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

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.

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Recruitment of Macrophages and Polymorphonuclear Leukocytes in Lyme Carditis

Infection and Immunity ◽

10.1128/iai.00685-06 ◽

2006 ◽

Vol 75 (2) ◽

pp. 613-620 ◽

Cited By ~ 41

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.

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GROα/KC, a chemokine receptor CXCR2 ligand, can be a potent trigger for neuronal ERK1/2 and PI-3 kinase pathways and for tau hyperphosphorylation—a role in Alzheimer's disease?

Journal of Neuroimmunology ◽

10.1016/s0165-5728(01)00463-5 ◽

2002 ◽

Vol 122 (1-2) ◽

pp. 55-64 ◽

Cited By ~ 54

Author(s):

MengQi Xia ◽

Bradley T Hyman

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Chemokine Receptor ◽

Tau Hyperphosphorylation ◽

Chemokine Receptor Cxcr2 ◽

Cxcr2 Ligand

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Immune Mediators of Murine Lyme Arthritis

10.32469/10355/45872 ◽

2014 ◽

Author(s):

◽

Anna Maria Cunningham

Keyword(s):

Lyme Disease ◽

Subsequent Development ◽

The United States ◽

Lyme Arthritis ◽

Immune Mediators ◽

Eicosanoid Production ◽

Immunological Mechanisms ◽

Serum Transfer ◽

Dietary Fish ◽

Vector Borne

Lyme disease is the most common vector-borne disease in both the United States and Europe; however, its pathogenesis is incompletely understood. The studies described in this thesis aid in the elucidation of mechanisms regulating murine Lyme arthritis and may suggest mechanisms by which human Lyme disease is mediated. (1) We found that the chemokine KC is responsible for neutrophil recruitment and subsequent development of Lyme arthritis and carditis. This was the first study to describe an immunological regulatory mechanism mediating disease susceptibility to murine Lyme disease, as resistant mice (B6) produce less KC than susceptible (C3H/HeJ) mice and do not develop disease. (2) We found that metabolites produced via the COX-2 pathway are important for functional resolution and that resolution is likely mediated via the PGE2/EP2 axis. (3) We found that although dietary fish oil substitution leads to a global shift in eicosanoid production (from AA/LA-derived eicosanoids to EPA/DHA-derived eicosanoids) and promotes antiinflammatory prostaglandin production, disease severity is not altered. (4) We found that eicosanoid production throughout the course of autoantibody-drive K/BxN serum-transfer arthritis differs significantly from that seen during Lyme arthritis and that patterns of eicosanoid expression reflect the severity and kinetics of each type of arthritis. These studies aid in understanding the immunological mechanisms regulating the occurrence and severity of murine Lyme arthritis.

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β2 Integrins Control the Severity of Murine Lyme Carditis

Infection and Immunity ◽

10.1128/iai.73.6.3242-3250.2005 ◽

2005 ◽

Vol 73 (6) ◽

pp. 3242-3250 ◽

Cited By ~ 16

Author(s):

Mireia Guerau-de-Arellano ◽

Joseph Alroy ◽

Brigitte T. Huber

Keyword(s):

Dendritic Cells ◽

Lyme Disease ◽

Lyme Arthritis ◽

Wild Type ◽

Β2 Integrin ◽

Lyme Carditis ◽

Inflammatory Processes ◽

Low Levels ◽

Β2 Integrins

ABSTRACT Infection of C57BL/6 (B6) mice with the Lyme disease spirochete Borrelia burgdorferi can result in development of arthritis and carditis. B. burgdorferi induces expression of β2/CD18 integrins, adhesion molecules that mediate the firm adhesion of leukocytes to the endothelium necessary for cellular extravasation during inflammation. The important role of β2/CD18 integrins during extravasation suggests that these molecules play a role in the development of Lyme arthritis and carditis. The dependency of these inflammatory processes on the β2 integrins was investigated in CD18 hypomorph mice, which express low levels of CD18. The results indicate that CD18 deficiency did not abrogate development of Lyme arthritis or carditis. Moreover, it resulted in increased severity of Lyme carditis. B. burgdorferi-infected CD18 hypomorph mice showed an increased macrophage infiltration of the heart, while they produced lower levels of borreliacidal anti-B. burgdorferi antibodies compared to wild-type mice. In accordance with these results, we demonstrate that dendritic cells from CD18 hypomorph mice secrete higher levels of monocyte/macrophage chemoattractant protein 1 (MCP-1/CCL2) in response to B. burgdorferi. Similarly, we show by real-time PCR that B. burgdorferi-infected hearts from CD18 hypomorph mice express increased levels of MCP-1 RNA compared to wild-type mice. Overall, our results indicate that β2 integrin deficiency does not abrogate B. burgdorferi-induced inflammation; rather, it results in increased recruitment of macrophages into the B. burgdorferi-infected heart, likely due to the increased expression of MCP-1 in this tissue. Thus, β2 integrins may play a regulatory role in B. burgdorferi-induced inflammation beyond mediating adhesion of leukocytes to the endothelium.

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Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR2

Blood ◽

10.1182/blood-2004-09-3578 ◽

2005 ◽

Vol 105 (11) ◽

pp. 4308-4313 ◽

Cited By ~ 72

Author(s):

J. Pablo Abonia ◽

K. Frank Austen ◽

Barrett J. Rollins ◽

Sunil K. Joshi ◽

Richard A. Flavell ◽

...

