scholarly journals Recruitment of Macrophages and Polymorphonuclear Leukocytes in Lyme Carditis

2006 ◽  
Vol 75 (2) ◽  
pp. 613-620 ◽  
Author(s):  
Ruth R. Montgomery ◽  
Carmen J. Booth ◽  
Xiaomei Wang ◽  
Victoria A. Blaho ◽  
Stephen E. Malawista ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Polymorphonuclear Leukocytes ◽  
Cellular Level ◽  
Lyme Arthritis ◽  
Compensatory Mechanisms ◽  
Lyme Carditis ◽  
Severe Arthritis ◽  
C3h Mice ◽  
Chemokine Receptor Cxcr2 ◽  
Organ Specific

ABSTRACT Lyme arthritis, caused by the spirochete Borrelia burgdorferi, can be recurrent or prolonged, whereas Lyme carditis is mostly nonrecurring. A prominent difference between arthritis and carditis is the differential representation of phagocytes in these lesions: polymorphonuclear leukocytes (PMN) are more prevalent in the joint, and macrophages predominate in the heart lesion. We have previously shown differential efficiency of B. burgdorferi clearance by PMN and macrophages, and we now investigate whether these functional differences at the cellular level may contribute to the observed differences in organ-specific pathogenesis. When we infected mice lacking the neutrophil chemokine receptor (CXCR2−/− mice) with spirochetes, we detected fewer PMN in joints and less-severe arthritis. Here we have investigated the effects of the absence of the macrophage chemokine receptor CCR2 on the development and resolution of Lyme carditis in resistant (C57BL/6J [B6]) and sensitive (C3H/HeJ [C3H]) strains of mice. In B6 CCR2−/− mice, although inflammation in hearts is mild, we detected an increased burden of B. burgdorferi compared to that in wild-type (WT) mice, suggesting reduced clearance in the absence of macrophages. In contrast, C3H CCR2−/− mice have severe inflammation but a decreased B. burgdorferi burden compared to that in WT C3H mice both at peak disease and during resolution. Histopathologic examination of infected hearts revealed that infected C3H CCR2−/− animals have an increased presence of PMN, suggesting compensatory mechanisms of B. burgdorferi clearance in the hearts of infected C3H CCR2−/− mice. The more efficient clearance of B. burgdorferi from hearts by CCR2−/− versus WT C3H mice suggests a natural defect in the recruitment or function of macrophages in C3H mice, which may contribute to the sensitivity of this strain to B. burgdorferi infection.

scholarly journals Clearance of Borrelia burgdorferi May Not Be Required for Resistance to Experimental Lyme Arthritis

1998 ◽  
Vol 66 (5) ◽  
pp. 2065-2071 ◽  
Author(s):  
Charles R. Brown ◽  
Steven L. Reiner
Keyword(s):  
Borrelia Burgdorferi ◽  
Inbred Mouse ◽  
Experimental Period ◽  
Lyme Arthritis ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Competitive Pcr ◽  
Experimental Animals ◽  
Severe Arthritis ◽  
C3h Mice

ABSTRACT Infection of inbred mouse strains with Borrelia burgdorferi results in the development of experimental Lyme arthritis. The degree of arthritic pathology has been suggested to correlate with the level of spirochete burden within tissues. To investigate this further, we infected resistant DBA/2 (DBA) and susceptible C3H/HeJ (C3H) mice in the hind footpads and monitored arthritis development for 21 days. To quantitate levels of spirochetes within tissues, we created a competitive PCR molecule containing modified ospA and fla gene segments. C3H mice developed severe arthritis of the tibiotarsal joints, while DBA mice developed only mild inflammation throughout the experimental period. At day 21, when the gross size and histologic composition of ankles revealed significant differences in arthritis between the strains, there was little difference in levels of spirochete DNA as determined by competitive PCR. Cultures of ankle tissue at day 21 were also uniformly positive in both C3H and DBA animals and contained relatively similar levels of spirochetes. These results indicate that the presence of spirochetes in the ankles of experimental animals is not sufficient for arthritis development. Since arthritic and nonarthritic animals can harbor relatively equal spirochete burdens yet retain their distinct phenotypic outcomes, an aberrant or overly exuberant immune response may be an additional requirement for pathology in arthritis-prone mice.

