protein that binds to the GTP-form of Rab7 as found with a two-hybrid system. We demonstrate further that Rab7 colocalizes with Rac1 at the fusion zone of the ruffled border in bone-resorbing osteoclasts. In other cell types, such as fibroblast-like cells, partial colocalization is perinuclear. Because Rac1 is known to control the actin cytoskeleton through its effectors, the Rab7-Rac1 interaction may mediate late endosomal transport between microtubules and microfilaments enabling endosomal vesicles to switch tracks and may thus also regulate ruffled border formation in osteoclasts.
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Affiliation(s)
- Yi Sun
- Department of Anatomy, Institute of Biomedicine, University of Turku, Finland
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