RESUMO
Inflammatory arthritis, including rheumatoid arthritis (RA), is characterized by infiltration of inflammatory cells into the joints. Biological agents targeting TNF-α and IL-6 dramatically improve RA. However, some RA patients do not respond to current treatments and these broadly active upstream biological agents increase the risk of severe infection. Therefore, there remains a need for other effective and safe treatments for RA. Many studies have implicated that blockade of leukotriene B4 (LTB4) and its high affinity receptor BLT1 dramatically suppress arthritis in animal models. In addition, levels of LTB4 in serum, synovial fluid and synovial tissue are increased in RA patients compared to healthy donors or osteoarthritis patients. These data suggest that LTB4 and BLT1 likely contribute to the pathogenesis of human RA. However, several clinical trials inhibiting BLT1 in RA were not successful. Our recent data revealed that LTB4 is a key mediator in a complement, lipid, cytokine and chemokine cascade that first initiates and then sustains neutrophilic inflammation in inflammatory arthritis. These new mechanistic studies suggest novel ways to target the LTB4-BLT1 pathway for the treatment of RA and other inflammatory diseases.
Assuntos
Artrite Reumatoide/terapia , Artrite/terapia , Leucotrieno B4/metabolismo , Receptores do Leucotrieno B4/metabolismo , Animais , Artrite/imunologia , Artrite Reumatoide/imunologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Humanos , Inflamação , Terapia de Alvo MolecularRESUMO
OBJECTIVES: We investigated the relationship between lysosomal-associated membrane protein-2 (LAMP-2) and anti-phosphatidylserine/prothrombin (PS/PT) antibody in the pathogenesis of cutaneous vasculitis. METHODS: Cell surface LAMP-2 expression of human neutrophils was measured using flow cytometry. Twenty inbred wild-type Wistar-King-Aptekman-Hokudai (WKAH) rats were divided into four groups: Group 1, rabbit IgG injection only as negative control (n=5); Group 2, both histone and rabbit IgG injection (n=5); Group 3, anti-LAMP-2 antibody injection only (n=5); and Group 4, both histone and anti-LAMP-2 antibody injection (n=5). Ten WKAH rats were divided into two groups: Group A, histone, anti-PS/PT antibody, and anti-LAMP-2 antibody injection (n=5), and Group B, histone, anti-PS/PT antibody, and rabbit IgG injection as control (n=5). RESULTS: LAMP-2 expression on human neutrophils was induced by cell-free histone exposure in a dose- and time-dependent manner. Histopathological examination revealed the recruitment of neutrophils in cutaneous small vessels in all Group 4 rats. These observations were not evident in systemic organs other than the skin. LAMP-2 expression on the surface of vascular endothelial cells was evident in Group 2, exclusively in the skin, but not in Group 1. Thrombi were detected in various organs in all Groups A and B rats. However, no apparent thrombi were observed in the skin. CONCLUSIONS: Anti-PS/PT and anti-LAMP-2 antibodies are responsible for independent effector mechanisms in the rats given intravenous injection of cell-free histones. We considered that undetermined factors other than cell-free histones could be required for the induction of cutaneous vasculitis by anti-PS/PT and anti-LAMP-2 antibodies.