scholarly journals Adenoviral Delivery of Interleukin-10 Fails To Attenuate Experimental Lyme Disease

2008 ◽  
Vol 76 (12) ◽  
pp. 5500-5507 ◽  
Author(s):  
Charles R. Brown ◽  
Annie Y.-C. Lai ◽  
Steven T. Callen ◽  
Victoria A. Blaho ◽  
Jennifer M. Hughes ◽  
...  
Keyword(s):  
Interleukin 10 ◽  
Lyme Arthritis ◽  
Mouse Strains ◽  
Susceptible Mouse ◽  
Lyme Carditis ◽  
Adenoviral Delivery ◽  
Severity Scores ◽  
C3h Mice

ABSTRACT Production of interleukin-10 (IL-10) by C57BL/6 mice following infection with Borrelia burgdorferi has been proposed as a mechanism whereby resistance to the development of experimental Lyme arthritis is maintained. In the current study, we sought to determine the role of IL-10 during infection of arthritis- and carditis-susceptible C3H mice. Infection of C3H IL-10−/− mice led to increased joint swelling and arthritis severity scores over those of wild-type C3H mice. Measurement of B. burgdorferi numbers in joints or disseminated tissues indicated a more efficient clearance of spirochetes in the absence of IL-10, similar to that reported in C57BL/6 IL-10−/− mice. However, in contrast to previous in vitro work, infection of C3H IL-10−/− mice led to decreased in vivo expression of the cytokines KC, IL-1β, IL-4, and IL-12p70 in the infected joints. Finally, adenoviral expression of IL-10 in the infected joints of C3H mice was unable to modulate the development of severe Lyme arthritis and had no effect on spirochete clearance or Borrelia-specific antibody production. Development of Lyme carditis appeared to be independent of modulation by IL-10. These results suggest that IL-10 limits the development of joint inflammation in both arthritis-resistant and -susceptible mouse strains infected with B. burgdorferi and that increased IL-10 production cannot rescue genetic susceptibility to development of pathology in this model.

scholarly journals Treatment of Mice with the Neutrophil-Depleting Antibody RB6-8C5 Results in Early Development of Experimental Lyme Arthritis via the Recruitment of Gr-1− Polymorphonuclear Leukocyte-Like Cells

2004 ◽  
Vol 72 (9) ◽  
pp. 4956-4965 ◽  
Author(s):  
Charles R. Brown ◽  
Victoria A. Blaho ◽  
Christie M. Loiacono
Keyword(s):  
Monoclonal Antibody ◽  
Early Development ◽  
Polymorphonuclear Leukocyte ◽  
Lyme Arthritis ◽  
Joint Tissue ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
C3h Mice ◽  
Chemokine Receptor Cxcr2

ABSTRACT Recently, we demonstrated that blocking the entry of neutrophils into Borrelia burgdorferi-infected joints in mice deficient in the chemokine receptor CXCR2 prevented the development of experimental Lyme arthritis. Neutrophils were marginalized in blood vessels at the site of infection but could not enter the joint tissue. In the present study, we treated both genetically arthritis-resistant DBA/2J (DBA) and arthritis-susceptible C3H/HeJ (C3H) mice with the neutrophil-depleting monoclonal antibody RB6-8C5 (RB6) to determine the effect on arthritis development. Surprisingly, both DBA and C3H mice treated with RB6 developed arthritis at 1 week postinfection, approximately 1 week earlier than the control-treated C3H mice. The early development of arthritis in the RB6-treated mice was accompanied by an influx into the joints of cells with ring-shaped polymorphonuclear leukocyte (PMN) cell morphology that were negative for the Gr-1 neutrophil maturation marker. RB6 treatment of mice also resulted in increased numbers of B. burgdorferi cells in the joints at 7 days postinfection and earlier expression of the chemokines KC and monocyte chemoattractant protein 1 in the joints compared to control-treated animals. Together, these results suggest that recruitment of neutrophils or PMN-like cells into an infected joint is a key requirement for Lyme arthritis development and that altered recruitment of these cells into the joints of arthritis-resistant mice can exacerbate the development of pathology.

