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Hefin I Rhys, Francesco Dell'Accio, Costantino Pitzalis, Adrian Moore, Lucy V Norling, Mauro Perretti
Microvesicles (MVs) are emerging as a novel means to enact cell-to-cell communication in inflammation. Here, we aimed to ascertain the ability of neutrophil-derived MVs to modulate target cell behaviour, the focus being the macrophage. MVs were generated in response to tumour necrosis factor-α, from healthy control neutrophils or those from rheumatoid arthritis patients. MVs were used to stimulate human monocyte-derived macrophages in vitro, or administered intra-articularly in the K/BxN mouse model of arthritis...
February 7, 2018: EBioMedicine
Janko Sattler, Jinwen Tu, Shihani Stoner, Jingbao Li, Frank Buttgereit, Markus Seibel, Hong Zhou, Mark S Cooper
Patients with chronic immune-mediated arthritis exhibit abnormal hypothalamo-pituitary-adrenal (HPA) axis activity. The basis for this abnormality is not known. Immune-mediated arthritis is associated with increased extra-adrenal synthesis of active glucocorticoids by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. 11β-HSD1 is expressed in the central nervous system, including regions involved in HPA axis regulation. We examined whether altered 11β-HSD1 expression within these regions contributes to HPA axis dysregulation during arthritis...
January 31, 2018: Endocrine Connections
Xinwen Wang, Jie Bai, Zhen Jia, Yangjun Zhu, Jijun Liu, Kun Zhang, Dingjun Hao, Lisong Heng
BACKGROUND: The purpose of this study is to identify key genes and microRNAs (miRNAs) involved in autoantibody-mediated arthritis (AMA). METHODS: A time-course microarray data (ID: GSE27492) of peripheral blood leukocytes, ankle tissue, and synovial fluid from K/BxN mouse serum-transferred mice were downloaded from Gene Expression Omnibus. Those samples were collected at days 0, 1, 3, 7, 12, and 18 after serum injection. Limma of R was employed to identify differentially expressed genes (DEGs) in samples collected at days 1-18 compared with those collected at day 0...
December 2, 2017: Journal of Orthopaedic Surgery and Research
Beth Friedman, Michael A Whitney, Elamprakash N Savariar, Christa Caneda, Paul Steinbach, Qing Xiong, Dina V Hingorani, Jessica Crisp, Stephen R Adams, Michael Kenner, Csilla N Lippert, Quyen T Nguyen, Monica Guma, Roger Y Tsien, Maripat Corr
OBJECTIVE: Functional imaging of synovitis could improve both early detection of rheumatoid arthritis (RA) and long-term outcomes. Given the intersection of inflammation with coagulation protease activation, this study was undertaken to examine coagulation protease activities in arthritic mice with a dual-fluorescence ratiometric activatable cell-penetrating peptide (RACPP) that has a linker, norleucine (Nle)-TPRSFL, with a cleavage site for thrombin. METHODS: K/BxN-transgenic mice with chronic arthritis and mice with day 1 passive serum-transfer arthritis were imaged in vivo for Cy5:Cy7 emission ratiometric fluorescence from proteolytic cleavage and activation of RACPPNleTPRSFL ...
January 2018: Arthritis & Rheumatology
Salina Dominguez, Anna B Montgomery, G Kenneth Haines, Christina L Bloomfield, Carla M Cuda
BACKGROUND: Caspase-8 is a well-established initiator of apoptosis and suppressor of necroptosis, but maintains functions beyond cell death that involve suppression of receptor-interacting serine-threonine kinases (RIPKs). A genome-wide association study meta-analysis revealed an SNP associated with risk of rheumatoid arthritis (RA) development within the locus containing the gene encoding for caspase-8. Innate immune cells, like macrophages and dendritic cells, are gaining momentum as facilitators of autoimmune disease pathogenesis, and, in particular, RA...
