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1.
Sci Immunol ; 2(7)2017 Jan.
Article in English | MEDLINE | ID: mdl-28529998

ABSTRACT

The deposition of immune complexes (IC) in tissues induces a "type III hypersensitivity" that results in tissue damage and underlies the pathogenesis of many autoimmune diseases. The neutrophil is the first immune cell recruited into sites of IC deposition and plays a critical role in shaping the overall tissue response. However, the mechanism by which IC initiate and propagate neutrophil infiltration into tissue is not known. Here, using intravital multiphoton joint imaging of IC-induced arthritis in live mice, we found that the complement C5a receptor (C5aR) was the key initiator of neutrophil adhesion on joint endothelium. C5a presented on joint endothelium induced ß2 integrin-dependent neutrophil arrest, facilitating neutrophil spreading and transition to crawling, and subsequent leukotriene B4 receptor (BLT1)-mediated extravasation of the first neutrophils. The chemokine receptor CCR1 promoted neutrophil crawling on the joint endothelium while CXCR2 amplified late neutrophil recruitment and survival once in the joint. Thus, imaging arthritis has defined a new paradigm for type III hypersensitivity where C5a directly initiates neutrophil adhesion on the joint endothelium igniting inflammation.

2.
Arthritis Rheumatol ; 69(5): 1100-1110, 2017 05.
Article in English | MEDLINE | ID: mdl-28076897

ABSTRACT

OBJECTIVE: Lyme arthritis (LA) is caused by infection with Borrelia burgdorferi and usually resolves following spirochetal killing with antibiotics. However, in some patients, arthritis persists after antibiotic therapy. To provide insights into underlying pathogenic processes associated with antibiotic-refractory LA (postinfectious LA), we analyzed differences in microRNA (miRNA) expression between LA patients with active infection and those with postinfectious LA. METHODS: MicroRNA expression was assayed in synovial fluid (SF) from LA patients before and after oral and intravenous antibiotic therapy, and in synovial tissue obtained months after antibiotic therapy from patients with postinfectious LA. SF and tissue from patients with other forms of arthritis, such as rheumatoid arthritis (RA) and osteoarthritis, were used for comparison. RESULTS: SF from LA patients during active infection had marked elevations of white blood cells, particularly polymorphonuclear leukocytes, accompanied by elevated levels of microRNA-223 (miR-223). In contrast, SF from postantibiotic LA patients contained greater percentages of lymphocytes and mononuclear cells. SF from postantibiotic LA patients also exhibited marked inflammatory (miR-146a, miR-155), wound repair (miR-142), and proliferative (miR-17-92) miRNA signatures, and higher levels of these miRNAs correlated with longer arthritis duration. Levels of miR-146a, miR-155, miR-142, miR-223, and miR-17-92 were also elevated in synovial tissue in late postinfectious LA, and levels of let-7a were reduced, similar to RA. CONCLUSION: During active infection, miRNA expression in SF reflected an immune response associated with bacterial killing, while in postinfectious LA, miRNA expression in SF and synovial tissue reflected chronic inflammation, synovial proliferation, and breakdown of wound repair processes, showing that the nature of the arthritis was altered after spirochetal killing.


Subject(s)
Arthritis, Reactive/genetics , Lyme Disease/genetics , MicroRNAs/metabolism , Synovial Membrane/metabolism , Adolescent , Adult , Aged , Anti-Bacterial Agents/therapeutic use , Arthritis, Reactive/metabolism , Child , Female , Gene Expression Regulation , Humans , Inflammation/genetics , Inflammation/metabolism , Lyme Disease/drug therapy , Lyme Disease/metabolism , Male , Middle Aged , Synovial Fluid/metabolism , Young Adult
3.
Ann Rheum Dis ; 76(5): 898-905, 2017 May.
Article in English | MEDLINE | ID: mdl-27927642