scholarly journals The Chemokine Receptor CXCR2 Ligand KC (CXCL1) Mediates Neutrophil Recruitment and Is Critical for Development of Experimental Lyme Arthritis and Carditis

2010 ◽  
Vol 78 (11) ◽  
pp. 4593-4600 ◽  
Author(s):  
Anna M. Ritzman ◽  
Jennifer M. Hughes-Hanks ◽  
Victoria A. Blaho ◽  
Laura E. Wax ◽  
William J. Mitchell ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Chemokine Receptor ◽  
Subsequent Development ◽  
Lyme Arthritis ◽  
Wild Type ◽  
Inflammatory Lesions ◽  
Severity Scores ◽  
Chemokine Receptor Cxcr2 ◽  
Cardiac Lesions ◽  
Cxcr2 Ligand

ABSTRACT Deletion of the chemokine receptor CXCR2 prevents the recruitment of neutrophils into tissues and subsequent development of experimental Lyme arthritis. Following footpad inoculation of Borrelia burgdorferi, the agent of Lyme disease, expression of the CXCR2 ligand KC (CXCL1) is highly upregulated in the joints of arthritis-susceptible mice and is likely to play an important role in the recruitment of neutrophils to the site of infection. To test this hypothesis, we infected C3H KC−/− mice with B. burgdorferi and followed the development of arthritis and carditis. Ankle swelling was significantly attenuated during the peak of arthritis in the KC−/− mice. Arthritis severity scores were significantly lower in the KC−/− mice on days 11 and 21 postinfection, with fewer neutrophils present in the inflammatory lesions. Cardiac lesions were also significantly decreased in KC−/− mice at day 21 postinfection. There were, however, no differences between C3H wild-type and KC−/− mice in spirochete clearance from tissues. Two other CXCR2 ligands, LIX (CXCL5) and MIP-2 (CXCL2), were not increased to compensate for the loss of KC, and the production of several innate cytokines was unaltered. These results demonstrate that KC plays a critical nonredundant role in the development of experimental Lyme arthritis and carditis via CXCR2-mediated recruitment of neutrophils into the site of infection.

scholarly journals Genetic Control of Experimental Lyme Arthritis in the Absence of Specific Immunity

1999 ◽  
Vol 67 (4) ◽  
pp. 1967-1973 ◽  
Author(s):  
Charles R. Brown ◽  
Steven L. Reiner
Keyword(s):  
Immune Response ◽  
Gene Knockout ◽  
Scid Mice ◽  
Lyme Arthritis ◽  
Mouse Strains ◽  
Specific Immunity ◽  
Severe Arthritis ◽  
Severity Scores ◽  
C3h Mice ◽  
Rag 1

ABSTRACT Host genetics play an important role in determining resistance or susceptibility to experimental Lyme arthritis. While specific immunity appears to regulate disease resolution, innate immunity appears to regulate disease severity. Intradermal infection with Borrelia burgdorferi yields severe arthritis in C3H/He (C3H) mice but only minimal arthritis in BALB/c mice. Intradermal infection of immunodeficient C3H SCID mice also results in severe arthritis, but arthritis of only moderate severity in BALB/c SCID mice. In the present study, we examined immunodeficient recombinase-activating gene-knockout (RAG-1 −/−) (RAG−) mice from resistant C57BL/6 (B6) and DBA/2 (DBA) mouse strains. B. burgdorferi-infected B6 RAG− and DBA RAG− mice had little or no ankle swelling, a low occurrence of inflammatory infiltrates in tibiotarsal joints, and low arthritis severity scores in comparison to RAG+ and RAG− BALB/c or C3H mice. Few differences in spirochete DNA levels in ankles of resistant and susceptible RAG− mice were seen. These data suggest that resistance to arthritis development following B. burgdorferi infection is not necessarily dependent on an acquired immune response and can occur despite the presence of high spirochete burden. Thus, genes expressed outside the specific immune response can be central regulators of experimental arthritis.

scholarly journals The role of CXC-chemokine receptor CXCR2 and suppressor of cytokine signaling-3 (SOCS-3) in renal cell carcinoma