October 4, 2017: Arthritis Research & Therapy
Takayuki Fujii, Eiichiro Nishi, Hiromu Ito, Hiroyuki Yoshitomi, Moritoshi Furu, Namiko Okabe, Mikiko Ohno, Kiyoto Nishi, Yusuke Morita, Yugo Morita, Masayuki Azukizawa, Akinori Okahata, Takuya Tomizawa, Takeshi Kimura, Shuichi Matsuda
OBJECTIVE: Tumour necrosis factor alpha (TNF-α) plays an important role in rheumatoid arthritis (RA). TNF-α is synthesised as a membrane-anchored precursor and is fully activated by a disintegrin and metalloproteinase 17 (ADAM17)-mediated ectodomain shedding. Nardilysin (NRDC) facilitates ectodomain shedding via activation of ADAM17. This study was undertaken to elucidate the role of NRDC in RA. METHODS: NRDC-deficient (Nrdc(-/-) ) mice and macrophage-specific NRDC-deficient (Nrdc(delM) ) mice were examined in murine RA models, collagen antibody-induced arthritis (CAIA) and K/BxN serum transfer arthritis (K/BxN STA)...
2017: RMD Open
Jinwen Tu, Shihani Stoner, Phillip D Fromm, Tingyu Wang, Di Chen, Jan Tuckermann, Mark S Cooper, Markus J Seibel, Hong Zhou
Previous studies demonstrated that endogenous glucocorticoid signaling in osteoblasts promotes inflammation in murine immune arthritis. The current study determined whether disruption of endogenous glucocorticoid signaling in chondrocytes also modulates the course and severity of arthritis. Tamoxifen-inducible chondrocyte-targeted glucocorticoid receptor knockout (chGRKO) mice were generated by breeding GR(flox/flox) mice with tamoxifen-inducible Collagen 2a1 Cre mice (Col2a1-CreER(T2)). Antigen-induced arthritis (AIA) and K/BxN serum transfer-induced arthritis (STIA) were induced in both chGRKO mice and their Cre-negative GR(flox/flox) littermates [wild type (WT)]...
September 19, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Laura Mandik-Nayak, James B DuHadaway, Jennifer Mulgrew, Elizabeth Pigott, Kaylend Manley, Summer Sedano, George C Prendergast, Lisa D Laury-Kleintop
During the development of autoimmune disease, a switch occurs in the antibody repertoire of B cells so that the production of pathogenic rather than non-pathogenic autoantibodies is enabled. However, there is limited knowledge concerning how this pivotal step occurs. Here, we present genetic and pharmacological evidence of a positive modifier function for the vesicular small GTPase RhoB in specifically mediating the generation of pathogenic autoantibodies and disease progression in the K/BxN preclinical mouse model of inflammatory arthritis...
November 1, 2017: Disease Models & Mechanisms
Min-Gyu Jeon, Yun-Hong Cheon, Hye-Song Lim, Sang Mi Yi, Young Sun Suh, Hyun-Ok Kim, Young-Sool Hah, Ki-Hun Park, Hae Sook Noh, Sang-Il Lee
The purpose of this study is to investigate the effect of TSAHC [4'-(p-toluenesulfonylamido)-4-hydroxychalcone] in K/BxN serum transfer arthritis model and fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLS). In in vivo experiments, TSAHC attenuated the incidence and severity of arthritis in comparison with the vehicle group. Histological findings showed that TSAHC decreased the inflammation, bone erosion, cartilage damage, and osteoclasts activity in the ankle. Furthermore, we confirmed by biochemical analysis that the observations were associated with the decreased expression of proinflammatory cytokines, matrix metalloproteinases (MMPs), and RANKL in serum and ankle...