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Imunoglobulina G/imunologia , Proteína 2 de Membrana Associada ao Lisossomo/imunologia , Fosfatidilserinas/imunologia , Protrombina/imunologia , Vasculite/imunologia , Animais , Células Endoteliais , Humanos , Neutrófilos , Ratos , Ratos WistarRESUMO
OBJECTIVES: Randomised-controlled trials have recently proven the efficacy of the interleukin (IL)-6 receptor antagonist tocilizumab (TCZ) in giant cell arteritis (GCA). However, the mechanism of action of IL-6 blockade in this disease is unknown. Moreover, the role of regulatory T (Treg) cells in the pathogenesis of GCA remains underexplored. Given the plasticity of Tregs and the importance of IL-6 in their biology, we hypothesised that TCZ might modulate the Treg response in GCA. We therefore characterised the Treg compartment of patients with GCA treated with TCZ. METHODS: We classified 41 patients with GCA into three groups: active disease (aGCA, n=11), disease remission on corticosteroids (rGCA-CS, n=19) and disease remission on TCZ (rGCA-TCZ, n=11). Healthy controls (HCs) were included for comparison. We determined the frequency, phenotype and function of peripheral blood Tregs. RESULTS: Patients with aGCA demonstrated a hypoproliferating Treg compartment enriched in IL-17-secreting Tregs (IL-17+Tregs). Tregs in patients with aGCA disproportionally expressed a hypofunctional isoform of Foxp3 that lacks exon 2 (Foxp3Δ2). Foxp3Δ2-expressing Tregs coexpressed CD161, a marker commonly associated with the Th17 linage, significantly more often than full-length Foxp3-expressing Tregs. Compared with those of HCs, GCA-derived Tregs demonstrated impaired suppressor capacity. Treatment with TCZ, in contrast to CS therapy, corrected the Treg abnormalities observed in aGCA. In addition, TCZ treatment increased the numbers of activated Tregs (CD45RA-Foxp3high) and the Treg expression of markers of trafficking (CCR4) and terminal differentiation (CTLA-4). CONCLUSIONS: TCZ may exert its therapeutic effects in GCA by increasing the proliferation and activation of Tregs, and by reverting the pathogenic Treg phenotype seen during active disease.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Arterite de Células Gigantes/sangue , Arterite de Células Gigantes/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Linfócitos T Reguladores/fisiologia , Corticosteroides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Antígeno CTLA-4/análise , Proliferação de Células , Estudos Transversais , Feminino , Fatores de Transcrição Forkhead/análise , Fatores de Transcrição Forkhead/genética , Humanos , Interleucina-17/metabolismo , Subunidade alfa de Receptor de Interleucina-2/análise , Ativação Linfocitária/efeitos dos fármacos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Subfamília B de Receptores Semelhantes a Lectina de Células NK/análise , Fenótipo , Receptores CCR4/análise , Linfócitos T Reguladores/química , Linfócitos T Reguladores/metabolismoRESUMO
OBJECTIVES: Sphingosine 1-phosphate (S1P) is a bioactive lipid that binds to cell surface receptors (S1P1-5). In this study, we examined the effect of S1P1 agonist, ONO-W061, on murine Candida albicans water-soluble fraction (CAWS)-induced vasculitis. METHODS: Mice were administered ONO-W061, and the number of peripheral blood cells was counted. Vasculitis was induced by an intraperitoneal injection of CAWS. Expression of S1P receptors and CXCL1 was analyzed by quantitative RT-PCR. ONO-W061 was orally administered, and vasculitis was evaluated histologically. Number of neutrophils, macrophages and T cells in the vasculitis tissue was counted using flow cytometry. Production of chemokines from S1P-stimulated human umbilical vein endothelial cells (HUVECs) was measured by ELISA. RESULTS: Number of peripheral blood lymphocytes was decreased by ONO-W061. Expression of CXCL1 and S1P1 was enhanced in CAWS-induced vasculitis tissue. Vasculitis score, CXCL1 and number of neutrophils in the vasculitis tissue were lower in ONO-W061-treated mice. Treatment of HUVECs with S1P upregulated the production of CXCL1 and IL-8 in vitro, and this was inhibited by ONO-W061. CONCLUSIONS: ONO-W061 significantly improved CAWS-induced vasculitis. This effect may be partly exerted through the inhibited production of chemokines by endothelial cells, which in turn could induce neutrophil recruitment into inflamed vessels.