ABSTRACT

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.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Giant Cell Arteritis/blood , Giant Cell Arteritis/drug therapy , Interleukin-6/antagonists & inhibitors , T-Lymphocytes, Regulatory/physiology , Adrenal Cortex Hormones/therapeutic use , Aged , Aged, 80 and over , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , CTLA-4 Antigen/analysis , Cell Proliferation , Cross-Sectional Studies , Female , Forkhead Transcription Factors/analysis , Forkhead Transcription Factors/genetics , Humans , Interleukin-17/metabolism , Interleukin-2 Receptor alpha Subunit/analysis , Lymphocyte Activation/drug effects , Lymphocyte Count , Male , Middle Aged , NK Cell Lectin-Like Receptor Subfamily B/analysis , Phenotype , Receptors, CCR4/analysis , T-Lymphocytes, Regulatory/chemistry , T-Lymphocytes, Regulatory/metabolism
4.
Methods Mol Biol ; 1407: 179-94, 2016.
Article in English | MEDLINE | ID: mdl-27271903

ABSTRACT

Adoptive cell transfer experiments can be used to study the roles of cell trafficking molecules on the migratory behavior of specific immune cell populations in vivo. Chemoattractants and their G protein-coupled seven-transmembrane-spanning receptors regulate migration of cells in vivo, and dysregulated expression of chemoattractants and their receptors is implicated in autoimmune and inflammatory diseases. Inflammatory arthritides, such as rheumatoid arthritis (RA), are characterized by the recruitment of inflammatory cells into joints. The K/BxN serum transfer mouse model of inflammatory arthritis shares many similar features with RA. In this autoantibody-induced model of arthritis, neutrophils are the critical immune cells necessary for the development of joint inflammation and damage. We have used adoptive neutrophil transfer to define the contributions of chemoattractant receptors, cytokines, and activation receptors expressed on neutrophils that critically regulate their entry into the inflamed joint. In this review, we describe the procedure of neutrophil adoptive transfer to study the influence of neutrophil-specific receptors or mediators upon the their recruitment into the joint using the K/BxN model of inflammatory arthritis as a model of how adoptive cell transfer studies can be used to study immune cell migration in vivo.


Subject(s)
Adoptive Transfer , Chemotaxis, Leukocyte/immunology , Neutrophils/physiology , Animals , Arthritis, Experimental/immunology , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Biomarkers , Biopsy , Bone Marrow Cells , Disease Models, Animal , Immunohistochemistry , Immunophenotyping , Mice , Microscopy, Fluorescence , Synovial Membrane/pathology
5.
Methods Enzymol ; 570: 207-31, 2016.
Article in English | MEDLINE | ID: mdl-26921948

ABSTRACT

Chemokines regulate the migration of cells in vivo and dysregulated expression of chemokines and their receptors are implicated in autoimmune and inflammatory diseases. Inflammatory arthritides, such as rheumatoid arthritis (RA), are characterized by the recruitment of inflammatory cells into joints. The K/BxN serum transfer mouse model of inflammatory arthritis shares many similar features with RA. In this autoantibody-induced model of arthritis, neutrophils are the critical immune cells necessary for the development of joint inflammation and damage. In this review, we describe the use of several methods to study the role of chemoattractant receptors, including chemokine receptors, on the recruitment of neutrophils into the joint in the K/BxN model of inflammatory arthritis. This includes both traditional methods, such as flow cytometry, immunohistochemistry, and enzyme assays, as well as multiphoton in vivo microscopy that we have adapted to study the role of immune cell trafficking in and around the joint in live mice.


Subject(s)
Arthritis, Experimental/pathology , Chemokines/metabolism , Neutrophils/metabolism , Animals , Arthritis, Experimental/etiology , Arthritis, Experimental/metabolism , Bone Marrow/radiation effects , Cell Movement , Disease Models, Animal , Flow Cytometry/methods , Immunohistochemistry/methods , Mice, Inbred NOD , Mice, Knockout , Neutrophils/pathology , Synovial Fluid
6.
J Rheumatol ; 43(1): 38-45, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26628607