Keyword(s):

Mast Cell ◽

Small Intestine ◽

Adhesion Molecule ◽

Chemokine Receptor ◽

Cellular Adhesion ◽

Wild Type ◽

Cellular Adhesion Molecule ◽

Mouse Small Intestine ◽

Chemokine Receptor Cxcr2 ◽

Cell Adhesion Molecule 1

Abstract Homing of mast cell progenitors (MCps) to the mouse small intestine involves the interaction of α4β7 integrin with mucosal addressin cellular adhesion molecule-1 (MAdCAM-1). We now demonstrate the dependence of this process on CXC chemokine receptor 2 (CXCR2) and vascular cell adhesion molecule-1 (VCAM-1) using null strains and mice sublethally irradiated and bone marrow (BM) reconstituted (SIBR) with wild-type or null BM or with wild-type BM followed by administration of blocking antibody. The intestinal MCp concentration in CXCR2-/- mice was reduced by 67%, but was unaltered in CC chemokine receptor 2-/- (CCR2-/-), CCR3-/-, or CCR5-/- mice. SIBR mice given CXCR2-/- BM had an intestinal MCp concentration that was 76% less than that in BALB/c BM reconstituted mice. Antibody blockade of VCAM-1 or of CXCR2 in SIBR mice reduced intestinal MCp reconstitution, and mice lacking endothelial VCAM-1 also had a marked reduction relative to wild-type mice. Finally, the half-life of intestinal MCps in wild-type mice was less than one week on the basis of a more than 50% reduction by administration of anti-α4β7 integrin or anti-CXCR2. Thus, the establishment and maintenance of MCps in the small intestine is a dynamic process that requires expression of the α4β7 integrin and the α-chemokine receptor CXCR2.

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The chemokine receptor CXCR2 contributes to murine adipocyte development

10.1101/339721 ◽

2018 ◽

Author(s):

Douglas P Dyer ◽

Joan Boix Nebot ◽

Christopher Kelly ◽

Laura Medina-Ruiz ◽

Fabian Schuette ◽

...

Keyword(s):

Chemokine Receptor ◽

Large Family ◽

Neutrophil Recruitment ◽

Leukocyte Migration ◽

Wild Type ◽

Fat Depots ◽

Chemokine Receptor Cxcr2 ◽

Similar Phenotype ◽

Subcutaneous Adipose ◽

Adipocyte Development

AbstractChemokines are members of a large family of chemotactic cytokines that signal through their receptors to mediate leukocyte recruitment during inflammation and homeostasis. The chemokine receptor CXCR2 has largely been associated with neutrophil recruitment. However, there is emerging evidence of roles for chemokines and their receptors in processes other than leukocyte migration. We have previously demonstrated that CXCR2 KO mice have thinner skin compared to wild type mice. Herein we demonstrate that this is due to a thinner subcutaneous adipose layer, as a result of fewer and smaller individual adipocytes. We observe a similar phenotype in other fat depots and present data that suggests this may be due to reduced expression of adipogenesis related genes associated with adipocyte specific CXCR2 signalling. Interestingly, this phenotype is evident in female, but not male, CXCR2 KO mice. These findings expand our understanding of non-leukocyte related chemokine receptor functions and help to explain some previously observed adipose-related phenotypes in CXCR2 KO mice.

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Faculty Opinions recommendation of A chemokine receptor CXCR2 macromolecular complex regulates neutrophil functions in inflammatory diseases.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13928956.15385056 ◽

2012 ◽

Author(s):

Richard L Stevens

Keyword(s):

Chemokine Receptor ◽

Inflammatory Diseases ◽

Macromolecular Complex ◽

Chemokine Receptor Cxcr2

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Deficiency of the chemokine receptor CXCR2 attenuates neutrophil infiltration and cortical damage following closed head injury

Neurobiology of Disease ◽

10.1016/j.nbd.2010.06.015 ◽

2010 ◽

Vol 40 (2) ◽

pp. 394-403 ◽

Cited By ~ 74

Author(s):

Bridgette D. Semple ◽

Nicole Bye ◽

Jenna M. Ziebell ◽

M. Cristina Morganti-Kossmann

Keyword(s):

Head Injury ◽

Chemokine Receptor ◽

Closed Head Injury ◽

Neutrophil Infiltration ◽

Cortical Damage ◽

Closed Head ◽

Chemokine Receptor Cxcr2

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Arthritis and Diagnostics in Lyme Disease

Tropical Medicine and Infectious Disease ◽

10.3390/tropicalmed6010018 ◽

2021 ◽

Vol 6 (1) ◽

pp. 18

Author(s):

Javier A. Quintero ◽

Raluchukwu Attah ◽

Reena Khianey ◽

Eugenio Capitle ◽

Steven E. Schutzer

Keyword(s):

Lyme Disease ◽

Borrelia Burgdorferi ◽

Diagnostic Tests ◽

Laboratory Tests ◽

Diagnostic Methods ◽

Lyme Arthritis ◽

Differential Diagnoses ◽

Antibody Testing ◽

Active Infection ◽

Indirect Measure

The diagnosis of Lyme disease, caused by Borrelia burgdorferi, is clinical but frequently supported by laboratory tests. Lyme arthritis is now less frequently seen than at the time of its discovery. However, it still occurs, and it is important to recognize this, the differential diagnoses, and how laboratory tests can be useful and their limitations. The most frequently used diagnostic tests are antibody based. However, antibody testing still suffers from many drawbacks and is only an indirect measure of exposure. In contrast, evolving direct diagnostic methods can indicate active infection.

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