December 2017: Inflammation
Fei Teng, Krysta M Felix, C Pierce Bradley, Debdut Naskar, Heqing Ma, Walid A Raslan, Hsin-Jung Joyce Wu
BACKGROUND: Age is an important risk factor for rheumatoid arthritis (RA), which often develops in middle age. However, how age-associated changes in immunity impact RA is poorly understood. Gut microbiota are known to be involved in the pathogenesis of RA, but the effects of microbiota in older subjects remain mostly unknown. METHODS: We used segmented filamentous bacteria (SFB), a gut commensal species with immunomodulatory effects, and K/BxN mice, a T cell receptor (TCR) transgenic model, to study the effect of age and microbiota on autoimmune arthritis...
August 15, 2017: Arthritis Research & Therapy
Aizhen Yang, Junsong Zhou, Bo Wang, Jihong Dai, Robert W Colman, Wenchao Song, Yi Wu
The plasma kallikrein-kinin system (KKS) consists of serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-MW kininogen (HK). Upon activation, activated pKal and FXII cleave HK to release bradykinin. Activation of this system has been noted in patients with rheumatoid arthritis, and its pathogenic role has been characterized in animal arthritic models. In this study, we generated 2 knockout mouse strains that lacked pKal and HK and determined the role of KKS in autoantibody-induced arthritis...
December 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Shinji Matsuda, Deepa Hammaker, Katharyn Topolewski, Karoline J Briegel, David L Boyle, Steven Dowdy, Wei Wang, Gary S Firestein
Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) display unique aggressive behavior, invading the articular cartilage and promoting inflammation. Using an integrative analysis of RA risk alleles, the transcriptome and methylome in RA FLS, we recently identified the limb bud and heart development (LBH) gene as a key dysregulated gene in RA and other autoimmune diseases. Although some evidence suggests that LBH could modulate the cell cycle, the precise mechanism is unknown and its impact on inflammation in vivo has not been defined...
October 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
Ramzi Nehmar, Ghada Alsaleh, Benjamin Voisin, Vincent Flacher, Alexandre Mariotte, Victoria Saferding, Antonia Puchner, Birgit Niederreiter, Thierry Vandamme, Gernot Schabbauer, Philippe Kastner, Susan Chan, Peggy Kirstetter, Martin Holcmann, Christopher Mueller, Jean Sibilia, Seiamak Bahram, Stephan Blüml, Philippe Georgel
OBJECTIVE: The role of plasmacytoid dendritic cells (PDCs) and type I interferons (IFNs) in rheumatoid arthritis (RA) remains a subject of controversy. This study was undertaken to explore the contribution of PDCs and type I IFNs to RA pathogenesis using various animal models of PDC depletion and to monitor the effect of localized PDC recruitment and activation on joint inflammation and bone damage. METHODS: Mice with K/BxN serum-induced arthritis, collagen-induced arthritis, and human tumor necrosis factor transgene insertion were studied...
November 2017: Arthritis & Rheumatology
Susan MacLauchlan, Maria A Zuriaga, José J Fuster, Carla M Cuda, Jennifer Jonason, Fernanda Behzadi, Jennifer Parker Duffen, G Kenneth Haines, Tamar Aprahamian, Harris Perlman, Kenneth Walsh
BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation...
July 19, 2017: Arthritis Research & Therapy
Zhenguang Zhang, Agnes E Coutinho, Tak Yung Man, Tiina M J Kipari, Patrick W F Hadoke, Donald M Salter, Jonathan R Seckl, Karen E Chapman
11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) predominantly converts inert glucocorticoids into active forms, thereby contributing to intracellular glucocorticoid levels. 11β-HSD1 is dynamically regulated during inflammation, including in macrophages where it regulates phagocytic capacity. The resolution of inflammation in some disease models including inflammatory arthritis is impaired by 11β-HSD1 deficiency or inhibition. However, 11β-HSD1 deficiency/inhibition also promotes angiogenesis, which is beneficial in mouse models of surgical wound healing, myocardial infarction or obesity...
