scholarly journals Interleukin-10 (IL-10) Inhibits Borrelia burgdorferi-Induced IL-17 Production and Attenuates IL-17-Mediated Lyme Arthritis

2013 ◽  
Vol 81 (12) ◽  
pp. 4421-4430 ◽  
Author(s):  
Emily S. Hansen ◽  
Velinka Medić ◽  
Joseph Kuo ◽  
Thomas F. Warner ◽  
Ronald F. Schell ◽  
...  
Keyword(s):  
Borrelia Burgdorferi ◽  
Interleukin 10 ◽  
Lyme Arthritis ◽  
Interleukin 17 ◽  
Spleen Cells ◽  
Content Type ◽  
Ankle Joints ◽  
Low Levels ◽  
Histopathological Effects ◽  
Deficient Mice

ABSTRACTPrevious studies have shown that cells and cytokines associated with interleukin-17 (IL-17)-driven inflammation are involved in the arthritic response toBorrelia burgdorferiinfection. Here, we report that IL-17 is a contributing factor in the development of Lyme arthritis and show that its production and histopathological effects are regulated by interleukin-10 (IL-10). Spleen cells obtained fromB. burgdorferi-infected, “arthritis-resistant” wild-type C57BL/6 mice produced low levels of IL-17 following stimulation with the spirochete. In contrast, spleen cells obtained from infected, IL-10-deficient C57BL/6 mice produced a significant amount of IL-17 following stimulation withB. burgdorferi. These mice developed significant arthritis, including erosion of the bones in the ankle joints. We further show that treatment with antibody to IL-17 partially inhibited the significant hind paw swelling and histopathological changes observed inB. burgdorferi-infected, IL-10-deficient mice. Taken together, these findings provide additional evidence of a role for IL-17 in Lyme arthritis and reveal an additional regulatory target of IL-10 following borrelial infection.

scholarly journals Regulatory T Cells Contribute to Resistance against Lyme Arthritis

2020 ◽  
Vol 88 (11) ◽  
Author(s):  
Emily M. Siebers ◽  
Elizabeth S. Liedhegner ◽  
Michael W. Lawlor ◽  
Ronald F. Schell ◽  
Dean T. Nardelli
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lyme Disease ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Interleukin 10 ◽  
Lyme Arthritis ◽  
Interleukin 17 ◽  
Content Type

ABSTRACT The symptoms of Lyme disease are caused by inflammation induced by species of the Borrelia burgdorferi sensu lato complex. The various presentations of Lyme disease in the population suggest that differences exist in the intensity and regulation of the host response to the spirochete. Previous work has described correlations between the presence of regulatory T cells and recovery from Lyme arthritis. However, the effects of Foxp3-expressing CD4+ T cells existing prior to, and during, B. burgdorferi infection have not been well characterized. Here, we used C57BL/6 “depletion of regulatory T cell” mice to assess the effects these cells have on the arthritis-resistant phenotype characteristic of this mouse strain. We showed that depletion of regulatory T cells prior to infection with B. burgdorferi resulted in sustained swelling, as well as histopathological changes, of the tibiotarsal joints that were not observed in infected control mice. Additionally, in vitro stimulation of splenocytes from these regulatory T cell-depleted mice resulted in increases in gamma interferon and interleukin-17 production and decreases in interleukin-10 production that were not evident among splenocytes of infected mice in which Treg cells were not depleted. Depletion of regulatory T cells at various times after infection also induced rapid joint swelling. Collectively, these findings provide evidence that regulatory T cells existing at the time of, and possibly after, B. burgdorferi infection may play an important role in limiting the development of arthritis.

scholarly journals Infection of Interleukin 17 Receptor A-Deficient C3H Mice with Borrelia burgdorferi Does Not Affect Their Development of Lyme Arthritis and Carditis

2015 ◽  
Vol 83 (7) ◽  
pp. 2882-2888 ◽  
Author(s):  
Carrie E. Lasky ◽  
Kara E. Jamison ◽  
Darcie R. Sidelinger ◽  
Carmela L. Pratt ◽  
Guoquan Zhang ◽  
...  
Keyword(s):  
Borrelia Burgdorferi ◽  
Lyme Borreliosis ◽  
Heart Tissue ◽  
Lyme Arthritis ◽  
Mouse Strains ◽  
Interleukin 17 ◽  
Content Type ◽  
C3h Mice ◽  
A Subunit