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Lisofosfolipídeos/metabolismo , Receptores de Lisoesfingolipídeo/agonistas , Esfingosina/análogos & derivados , Vasculite/tratamento farmacológico , Animais , Candida albicans , Quimiocina CXCL1/metabolismo , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Interleucina-8/metabolismo , Contagem de Leucócitos , Masculino , Camundongos Endogâmicos BALB C , Esfingosina/metabolismo , Vasculite/imunologia , Vasculite/metabolismoRESUMO
Retinoid, a derivative of vitamin A, is a general term used to describe compounds that bind to and activate retinoic acid receptors [RARs (RARα, RARß, and RARγ)] and/or retinoid X receptors [RXRs (RXRα, RXRß, and RXRγ)]. They have been shown to surpress the differentiation of Th1/Th17 cells and induce the development of Th1/regulatory T cells. They also affect the proliferation of B cells as both an inducer and suppressor. Furthermore, retinoids may induce the maturation of dendritic cells and production of interleukin-10 from monocytes/macrophages. We recently demonstrated that retinoids suppressed the production of reactive oxygen species, the release of elastase from neutrophils by inhibiting mitogen-activated protein kinase signals, and both the migration speed and chemotaxis directionality of neutrophils. Retinoids, such as all-trans retinoic acid and tamibarotene, were previously shown to have positive effects on animal models of several rheumatic diseases, including arthritis, myositis, and vasculitis in vivo. Moreover, retinoids have been used in a pilot study to effectively treat patients with lupus nephritis and systemic sclerosis. We herein reviewed the effects of retinoids on immune cells, animal models of rheumatic diseases, and rheumatic patients.
Assuntos
Retinoides/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Animais , Modelos Animais de Doenças , Humanos , Projetos PilotoRESUMO
OBJECTIVE: Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA1-6 ]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA1 on the development of arthritis. METHODS: Expression of LPA receptors on synovial tissue was analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The effects of abrogation of LPA1 on collagen-induced arthritis (CIA) were evaluated using LPA1 -deficient mice or LPA1 antagonist. Migrating fluorescence-labeled CD11b+ splenocytes, which were transferred into the synovium of mice with CIA, were counted. CD4+ naive T cells were incubated under Th1-, Th2-, or Th17-polarizing conditions, and T helper cell differentiation was assessed. Osteoclast formation from bone marrow cells was examined. RESULTS: LPA1 was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA1 -deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA1 antagonist also ameliorated murine CIA. Abrogation of LPA1 was associated with reductions in cell infiltration, bone destruction in the joints, and interleukin-17 production from CII-stimulated splenocytes. Infiltration of transferred CD11b+ macrophages from LPA1 -deficient mice into the synovium was suppressed compared with infiltration of macrophages from wild-type mice. LPA1 antagonist inhibited the infiltration of macrophages from wild-type mice. Differentiation into Th17, but not Th1 or Th2, and osteoclast formation were also suppressed under conditions of LPA1 deficiency or LPA1 inhibition in vitro. CONCLUSION: Collectively, these results indicate that LPA/LPA1 signaling contributes to the development of arthritis via cellular infiltration, Th17 differentiation, and osteoclastogenesis. Thus, LPA1 may be a promising target molecule for RA therapy.
Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Membrana Sinovial/metabolismo , Idoso , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Antígeno CD11b , Diferenciação Celular , Transplante de Células , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/deficiência , Transdução de Sinais , Baço/metabolismo , Baço/patologia , Membrana Sinovial/patologia , Células Th17RESUMO
OBJECTIVE: Vasculitis is characterized by leukocyte infiltration in the vessel walls, with destructive damage to mural structures. Retinoids are compounds that bind to retinoic acid receptors and exert biologic activities similar to those of vitamin A, including modulatory effects on cell proliferation and differentiation. This study was undertaken to examine the therapeutic effects of a synthetic retinoid, Am80, in a murine model of vasculitis induced by Candida albicans water-soluble fraction (CAWS). METHODS: Vasculitis was induced in BALB/c mice by intraperitoneal injection of CAWS. Neutrophils were depleted by injection of antineutrophil antibody-positive serum. Am80 was administered orally once daily. Vasculitis was evaluated histologically. Migration of labeled adoptively transferred cells was quantified. Chemotaxis was assessed by cell mobility analysis. Production of reactive oxygen species (ROS) and phosphorylation of MAPKs were measured by flow cytometry. Concentrations of elastase were measured by enzyme-linked immunosorbent assay. RESULTS: Administration of CAWS induced vasculitis in the coronary arteries and aortic root, with abundant neutrophil infiltration. Depletion of neutrophils reduced CAWS-induced vasculitis. Treatment with Am80 led to a significant attenuation of the vasculitis score and inhibition of the migration of transferred neutrophils into the site of vasculitis. In vitro, Am80 suppressed fMLP-induced chemotaxis of human peripheral blood neutrophils. ROS production and elastase release by stimulated neutrophils were reduced by AM80 treatment, and Am80 also inhibited phosphorylation of ERK-1/2 and p38 in neutrophils stimulated with fMLP plus lipopolysaccharide. CONCLUSION: Am80 significantly suppressed CAWS-induced vasculitis. This effect was presumably exerted via inhibition of neutrophil migration and activation.