ABSTRACT

OBJECTIVE: Clinical trials have shown that serotonin norepinephrine reuptake inhibitors, such as milnacipran, decrease pain in noninflammatory pain conditions such as fibromyalgia and osteoarthritis. We examined the effect of milnacipran on self-reported pain intensity and experimental pain sensitivity among patients with rheumatoid arthritis (RA) with widespread pain and stable RA disease activity. METHODS: In this double-blind, crossover study, patients with RA with widespread pain, receiving a stable treatment regimen, were randomized (by a random number generator) to receive milnacipran 50 mg twice daily or placebo for 6 weeks, followed by a 3-week washout and crossed over to the other arm for the remaining 6 weeks. The primary outcome was change in average pain intensity, assessed by the Brief Pain Inventory short form. The sample size was calculated to detect a 30% improvement in pain with power = 0.80 and α = 0.05. RESULTS: Of the 43 randomized subjects, 41 received the study drug, and 32 completed the 15-week study per protocol. On a 0-10 scale, average pain intensity decreased by 0.39 (95% CI -1.27 to 0.49, p = 0.37) more points during 6 weeks of milnacipran treatment compared with placebo. In the subgroup of subjects with swollen joint count ≤ 1, average pain intensity decreased by 1.14 more points during 6 weeks of milnacipran compared with placebo (95% CI -2.26 to -0.01, p = 0.04). Common adverse events included nausea (26.8%) and loss of appetite (9.7%). CONCLUSION: Compared with placebo, milnacipran did not improve overall, self-reported pain intensity among subjects with widespread pain receiving stable RA medications. TRIAL REGISTRATION: ClinicalTrials.gov NCT01207453.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/physiopathology , Cyclopropanes/administration & dosage , Pain Measurement/drug effects , Selective Serotonin Reuptake Inhibitors/administration & dosage , Academic Medical Centers , Adult , Aged , Confidence Intervals , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Male , Middle Aged , Milnacipran , Pain Management/methods , Pain Threshold/drug effects , Reference Values , Self Report , Severity of Illness Index , Treatment Outcome , United States
7.
Trends Immunol ; 36(9): 547-55, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26297103

ABSTRACT

Neutrophils are first responders of the immune system, rapidly migrating into affected tissues in response to injury or infection. To effectively call in this first line of defense, strategically placed cells within the vasculature and tissue respond to noxious stimuli by sending out coordinated signals that recruit neutrophils. Regulation of organ-specific neutrophil entry occurs at two levels. First, the vasculature supplying the organ provides cues for neutrophil egress out of the bloodstream in a manner dependent upon its unique cellular composition and architectural features. Second, resident immune cells and stromal cells within the organ send coordinated signals that guide neutrophils to their final destination. Here, we review recent findings that highlight the importance of these tissue-specific responses in the regulation of neutrophil recruitment and the initiation and resolution of inflammation.


Subject(s)
Neutrophil Infiltration/immunology , Neutrophils/immunology , Animals , Blood Vessels/immunology , Blood Vessels/metabolism , Chemotaxis, Leukocyte/immunology , Endothelium, Vascular/metabolism , Humans , Immunity, Innate , Immunomodulation , Inflammation/immunology , Inflammation/metabolism , Mononuclear Phagocyte System/cytology , Mononuclear Phagocyte System/immunology , Mononuclear Phagocyte System/metabolism , Neutrophils/metabolism , Organ Specificity/immunology , Pericytes/metabolism
8.
N Engl J Med ; 372(9): 864-72, 2015 Feb 26.
Article in English | MEDLINE | ID: mdl-25714165

ABSTRACT

A 25-year-old man presented with oral ulcers and odynophagia. On examination, there were scattered pink papules and plaques on the trunk, thighs, and buttocks and multiple raised, erythematous nodules on both shins. A diagnostic procedure was performed.