Recently, a number of studies have reported the presence of interleukin 17 (IL-17) in patients with Lyme disease, and several murine studies have suggested a role for this cytokine in the development of Lyme arthritis. However, the role of IL-17 has not been studied using the experimental Lyme borreliosis model of infection of C3H mice withBorrelia burgdorferi. In the current study, we investigated the role of IL-17 in the development of experimental Lyme borreliosis by infecting C3H mice devoid of the common IL-17 receptor A subunit (IL-17RA) and thus deficient in most IL-17 signaling. Infection of both C3H and C3H IL-17RA−/−mice led to the production of high levels of IL-17 in the serum, low levels in the heart tissue, and no detectable IL-17 in the joint tissue. The development and severity of arthritis and carditis in the C3H IL-17RA−/−mice were similar to what was seen in wild-type C3H mice. In addition, development of antiborrelia antibodies and clearance of spirochetes from tissues were similar for the two mouse strains. These results demonstrate a limited role for IL-17 signaling through IL-17RA in the development of disease following infection of C3H mice withB. burgdorferi.

scholarly journals Role of Osteopontin in Murine Lyme Arthritis and Host Defense against Borrelia burgdorferi

2002 ◽  
Vol 70 (3) ◽  
pp. 1372-1381 ◽  
Author(s):  
Melissa R. Potter ◽  
Susan R. Rittling ◽  
David T. Denhardt ◽  
Randall J. Roper ◽  
John H. Weis ◽  
...  
Keyword(s):  
Borrelia Burgdorferi ◽  
Host Defense ◽  
Bacterial Infections ◽  
Inbred Mice ◽  
Interleukin 10 ◽  
Lyme Arthritis ◽  
Chromosome 5 ◽  
Severe Arthritis ◽  
Antibody Isotypes ◽  
Deficient Mice

ABSTRACT Several genetic loci in the mouse have been identified that regulate the severity of Lyme arthritis. The region of chromosome 5 including the osteopontin (OPN) gene (Opn) has been identified in intercross populations of C3H/HeN × C57BL/6 and C3H/HeJ × BALB/cAnN mice. OPN is of particular interest as it is involved in the maintenance and remodeling of tissue during inflammation, it regulates production of interleukin-10 (IL-10) and IL-12 (cytokines implicated in Lyme arthritis), it is necessary for host control of certain bacterial infections, and mice displaying different severities of Lyme arthritis possess different alleles of the OPN gene. Macrophages and splenocytes from OPN-deficient mice on mixed C57BL/6J-129S or inbred 129S backgrounds were stimulated with the Pam3Cys modified lipoprotein from Borrelia burgdorferi, OspA. OPN was not required for OspA-induced cytokine production; however, macrophages from 129S-Opn−/− mice displayed a reduced level of IL-10 production. OPN was also not required for resistance to severe arthritis, as B. burgdorferi-infected 129S-Opn−/− mice developed mild arthritis, as did their wild-type littermates. Arthritis was more severe in OPN-deficient mice on the mixed C57BL/6J-129S backgrounds than in inbred mice of either strain. This increase was most likely due to a gene(s) closely linked to Opn on chromosome 5 in conjunction with other randomly assorting genes. Deficiency in OPN did not influence the numbers of spirochetes in tissues from B. burgdorferi-infected mice, indicating OPN is not part of the host defense to this pathogen. Interestingly, there was no alteration in the B. burgdorferi-specific antibody isotypes in OPN-deficient mice, indicating that its effect on helper T-cell responses is not relevant to the host response to B. burgdorferi.

scholarly journals Pulmonary Interleukin-17-Positive Lymphocytes Increase during Pneumocystis murina Infection but Are Not Required for Clearance of Pneumocystis

2017 ◽  
Vol 85 (7) ◽  
Author(s):  
Chiara Ripamonti ◽  
Lisa R. Bishop ◽  
Joseph A. Kovacs
Keyword(s):  
T Cells ◽  
Fungal Infections ◽  
Intracellular Cytokine Staining ◽  
Γδ T Cells ◽  
Interleukin 17 ◽  
Content Type ◽  
Immunosuppressed Patients ◽  
Ifn Γ ◽  
Immunocompetent Mice ◽  
Deficient Mice