Assuntos
Benzoatos/uso terapêutico , Movimento Celular/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Receptores do Ácido Retinoico/agonistas , Tetra-Hidronaftalenos/uso terapêutico , Vasculite/tratamento farmacológico , Animais , Aorta/efeitos dos fármacos , Aorta/imunologia , Aorta/metabolismo , Benzoatos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Camundongos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Tetra-Hidronaftalenos/farmacologia , Vasculite/imunologia , Vasculite/metabolismoRESUMO
BACKGROUND: Some of cannabinoids, which are chemical compounds contained in marijuana, are immunosuppressive. One of the receptors, CB receptor 1 (CB1), is expressed predominantly by the cells in the central nervous system, whereas CB receptor 2 (CB(2)) is expressed primarily by immune cells. Theoretically, selective CB(2) agonists should be devoid of psychoactive effects. In this study, we investigated therapeutic effects of a selective CB(2) agonist on arthritis. METHODS: The expression of CB(2) was analyzed with immunohistochemistry and Western blotting. Interleukin (IL)-6, matrix metalloproteinase-3 (MMP-3), and chemokine (C-C motif) ligand 2 (CCL2) were quantified with enzyme-linked immunosorbent assays (ELISA). Osteoclastogenesis was assessed with tartrate-resistant acid phosphatase staining and the resorption of coated-calcium phosphate. Effect of JWH133, a selective CB(2) agonist, on murine collagen type II (CII)-induced arthritis (CIA) was evaluated with arthritis score, and histological and radiographic changes. IFN-γ and IL-17 production by CII-stimulated splenocytes and serum anti-CII Ab were analyzed by ELISA. RESULTS: Immunohistochemistry showed that CB(2) was expressed more in the synovial tissues from the rheumatoid joints than in those from the osteoarthritis joints. CB(2) expression on RA FLS was confirmed with Western blot analysis. JWH133 inhibited IL-6, MMP-3, and CCL2 production from tumor necrosis factor-α-stimulated fibroblast-like synoviocytes (FLS) derived from the rheumatoid joints, and osteoclastogenesis of peripheral blood monocytes. Administration of JWH133 to CIA mice reduced the arthritis score, inflammatory cell infiltration, bone destruction, and anti-CII IgG1 production. CONCLUSION: The present study suggests that a selective CB(2) agonist could be a new therapy for RA that inhibits production of inflammatory mediators from FLS, and osteoclastogenesis.
Assuntos
Artrite Reumatoide/metabolismo , Canabinoides/administração & dosagem , Sistemas de Liberação de Medicamentos , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/biossíntese , Adulto , Idoso , Animais , Artrite Reumatoide/tratamento farmacológico , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos DBA , Pessoa de Meia-Idade , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismoRESUMO
Excessive activation of immune cells by environmental factors, such as infection or individual genetic risk, causes various autoimmune diseases. Streptococcus species are gram-positive bacteria that colonize the nasopharynx, respiratory tract, gastrointestinal tract, genitourinary tract, and skin. Group A Streptococcus (GAS) species cause various symptoms, ranging from mild infections, such as tonsillitis and pharyngitis, to serious infections, such as necrotizing fasciitis and streptococcal toxic shock syndrome. The contribution of GAS infections to several autoimmune diseases, including acute rheumatic fever, vasculitis, and neuropsychiatric disorders, has been studied. In this review, we focus on the association between streptococcal infections and autoimmune diseases, and discuss current research on the mechanisms underlying the initiation and progression of autoimmune diseases.