Subject(s)
Behcet Syndrome/pathology , Hair Follicle/pathology , Lip/pathology , Oral Ulcer/etiology , Adult , Behcet Syndrome/complications , Deglutition Disorders/etiology , Diagnosis, Differential , Exanthema/etiology , Folliculitis/etiology , Folliculitis/pathology , Genital Diseases, Male/etiology , Humans , Male , Sexually Transmitted Diseases/diagnosis , Skin Diseases/diagnosis
9.
J Immunol ; 192(5): 2291-304, 2014 Mar 01.
Article in English | MEDLINE | ID: mdl-24477914

ABSTRACT

The transcriptional repressor B lymphocyte-induced maturation protein 1 (BLIMP1) is a master regulator of B and T cell differentiation. To examine the role of BLIMP1 in innate immunity, we used a conditional knockout (CKO) of Blimp1 in myeloid cells and found that Blimp1 CKO mice were protected from lethal infection induced by Listeria monocytogenes. Transcriptome analysis of Blimp1 CKO macrophages identified the murine chemokine (C-C motif) ligand 8, CCL8, as a direct target of Blimp1-mediated transcriptional repression in these cells. BLIMP1-deficient macrophages expressed elevated levels of Ccl8, and consequently Blimp1 CKO mice had higher levels of circulating CCL8, resulting in increased neutrophils in the peripheral blood, promoting a more aggressive antibacterial response. Mice lacking the Ccl8 gene were more susceptible to L. monocytogenes infection than were wild-type mice. Although CCL8 failed to recruit neutrophils directly, it was chemotactic for γ/δ T cells, and CCL8-responsive γ/δ T cells were enriched for IL-17F. Finally, CCL8-mediated enhanced clearance of L. monocytogenes was dependent on γ/δ T cells. Collectively, these data reveal an important role for BLIMP1 in modulating host defenses by suppressing expression of the chemokine CCL8.


Subject(s)
Chemokine CCL8/immunology , Gene Expression Regulation/immunology , Listeria monocytogenes/immunology , Listeriosis/immunology , Macrophages/immunology , Transcription Factors/immunology , Animals , Chemokine CCL8/genetics , Gene Expression Regulation/genetics , Listeriosis/genetics , Macrophages/pathology , Mice , Mice, Knockout , Neutrophils/immunology , Neutrophils/pathology , Positive Regulatory Domain I-Binding Factor 1 , Receptors, Antigen, T-Cell, gamma-delta/genetics , Receptors, Antigen, T-Cell, gamma-delta/immunology , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Transcription Factors/genetics , Transcription, Genetic/genetics , Transcription, Genetic/immunology
10.
Nat Med ; 19(10): 1208-10, 2013 Oct.
Article in English | MEDLINE | ID: mdl-24100978

ABSTRACT

After myocardial infarction (MI), circulating B cells produce the chemokine Ccl7, which mobilizes inflammatory monocytes from the bone marrow into the blood, after which they are then recruited to the injured heart, a new study shows. B cell depletion after MI limits myocardial injury and improves heart function, suggesting a new approach for the management of acute MI (pages 1273­1280).


Subject(s)
B-Lymphocytes/physiology , Heart/physiopathology , Monocytes/physiology , Myocardial Infarction/physiopathology , Animals , Humans
11.
Exp Dermatol ; 22(11): 705-9, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24433180

ABSTRACT

Leukotrienes constitute a group of lipid mediators, which may be subdivided into two groups, with leukotriene B4 on the one hand and cysteinyl leukotrienes on the other. Although leukotrienes are abundantly expressed in skin affected by diverse chronic inflammatory diseases, including atopic dermatitis, psoriasis, pemphigus vulgaris and bullous pemphigoid, their pathological roles in these diseases have remained elusive. Recent data now reveal that both leukotriene B4 and cysteinyl leukotrienes are indispensable in the pathogenesis of atopic dermatitis, with leukotriene B4 initiating the recruitment of inflammatory cells, particularly neutrophils and TH 2 cells into the skin, and cysteinyl leukotrienes later inducing characteristic structural alterations of chronically affected skin, specifically skin fibrosis and keratinocyte proliferation. Thus, these results reveal a sequential cooperation of LTB4 and cysteinyl leukotrienes to initiate and perpetuate allergic skin inflammation. These new insights highlight leukotrienes as promising therapeutic targets in allergic skin inflammation and should encourage more research into the role of leukotrienes in other inflammatory skin diseases.