ABSTRACT Pneumocystis remains an important pathogen of immunosuppressed patients, causing a potentially life-threatening pneumonia. Despite its medical importance, the immune responses required to control infection, including the role of interleukin-17 (IL-17), which is important in controlling other fungal infections, have not been clearly defined. Using flow cytometry and intracellular cytokine staining after stimulation with phorbol myristate acetate and ionomycin, we examined gamma interferon (IFN-γ), IL-4, IL-5, and IL-17 production by lung lymphocytes in immunocompetent C57BL/6 mice over time following infection with Pneumocystis murina. We also examined the clearance of Pneumocystis infection in IL-17A-deficient mice. The production of both IFN-γ and IL-17 by pulmonary lymphocytes increased during infection, with maximum production at approximately days 35 to 40, coinciding with peak Pneumocystis levels in the lungs, while minimal changes were seen in IL-4- and IL-5-positive cells. The proportion of cells producing IFN-γ was consistently higher than for cells producing IL-17, with peak levels of ∼25 to 30% of CD3+ T cells for the former compared to ∼15% for the latter. Both CD4+ T cells and γδ T cells produced IL-17. Administration of anti-IFN-γ antibody led to a decrease in IFN-γ-positive cells, and an increase in IL-5-positive cells, but did not impact clearance of Pneumocystis infection. Despite the increases in IL-17 production during infection, IL-17A-deficient mice cleared Pneumocystis infection with kinetics similar to C57BL/6 mice. Thus, while IL-17 production in the lungs is increased during Pneumocystis infection in immunocompetent mice, IL-17A is not required for control of Pneumocystis infection.

scholarly journals Induction of Interleukin 10 byBorrelia burgdorferiIs Regulated by the Action of CD14-Dependent p38 Mitogen-Activated Protein Kinase and cAMP-Mediated Chromatin Remodeling

2018 ◽  
Vol 86 (4) ◽  
Author(s):  
Bikash Sahay ◽  
Kathleen Bashant ◽  
Nicole L. J. Nelson ◽  
Rebeca L. Patsey ◽  
Shiva Kumar Gadila ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Lyme Borreliosis ◽  
Human Peripheral Blood ◽  
Interleukin 10 ◽  
Mapk Signaling ◽  
Lyme Arthritis ◽  
Mitogen Activated Protein Kinase ◽  
Content Type ◽  
C3h Mice ◽  
Mitogen Activated Protein

ABSTRACTHost genotype influences the severity of murine Lyme borreliosis, caused by the spirochetal bacteriumBorrelia burgdorferi. C57BL/6 (B6) mice develop mild Lyme arthritis, whereas C3H/HeN (C3H) mice develop severe Lyme arthritis. Differential expression of interleukin 10 (IL-10) has long been associated with mouse strain differences in Lyme pathogenesis; however, the underlying mechanism(s) of this genotype-specific IL-10 regulation remained elusive. Herein we reveal a cAMP-mediated mechanism of IL-10 regulation in B6 macrophages that is substantially diminished in C3H macrophages. Under cAMP and CD14-p38 mitogen-activated protein kinase (MAPK) signaling, B6 macrophages stimulated withB. burgdorferiproduce increased amounts of IL-10 and decreased levels of arthritogenic cytokines, including tumor necrosis factor (TNF). cAMP relaxes chromatin, while p38 increases binding of the transcription factors signal transducer and activator of transcription 3 (STAT3) and specific protein 1 (SP1) to the IL-10 promoter, leading to increased IL-10 production in B6 bone marrow-derived monocytes (BMDMs). Conversely, macrophages derived from arthritis-susceptible C3H mice possess significantly less endogenous cAMP, produce less IL-10, and thus are ill equipped to mitigate the damaging consequences ofB. burgdorferi-induced TNF. Intriguingly, an altered balance between anti-inflammatory and proinflammatory cytokines and CD14-dependent regulatory mechanisms also is operative in primary human peripheral blood-derived monocytes, providing potential insight into the clinical spectrum of human Lyme disease. In line with this notion, we have demonstrated that cAMP-enhancing drugs increase IL-10 production in myeloid cells, thus curtailing inflammation associated with murine Lyme borreliosis. Discovery of novel treatments or repurposing of FDA-approved cAMP-modulating medications may be a promising avenue for treatment of patients with adverse clinical outcomes, including certain post-Lyme complications, in whom dysregulated immune responses may play a role.

scholarly journals The DBA/1 Strain Is a Novel Mouse Model for Experimental Borrelia burgdorferi Infection

2012 ◽  
Vol 19 (10) ◽  
pp. 1567-1573 ◽  
Author(s):  
Brian T. Campfield ◽  
Christi L. Nolder ◽  
Amy Davis ◽  
Raphael Hirsch ◽  
Andrew J. Nowalk
Keyword(s):  
Rheumatoid Arthritis ◽  
Borrelia Burgdorferi ◽  
Lyme Arthritis ◽  
Suitable Model ◽  
Collagen Induced Arthritis ◽  
Content Type ◽  
Humoral Immune ◽  
Significant Difference ◽  
Specific Antigens ◽  
Experimental Murine Model