Assuntos
Doenças Autoimunes , Faringite , Febre Reumática , Infecções Estreptocócicas , Humanos , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes , Doenças Autoimunes/complicaçõesRESUMO
Rheumatoid arthritis (RA) is an autoimmune disease that commonly causes inflammation and bone destruction in multiple joints. Inflammatory cytokines, such as IL-6 and TNF-α, play important roles in RA development and pathogenesis. Biological therapies targeting these cytokines have revolutionized RA therapy. However, approximately 50% of the patients are non-responders to these therapies. Therefore, there is an ongoing need to identify new therapeutic targets and therapies for patients with RA. In this review, we focus on the pathogenic roles of chemokines and their G-protein-coupled receptors (GPCRs) in RA. Inflamed tissues in RA, such as the synovium, highly express various chemokines to promote leukocyte migration, tightly controlled by chemokine ligand-receptor interactions. Because the inhibition of these signaling pathways results in inflammatory response regulation, chemokines and their receptors could be promising targets for RA therapy. The blockade of various chemokines and/or their receptors has yielded prospective results in preclinical trials using animal models of inflammatory arthritis. However, some of these strategies have failed in clinical trials. Nonetheless, some blockades showed promising results in early-phase clinical trials, suggesting that chemokine ligand-receptor interactions remain a promising therapeutic target for RA and other autoimmune diseases.
Assuntos
Artrite Reumatoide , Doenças Autoimunes , Animais , Receptores de Quimiocinas , Ligantes , Estudos Prospectivos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/etiologia , Quimiocinas , CitocinasRESUMO
Vasculitis is a systemic autoimmune disease characterized by leukocyte infiltration into blood vessels. Various microorganisms have been associated with the pathogenesis of vasculitis; however, the causal microbial agents and underlying mechanisms are not fully understood, possibly because of the technical limitations of pathogen detection. In the present study, we characterized the microbiome profile of patients with cutaneous vasculitis using comprehensive metagenome shotgun sequencing. We found that the abundance of the SEN virus was increased in the affected skin and serum of patients with vasculitis compared to healthy donors. In particular, the abundance of SEN virus reads was increased in the sera of patients with cutaneous arteritis. Among the bacteria identified, Corynebacteriales was the most differentially associated with vasculitis. Linear discriminant analysis effect size also indicated differences in the microbial taxa between patients with vasculitis and healthy donors. These findings demonstrate that vasculitis is associated with considerable alteration of the microbiome in the blood and skin and suggest a role for the infectious trigger in vasculitis.
Assuntos
Actinomycetales , Vasculite , Humanos , Pele , Leucócitos , Análise DiscriminanteRESUMO
Vasculitis is an autoimmune disease characterized by the infiltration of leukocytes in blood vessels. An increasing number of studies on human and animal models have implicated various microorganisms in the pathogenesis of vasculitis. Previous studies have shown the presence of infectious agents, including viruses, bacteria, and fungi, in diseased vessels. However, despite continued research, the link between infection and vasculitis is not fully understood, possibly owing to the lack of appropriate animal models that mirror human disease and the technical limitations of pathogen detection in blood vessels. Among the pathogen-induced animal models, Candida albicans water-soluble fraction (CAWS)-induced coronary arteritis is currently considered one of the representative models of Kawasaki (KD) disease. Advances in metagenomic next-generation sequencing have enabled the detection of all nucleic acids in tissue, which can help identify candidate pathogens, including previously unidentified viruses. In this review, we discuss the findings from reports on pathogen-associated vasculitis in animal models and humans, with a specific focus on the investigation of the pathogenesis of vasculitis. Further studies on animal models and microbes in diseased vessels may provide important insights into the pathogenesis of vasculitis, which is often considered an idiopathic disease.