Subject(s)
Hypersensitivity/immunology , Inflammation/pathology , Leukotriene B4/metabolism , Neutrophils/cytology , Animals , Cell Proliferation , Dermatitis, Atopic/immunology , Fibrosis , Humans , Keratinocytes/cytology , Lipids/chemistry , Mice , Receptors, Leukotriene/immunology , Skin/pathology , Skin Diseases/immunology , Th2 Cells/cytology
12.
Proc Natl Acad Sci U S A ; 109(46): E3177-85, 2012 Nov 13.
Article in English | MEDLINE | ID: mdl-23112187

ABSTRACT

Neutrophil recruitment into the joint is a hallmark of inflammatory arthritides, including rheumatoid arthritis (RA). In a mouse model of autoantibody-induced inflammatory arthritis, neutrophils infiltrate the joint via multiple chemoattractant receptors, including the leukotriene B(4) (LTB(4)) receptor BLT1 and the chemokine receptors CCR1 and CXCR2. Once in the joint, neutrophils perpetuate their own recruitment by releasing LTB(4) and IL-1ß, presumably after activation by immune complexes deposited on joint structures. Two pathways by which immune complexes may activate neutrophils include complement fixation, resulting in the generation of C5a, and direct engagement of Fcγ receptors (FcγRs). Previous investigations showed that this model of autoantibody-induced arthritis requires the C5a receptor C5aR and FcγRs, but the simultaneous necessity for both pathways was not understood. Here we show that C5aR and FcγRs work in sequence to initiate and sustain neutrophil recruitment in vivo. Specifically, C5aR activation of neutrophils is required for LTB(4) release and early neutrophil recruitment into the joint, whereas FcγR engagement upon neutrophils induces IL-1ß release and subsequent neutrophil-active chemokine production, ensuring continued inflammation. These findings support the concept that immune complex-mediated leukocyte activation is not composed of overlapping and redundant pathways, but that each element serves a distinct and critical function in vivo, culminating in tissue inflammation.


Subject(s)
Arthritis, Experimental/immunology , Neutrophil Infiltration/immunology , Neutrophils/immunology , Receptor, Anaphylatoxin C5a/immunology , Receptors, IgG/immunology , Signal Transduction/immunology , Animals , Arthritis, Experimental/chemically induced , Arthritis, Experimental/genetics , Arthritis, Experimental/pathology , Autoantibodies/adverse effects , Autoantibodies/pharmacology , Chemokines/genetics , Chemokines/immunology , Complement C5a/genetics , Complement C5a/immunology , Interleukin-1beta/genetics , Interleukin-1beta/immunology , Joints/immunology , Joints/pathology , Leukotriene B4/genetics , Leukotriene B4/immunology , Mice , Mice, Knockout , Neutrophil Infiltration/genetics , Neutrophils/pathology , Receptor, Anaphylatoxin C5a/genetics , Receptors, CCR1/genetics , Receptors, CCR1/immunology , Receptors, IgG/genetics , Receptors, Interleukin-8B/genetics , Receptors, Interleukin-8B/immunology , Receptors, Leukotriene B4/genetics , Receptors, Leukotriene B4/immunology , Signal Transduction/genetics
13.
PLoS One ; 6(10): e26342, 2011.
Article in English | MEDLINE | ID: mdl-22028860