ABSTRACTLyme arthritis, caused byBorrelia burgdorferi, has similarities to rheumatoid arthritis and its experimental murine model, collagen-induced arthritis (CIA). Currently, no common strain exists for examination of arthritis models of Lyme arthritis and CIA, which are typically studied in C3H/HeJ and DBA/1 mice, respectively. The aim of this study was to define the characteristics ofBorrelia burgdorferiinfection and arthritis in the DBA/1 murine strain. Murine Lyme arthritis was induced in C3H/HeJ and DBA/1 mice by subcutaneous infection withB. burgdorferi. Tibiotarsal joints were measured during infection, and mice were sacrificed for histologic, microbiologic, and serologic analysis on days 14 and 42 postinfection. All bladder cultures obtained from C3H/HeJ and DBA/1 mice at 14 days postinfection grewBorrelia. There was no significant difference in spirochetal burdens in hearts and tibiotarsal joints at days 14 and 42 postinfection. Tibiotarsal joint swelling and histologic scoring were not significantly different between the two strains. Serologic analysis revealed increased IgG2a production in C3H/HeJ mice compared to DBA/1 mice. Analysis of 2-dimensional immunoblots revealed several specific antigens (LA7, BBA03, BBA64, BBA73, OspA, and VlsE) which were not recognized by DBA/1 sera. We conclude that the DBA/1 murine strain is a suitable model for the study of Lyme arthritis and experimentalB. burgdorferiinfection, allowing direct comparison between Lyme arthritis and collagen-induced arthritis. The specificity of the humoral immune response differs between the two strains, further study of which may reveal important findings about how individual strains respond toB. burgdorferiinfection.

scholarly journals Attenuation of Intestinal Inflammation in Interleukin-10-Deficient Mice Infected with Citrobacter rodentium

2014 ◽  
Vol 82 (5) ◽  
pp. 1949-1958 ◽  
Author(s):  
Sara M. Dann ◽  
Christine Le ◽  
Barun K. Choudhury ◽  
Houpu Liu ◽  
Omar Saldarriaga ◽  
...  
Keyword(s):  
Immune Responses ◽  
Intestinal Inflammation ◽  
Acute Infection ◽  
Interleukin 10 ◽  
Mucosal Inflammation ◽  
Immune Functions ◽  
Citrobacter Rodentium ◽  
Microbial Infection ◽  
Content Type ◽  
Deficient Mice

ABSTRACTInterleukin-10 (IL-10) curtails immune responses to microbial infection and autoantigens and contributes to intestinal immune homeostasis, yet administration of IL-10 has not been effective at attenuating chronic intestinal inflammatory conditions, suggesting that its immune functions may be context dependent. To gain a broader understanding of the importance of IL-10 in controlling mucosal immune responses to infectious challenges, we employed the murine attaching and effacing pathogenCitrobacter rodentium, which colonizes primarily the surfaces of the cecum and colon and causes transient mucosal inflammation driven by Th17 and Th1 T helper cells. Infection induced macrophage and dendritic cell production of IL-10, which diminished antibacterial host defenses, because IL-10-deficient mice cleared infection faster than wild-type controls. In parallel, the mice had less acute infection-associated colitis and resolved it more rapidly than controls. Importantly, transientC. rodentiuminfection protected IL-10-deficient mice against the later development of spontaneous colitis that normally occurs with aging in these mice. Genome-wide expression studies revealed that IL-10 deficiency was associated with downregulation of proinflammatory pathways but increased expression of the anti-inflammatory cytokine IL-27 in response to infection. IL-27 was found to suppressin vitroTh17 and, to a lesser degree, Th1 differentiation independent of IL-10. Furthermore, neutralization of IL-27 resulted in more severe colitis in infected IL-10-deficient mice. Together, these findings indicate that IL-10 is dispensable for resolvingC. rodentium-associated colitis and further suggest that IL-27 may be a critical factor for controlling intestinal inflammation and Th17 and Th1 development by IL-10-independent mechanisms.