RESUMO
Dysfunction of immunoinhibitory signals and persistent T cell activation reportedly play important roles in the development of vasculitis. The skin is one of the most accessible organs, and it is suitable for the characterization of immune cell signatures. However, the inhibitory checkpoint molecules in the skin and their relevance to vasculitis have not been studied. Here, we investigated the profile of immune checkpoint molecules in the skin and peripheral blood of patients with vasculitis and healthy donors. We found that some of the inhibitory checkpoint molecules, including programmed cell death 1 receptor (PD-1), were elevated in T-cells in the blood of patients with systemic and cutaneous vasculitis. In addition, programmed death-ligand 1 (PD-L1) expression was elevated in the skin of patients with cutaneous vasculitis. Histologically, PD-L1 was highly expressed in the vessels in the skin along with CD4+ and CD8+ T-cell infiltration in patients with cutaneous vasculitis. Notably, plasma soluble PD-L1 levels were increased, and these correlated with C-reactive protein in patients with systemic vasculitis. Our findings suggest that inhibitory checkpoint molecules might be differentially modulated in the skin and peripheral blood of patients with vasculitis, and that the alteration of the PD-L1/PD-1 axis may be associated with the regulation of T-cell activation in vasculitis.
Assuntos
Antígeno B7-H1 , Biomarcadores , Ativação Linfocitária/imunologia , Receptor de Morte Celular Programada 1 , Vasculite/imunologia , Adulto , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Pele/metabolismoRESUMO
Arrest of circulating leukocytes and subsequent diapedesis is a fundamental component of inflammation. In general, the leukocyte migration cascade is tightly regulated by chemoattractants, such as chemokines. Chemokines, small secreted chemotactic cytokines, as well as their G-protein-coupled seven transmembrane spanning receptors, control the migratory patterns, positioning and cellular interactions of immune cells. Increased levels of chemokines and their receptors are found in the blood and within inflamed tissue in patients with rheumatoid arthritis (RA) and vasculitis. Chemokine ligand-receptor interactions regulate the recruitment of leukocytes into tissue, thus contributing in important ways to the pathogenesis of RA and vasculitis. Despite the fact that blockade of chemokines and chemokine receptors in animal models have yielded promising results, human clinical trials in RA using inhibitors of chemokines and their receptors have generally failed to show clinical benefits. However, recent early phase clinical trials suggest that strategies blocking specific chemokines may have clinical benefits in RA, demonstrating that the chemokine system remains a promising therapeutic target for rheumatic diseases, such as RA and vasuculitis and requires further study.
RESUMO
Chemokines, a family of small secreted chemotactic cytokines, and their G protein-coupled seven transmembrane spanning receptors control the migratory patterns, positioning and cellular interactions of immune cells. The levels of chemokines and their receptors are increased in the blood and within inflamed tissue of patients with rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis or idiopathic inflammatory myopathies. Chemokine ligand-receptor interactions control the recruitment of leukocytes into tissue, which are central to the pathogenesis of these rheumatic diseases. Although the blockade of various chemokines and chemokine receptors has yielded promising results in preclinical animal models of rheumatic diseases, human clinical trials have, in general, been disappointing. However, there have been glimmers of hope from several early-phase clinical trials that suggest that sufficiently blocking the relevant chemokine pathway might in fact have clinical benefits in rheumatic diseases. Hence, the chemokine system remains a promising therapeutic target for rheumatic diseases and requires further study.
Assuntos
Antirreumáticos/uso terapêutico , Autoimunidade , Fatores Biológicos/uso terapêutico , Quimiocinas/metabolismo , Doenças Reumáticas , Animais , Humanos , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/imunologia , Doenças Reumáticas/metabolismoRESUMO
Chemoattractant-induced arrest of circulating leukocytes and their subsequent diapedesis is a fundamental component of inflammation. However, how tissue-derived chemoattractants are transported into the blood vessel lumen to induce leukocyte entry into tissue is not well understood. Here, intravital microscopy in live mice has shown that the "atypical" complement C5a receptor 2 (C5aR2) and the atypical chemokine receptor 1 (ACKR1) expressed on endothelial cells were required for the transport of C5a and CXCR2 chemokine ligands, respectively, into the vessel lumen in a murine model of immune complex-induced arthritis. Transported C5a was required to initiate C5aR1-mediated neutrophil arrest, whereas transported chemokines were required to initiate CXCR2-dependent neutrophil transdendothelial migration. These findings provide new insights into how atypical chemoattractant receptors collaborate with "classical" signaling chemoattractant receptors to control distinct steps in the recruitment of neutrophils into tissue sites of inflammation.