September 2017: Journal of Endocrinology
Trevor P Fidler, Elizabeth A Middleton, Jesse W Rowley, Luc H Boudreau, Robert A Campbell, Rhonda Souvenir, Trevor Funari, Nicolas Tessandier, Eric Boilard, Andrew S Weyrich, E Dale Abel
OBJECTIVE: On activation, platelets increase glucose uptake, glycolysis, and glucose oxidation and consume stored glycogen. This correlation between glucose metabolism and platelet function is not well understood and even less is known about the role of glucose metabolism on platelet function in vivo. For glucose to enter a cell, it must be transported through glucose transporters. Here we evaluate the contribution of GLUT3 (glucose transporter 3) to platelet function to better understand glucose metabolism in platelets...
September 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
Qi-Quan Huang, Robert Birkett, Renee E Doyle, G Kenneth Haines, Harris Perlman, Bo Shi, Philip Homan, Lianping Xing, Richard M Pope
OBJECTIVE: Macrophages are critical in the pathogenesis of rheumatoid arthritis (RA). We recently demonstrated that FLIP is necessary for the differentiation and/or survival of macrophages. We also showed that FLIP is highly expressed in RA synovial macrophages. This study was undertaken to determine if a reduction in FLIP in mouse macrophages reduces synovial tissue macrophages and ameliorates serum-transfer arthritis. METHODS: Mice with Flip deleted in myeloid cells (Flip(f/f) LysM(c/+) mice) and littermate controls were used...
September 2017: Arthritis & Rheumatology
Dennis J Wu, Iannis E Adamopoulos
WDFY3 is a master regulator of selective autophagy that we recently showed to interact with TRAF6 and augment RANKL-induced osteoclastogenesis in vitro and in vivo via the NF-κB pathway. Since the NF-κB pathway plays a major role in inflammation herein, we investigate the role of WDFY3 in an arthritis animal model. Our data show that WDFY3 conditional knockout mice (Wdfy3(loxP/loxP)-LysM-Cre+) were protected in the K/BxN serum transfer-induced arthritis animal model. These effects were independent of alterations in starvation-induced autophagy as evidenced by Western blot analysis of the autophagy marker LC3, autophagosome formation in osteoclast precursors and lysosome formation in osteoclasts derived from WDFY3-cKO mice compared to controls...
June 2017: Cellular Immunology
Marie-Astrid Boutet, Aurélie Najm, Géraldine Bart, Régis Brion, Sophie Touchais, Valérie Trichet, Pierre Layrolle, Cem Gabay, Gaby Palmer, Frédéric Blanchard, Benoit Le Goff
OBJECTIVES: Interleukin (IL)-38 is a newly characterised cytokine that belongs to the IL-1 family. This cytokine is expressed in the rheumatoid arthritis (RA) synovial tissue and IL-38 deficient mice have exacerbated arthritis. Here, we analysed the effect of IL-38 overexpression in the joints of arthritic mice, in human macrophages and synovial fibroblasts in vitro. METHODS: Articular injections of an adeno-associated virus (AAV) 2/8 encoding IL-38 were performed in collagen-induced arthritis (CIA), K/BxN serum transfer-induced arthritis (STIA) and antigen-induced arthritis (AIA) in mice...
July 2017: Annals of the Rheumatic Diseases
Praxedis Martin, Gaby Palmer, Emiliana Rodriguez, Christian Alexander Seemayer, Jennifer Palomo, Dominique Talabot-Ayer, Cem Gabay
The biological activity of IL-1 is tightly regulated by the specific receptor antagonist (IL-1Ra) and the decoy receptor IL-1 receptor type 2 (IL-1R2). The role of IL-1Ra has been well demonstrated in IL-1Ra-deficient mice. In contrast, the role of endogenous IL-1R2 remains widely unknown. To define the functional role of endogenous IL-1R2 in the K/BxN serum transfer arthritis model and in IL-1β- or LPS-induced systemic inflammation in vivo, IL-1R2(-/-) mice were created and compared with wild type mice. IL-1R2(-/-) mice bred habitually and exhibited a normal phenotype...
April 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
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