Fenofibrate Represses Interleukin-17 and Interferon-γ Expression and Improves Colitis in Interleukin-10–Deficient Mice

2007 ◽  
Vol 133 (1) ◽  
pp. 108-123 ◽  
Author(s):  
Jimmy W. Lee ◽  
Poonam J. Bajwa ◽  
Monica J. Carson ◽  
Daniel R. Jeske ◽  
Yingzi Cong ◽  
...  
Keyword(s):  
Interleukin 10 ◽  
Interferon Γ ◽  
Interleukin 17 ◽  
Deficient Mice

scholarly journals Interleukin-35 Enhances Lyme Arthritis inBorrelia-Vaccinated and -Infected Mice

2011 ◽  
Vol 18 (7) ◽  
pp. 1125-1132 ◽  
Author(s):  
Joseph Kuo ◽  
Dean T. Nardelli ◽  
Thomas F. Warner ◽  
Steven M. Callister ◽  
Ronald F. Schell
Keyword(s):  
Therapeutic Agent ◽  
Inflammatory Diseases ◽  
Lyme Arthritis ◽  
Interleukin 17 ◽  
Histopathological Changes ◽  
Content Type ◽  
Severe Arthritis ◽  
Time Of Infection ◽  
Cartilage Erosion ◽  
And Cartilage

ABSTRACTInterleukin-35 (IL-35) has been reported to inhibit the production of interleukin-17 (IL-17) as a means of preventing arthritis and other inflammatory diseases. We previously showed that treatment ofBorrelia-vaccinated and -infected mice with anti-IL-17 antibody at the time of infection prevented the development of arthritis. The anti-IL-17 antibody-treated mice lacked the extensive tissue damage, such as bone and cartilage erosion, that occurred in the tibiotarsal joints of untreatedBorrelia-vaccinated and -infected control mice. We hypothesized that IL-35 would reduce the severity of arthritis by suppressing the production of IL-17 inBorrelia-vaccinated and -infected mice. Here, we show that administration of recombinant IL-35 (rIL-35) toBorrelia-vaccinated and -infected mice augments the development of severe arthritis compared to the results seen with untreated control mice.Borrelia-vaccinated and -infected mice treated with rIL-35 had significantly (P< 0.05) greater hind paw swelling and histopathological changes from day 4 through day 10 than non-rIL-35-treatedBorrelia-vaccinated and -infected mice. In addition, the treatment with IL-35 only slightly decreased the production of IL-17 inBorrelia-primed immune cells and did not prevent the development of borreliacidal antibody. Our data do not support a role for IL-35 as a potential therapeutic agent to reduce inflammation in Lyme arthritis.

scholarly journals Borrelia burgdorferi bbk13Is Critical for Spirochete Population Expansion in the Skin during Early Infection

2019 ◽  
Vol 87 (5) ◽  
Author(s):  
George F. Aranjuez ◽  
Hunter W. Kuhn ◽  
Philip P. Adams ◽  
Mollie W. Jewett
Keyword(s):  
Borrelia Burgdorferi ◽  
Population Expansion ◽  
Targeted Mutagenesis ◽  
Lyme Arthritis ◽  
Content Type ◽  
Lyme Carditis ◽  
Inoculation Site ◽  
Full Complement ◽  
Mammalian Infection ◽  
Mouse Model Of Infection

ABSTRACTLyme disease is caused by the spirocheteBorrelia burgdorferiand is transmitted via the bite of an infected tick.B. burgdorferienters the skin, disseminates via the bloodstream, and infects various distal tissues, leading to inflammatory sequelae, such as Lyme arthritis and Lyme carditis.B. burgdorferilinear plasmid 36 (lp36) is critical for mammalian infectivity; however, the full complement of genes on lp36 that contribute to this process remains unknown. Through a targeted mutagenesis screen of the genes on lp36, we identified a novel infectivity gene of unknown function,bbk13, which encodes an immunogenic, non-surface-exposed membrane protein that is important for efficient mammalian infection. Loss ofbbk13resulted in reduced spirochete loads in distal tissues in a mouse model of infection. Through a detailed analysis ofB. burgdorferiinfection kinetics, we discovered thatbbk13is important for promoting spirochete proliferation in the skin inoculation site. The attenuated ability of Δbbk13spirochetes to proliferate in the inoculation site was followed by reduced numbers ofB. burgdorferispirochetes in the bloodstream and, ultimately, consistently reduced spirochete loads in distal tissues. Together, our data indicate thatbbk13contributes to disseminated infection by promoting spirochete proliferation in the early phase of infection in the skin. This work not only increases the understanding of the contribution of the genes on lp36 toB. burgdorferiinfection but also begins to define the genetic basis forB. burgdorferiexpansion in the skin during localized infection and highlights the influence of the early expansion of spirochetes in the skin on the outcome of infection.

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