Assuntos
Artrite , Adesão Celular , Complemento C5a , Neutrófilos , Receptor da Anafilatoxina C5a , Animais , Masculino , Camundongos , Artrite/induzido quimicamente , Artrite/imunologia , Adesão Celular/imunologia , Quimiocinas/metabolismo , Complemento C5a/metabolismo , Modelos Animais de Doenças , Sistema do Grupo Sanguíneo Duffy/metabolismo , Células Endoteliais/imunologia , Inflamação/imunologia , Camundongos Endogâmicos NOD , Camundongos Knockout , Neutrófilos/imunologia , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores de Interleucina-8B/metabolismo , Migração Transendotelial e Transepitelial/imunologiaRESUMO
BACKGROUND: Lysophosphatidic acid (LPA), generated by autotaxin (ATX), is a bioactive lipid mediator that binds to the receptors (LPA1-6), and serves as an important mediator in inflammation. Previous studies have demonstrated that LPA-LPA1 cascade contributes to arthritis and skin sclerosis. In this study, we examined the role of LPA signals in murine Candida albicans water-soluble fraction (CAWS)-induced vasculitis. METHODS: ATX and LPA receptor expressions were analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. Effects of LPA1 inhibition on CAWS-induced vasculitis were evaluated in LPA1-deficient mice or using an LPA1 antagonist, LA-01. Migration activity was assessed using a chemotaxis chamber. The number of migrated fluorescently labeled neutrophils, which were transferred into the vasculitis mice, was counted in the aortic wall. CXCL1 and IL-8 concentrations were determined by enzyme-linked immunosorbent assay. RESULTS: ATX and LPA1 were highly expressed in the inflamed region of CAWS-induced vasculitis. Severity of the vasculitis in LPA1-deficient mice was suppressed. The LPA1 antagonist, LA-01, also ameliorated the CAWS-induced vasculitis. LPA induced neutrophil migration, which was inhibited by LA-01 in vitro. Infiltration of transferred neutrophils from LPA1-deficient mice into the coronary arteries was suppressed. LA-01 also inhibited the infiltration of wild-type neutrophils. Expression of CXCL1 and IL-8 in human endothelial cells was enhanced by LPA, but was inhibited by LA-01. ATX and LPA1 expression levels were higher in the affected skin region of vasculitis patients than in healthy controls. CONCLUSIONS: These results suggest that LPA-LPA1 signaling contributes to the development of vasculitis via chemoattractant production from endothelial cells followed by neutrophil recruitment. Thus, LPA1 has potential as a novel target for vasculitis therapies.
Assuntos
Quimiocina CXCL1/metabolismo , Interleucina-8/metabolismo , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Vasculite/metabolismo , Animais , Movimento Celular , Cefalosporinas , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/patologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais , Vasculite/diagnóstico , Vasculite/tratamento farmacológicoRESUMO
Environmental triggers, including those from pathogens, are thought to play an important role in triggering autoimmune diseases, such as vasculitis, in genetically susceptible individuals. The mechanism by which activation of the innate immune system contributes to vessel-specific autoimmunity in vasculitis is not known. Systemic administration of Candida albicans water-soluble extract (CAWS) induces vasculitis in the aortic root and coronary arteries of mice that mimics human Kawasaki disease. We found that Dectin-2 signaling in macrophages resident in the aortic root of the heart induced early CCL2 production and the initial recruitment of CCR2+ inflammatory monocytes (iMo) into the aortic root and coronary arteries. iMo differentiated into monocyte-derived dendritic cells (Mo-DC) in the vessel wall and were induced to release IL-1ß in a Dectin-2-Syk-NLRP3 inflammasome dependent pathway. IL-1ß then activated cardiac endothelial cells to express CXCL1 and CCL2 and adhesion molecules that induced neutrophil and further iMo recruitment and accumulation in the aortic root and coronary arteries. Our findings demonstrate that Dectin-2-mediated induction of CCL2 production by macrophages resident in the aortic root and coronary arteries initiates vascular inflammation in a model of Kawasaki disease, suggesting an important role for the innate immune system in initiating vasculitis.