ABSTRACT

OBJECTIVE: To investigate the role of IL-17RA signaling in the effector phase of inflammatory arthritis using the K/BxN serum-transfer model. METHODS: Wild-type and Il17ra(-/-) mice were injected with serum isolated from arthritic K/BxN mice and their clinical score was recorded daily. Mice were also harvested on days 12 and 21 and ankles were analyzed for cytokine and chemokine mRNA expression by qPCR on day 12 and for bone and cartilage erosions by histology on day 21, respectively. The induction of cytokine and chemokine expression levels by IL-17A in synovial-like fibroblasts was also analyzed using qPCR. RESULTS: Il17ra(-/-) mice were partially protected from clinical signs of arthritis and had markedly fewer cartilage and bone erosions. The expression of several pro-inflammatory mediators, including the chemokines KC/CXCL1, MIP-2/CXCL2, LIX/CXCL5 MIP-1γ/CCL9, MCP-3/CCL7, MIP-3α/CCL20, the cytokines IL-1ß, IL-6, RANKL and the matrix metalloproteinases MMP2, MMP3, and MMP13 were decreased in the ankles of Il17ra(-/-) mice compared to wild-type mice. Many of these proinflammatory genes attenuated in the ankles of Il17ra(-/-) mice were shown to be directly induced by IL-17A in synovial fibroblasts in vitro. CONCLUSIONS: IL-17RA signaling plays a role as an amplifier of the effector phase of inflammatory arthritis. This effect is likely mediated by direct activation of synovial fibroblasts by IL-17RA to produce multiple inflammatory mediators, including chemokines active on neutrophils. Therefore, interrupting IL-17RA signaling maybe a promising pharmacological target for the treatment of inflammatory arthritis.


Subject(s)
Antibodies/adverse effects , Arthritis, Experimental/chemically induced , Arthritis, Experimental/pathology , Receptors, Interleukin-17/metabolism , Signal Transduction , Animals , Antibodies/blood , Antibodies/immunology , Arthritis, Experimental/metabolism , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Inflammation Mediators/metabolism , Matrix Metalloproteinase 3/metabolism , Mice , Neutrophils/metabolism , RANK Ligand/metabolism , Receptors, Interleukin-17/deficiency , Synovial Fluid/metabolism
14.
Trends Immunol ; 32(10): 452-60, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21839682

ABSTRACT

Neutrophils are pivotal effector cells of innate immunity. Their recruitment into peripheral tissues is indispensable for host defense. Given their destructive potential, neutrophil entry into tissue must be tightly regulated in vivo to avoid damage to the host. An array of chemically diverse chemoattractants is active on neutrophils and participates in recruitment. Neutrophil chemoattractants were thought redundant in the control of neutrophil recruitment into peripheral tissue, based on their often indistinguishable effects on neutrophils in vitro and their frequently overlapping patterns of expression at inflammatory sites in vivo. Recent data, however, suggest that neutrophil chemoattractants have unique functions in the recruitment of neutrophils into inflammatory sites in vivo, dictated by their distinct patterns of temporal and spatial expression.


Subject(s)
Chemokines/immunology , Immunity, Innate , Inflammation/immunology , Neutrophil Infiltration/immunology , Neutrophils , Receptors, Chemokine/immunology , Signal Transduction/immunology , Animals , Bone Marrow/immunology , Cell Movement , Chemokines/metabolism , Humans , Inflammation/metabolism , Inflammation/pathology , Leukocyte Count , Mice , Neutrophils/immunology , Neutrophils/metabolism , Receptors, Chemokine/metabolism
15.
Immunity ; 33(2): 266-78, 2010 Aug 27.
Article in English | MEDLINE | ID: mdl-20727790

ABSTRACT

A large and diverse array of chemoattractants control leukocyte trafficking, but how these apparently redundant signals collaborate in vivo is still largely unknown. We previously demonstrated an absolute requirement for the lipid chemoattractant leukotriene B(4) (LTB(4)) and its receptor BLT1 for neutrophil recruitment into the joint in autoantibody-induced arthritis. We now demonstrate that BLT1 is required for neutrophils to deliver IL-1 into the joint to initiate arthritis. IL-1-expressing neutrophils amplify arthritis through the production of neutrophil-active chemokines from synovial tissue cells. CCR1 and CXCR2, two neutrophil chemokine receptors, operate nonredundantly to sequentially control the later phase of neutrophil recruitment into the joint and mediate all neutrophil chemokine activity in the model. Thus, we have uncovered a complex sequential relationship involving unique contributions from the lipid mediator LTB(4), the cytokine IL-1, and CCR1 and CXCR2 chemokine ligands that are all absolutely required for effective neutrophil recruitment into the joint.