BMC Cancer ◽  
2014 ◽  
Vol 14 (1) ◽  
Author(s):  
Anastasios Stofas ◽  
Georgia Levidou ◽  
Christina Piperi ◽  
Christos Adamopoulos ◽  
Georgia Dalagiorgou ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Chemokine Receptor ◽  
Renal Cell ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Cxc Chemokine ◽  
Chemokine Receptor Cxcr2

scholarly journals Hamster and Murine Models of Severe Destructive Lyme Arthritis

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Erik Munson ◽  
Dean T. Nardelli ◽  
Brian K. Du Chateau ◽  
Steven M. Callister ◽  
Ronald F. Schell
Keyword(s):  
Lyme Borreliosis ◽  
Bone Erosion ◽  
Lyme Arthritis ◽  
Murine Models ◽  
Transient Synovitis ◽  
Hamster Model ◽  
C3h Mice ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Reaction Characteristic

Arthritis is a frequent complication of infection in humans withBorrelia burgdorferi. Weeks to months following the onset of Lyme borreliosis, a histopathological reaction characteristic of synovitis including bone, joint, muscle, or tendon pain may occur. A subpopulation of patients may progress to a chronic, debilitating arthritis months to years after infection which has been classified as severe destructive Lyme arthritis. This arthritis involves focal bone erosion and destruction of articular cartilage. Hamsters and mice are animal models that have been utilized to study articular manifestations of Lyme borreliosis. Infection of immunocompetent LSH hamsters or C3H mice results in a transient synovitis. However, severe destructive Lyme arthritis can be induced by infecting irradiated hamsters or mice and immunocompetentBorrelia-vaccinated hamsters, mice, and interferon-gamma- (IFN-γ-) deficient mice with viableB. burgdorferi. The hamster model of severe destructive Lyme arthritis facilitates easy assessment of Lyme borreliosis vaccine preparations for deleterious effects while murine models of severe destructive Lyme arthritis allow for investigation of mechanisms of immunopathology.

scholarly journals The impact of genetic background and sex on the phenotype of IL-23 induced murine arthritis

2021 ◽  
Author(s):  
Emma Haley ◽  
Mederbek Matmusaev ◽  
Imtiyaz N. Hossain ◽  
Sean Davin ◽  
Tammy M. Martin ◽  
...  
Keyword(s):  
Weight Loss ◽  
Genetic Background ◽  
Skin Inflammation ◽  
Control Mechanisms ◽  
Adult Mice ◽  
Severe Arthritis ◽  
Cytokine Levels ◽  
Clinical Arthritis ◽  
Organ Specific ◽  
The Impact

AbstractBackgroundOverexpression of IL-23 in adult mice by means of hydrodynamic tail vein injection of IL-23 minicircles has been reported to result in spondyloarthritis-like disease. The impact of genetic background and sex on the disease phenotype in this model has not been investigated.MethodsWe compared male B10.RIII mice with male C57BL/6 mice, and male with female B10.RIII mice after hydrodynamic injection of IL-23 enhanced episomal vector (EEV) at 8-12 weeks of age. We monitored clinical arthritis scores, paw swelling, and body weight. Animals were euthanized after two weeks and tissues were harvested for histology, flow cytometry and gene expression analysis. Serum cytokine levels were determined by ELISA.FindingsMale B10.RIII mice developed arthritis in the forepaws and feet within 6 days after IL-23 EEV injection; they also exhibited psoriasis-like skin disease, colitis, weight loss, and osteopenia. In contrast to previous reports, we did not observe spondylitis or uveitis. Male C57BL/6 mice injected with IL-23 EEV had serum IL-23 levels comparable with B10.RIII mice and developed skin inflammation, colitis, weight loss, and osteopenia but failed to develop arthritis. Female B10.RIII mice had more severe arthritis than male B10.RIII mice but did not lose weight.ConclusionsSystemic IL-23 overexpression results in spondyloarthritis-like disease in B10.RIII mice. The development of extra-articular manifestations but absence of arthritis in C57BL/6 mice suggests organ-specific genetic control mechanisms of IL-23 driven inflammation. Discrepancies regarding the phenotype of IL-23 induced disease in different labs and the sexual dimorphism observed in this study warrant further exploration.

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