Subject(s)
Arthritis/immunology , Chemokines/immunology , Interleukin-1alpha/immunology , Interleukin-1beta/immunology , Leukotriene B4/immunology , Neutrophils/immunology , Animals , Arthritis/genetics , Arthritis/pathology , Cells, Cultured , Chemokines/biosynthesis , Disease Models, Animal , Disease Susceptibility , Interleukin-1alpha/deficiency , Interleukin-1beta/biosynthesis , Interleukin-1beta/deficiency , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, CCR1/immunology , Receptors, Interleukin-8B/immunology , Receptors, Leukotriene/deficiency , Receptors, Leukotriene/immunology , Synovial Fluid/immunology
16.
Nat Med ; 14(1): 45-54, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18066075

ABSTRACT

Aberrant wound-healing responses to injury have been implicated in the development of pulmonary fibrosis, but the mediators directing these pathologic responses have yet to be fully identified. We show that lysophosphatidic acid levels increase in bronchoalveolar lavage fluid following lung injury in the bleomycin model of pulmonary fibrosis, and that mice lacking one of its receptors, LPA1, are markedly protected from fibrosis and mortality in this model. The absence of LPA1 led to reduced fibroblast recruitment and vascular leak, two responses that may be excessive when injury leads to fibrosis rather than to repair, whereas leukocyte recruitment was preserved during the first week after injury. In persons with idiopathic pulmonary fibrosis, lysophosphatidic acid levels in bronchoalveolar lavage fluid were also increased, and inhibition of LPA1 markedly reduced fibroblast responses to the chemotactic activity of this fluid. LPA1 therefore represents a new therapeutic target for diseases in which aberrant responses to injury contribute to fibrosis, such as idiopathic pulmonary fibrosis.


Subject(s)
Fibroblasts/metabolism , Lung Injury , Receptors, Lysophosphatidic Acid/physiology , Animals , Bleomycin/pharmacology , Bronchoalveolar Lavage Fluid , Female , Leukocytes/metabolism , Lung/pathology , Lysophospholipids/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Biological , Pulmonary Fibrosis/pathology , Receptors, Lysophosphatidic Acid/metabolism
17.
J Exp Med ; 203(4): 829-35, 2006 Apr 17.
Article in English | MEDLINE | ID: mdl-16567386

ABSTRACT

Neutrophil recruitment into tissue plays an important role in host defense and disease pathogenesis, including the inflammatory arthritides. A multitude of diverse chemoattractants have been implicated in neutrophil recruitment, suggesting that they have overlapping functions in mediating this critical biological response. However, here we demonstrate a unique, non-redundant role for the leukotriene B4 receptor BLT1 in mediating neutrophil recruitment into the joint in the K/BxN mouse model of inflammatory arthritis. We demonstrate that neutrophil expression of BLT1 was absolutely required for arthritis generation and chemokine production in this model, and that specific BLT1 inhibition reversed established disease. Adoptive transfer of wild-type (WT) neutrophils restored arthritis and chemokine production in BLT1(-/-) mice. Surprisingly, the primary effect of the transferred WT neutrophils into BLT1(-/-) mice was to promote the entry of endogenous BLT1(-/-) neutrophils into the joints of these mice. However, continued joint inflammation was dependent on the presence of WT neutrophils, indicating an ongoing specific requirement for BLT1-activated neutrophils in mediating BLT1(-/-) neutrophil recruitment by other chemoattractants. These experiments demonstrate that neutrophil BLT1 functions in a novel and essential non-cell-autonomous manner to enable the recruitment of additional neutrophils not expressing this receptor, thereby amplifying the inflammatory response in autoantibody-induced arthritis.


Subject(s)
Arthritis, Experimental/immunology , Leukotriene B4/metabolism , Neutrophil Infiltration/immunology , Neutrophils/immunology , Neutrophils/pathology , Receptors, Leukotriene B4/physiology , Receptors, Purinergic P2/physiology , Animals , Arthritis, Experimental/pathology , Autoantibodies/administration & dosage , Cell Movement/immunology , Cells, Cultured , Chemokines/metabolism , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Neutrophils/metabolism , Receptors, Leukotriene B4/metabolism , Receptors, Purinergic P2/metabolism , Synovial Membrane/metabolism
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