Grespan, R. et al. CXCR2-specific chemokines mediate leukotriene B4-dependent recruitment of neutrophils to inflamed joints in mice with antigen-induced arthritis. Arthritis Rheum. 58, 2030-2040

University of São Paulo, São Paulo, Brazil.
Arthritis & Rheumatology (Impact Factor: 7.76). 07/2008; 58(7):2030-40. DOI: 10.1002/art.23597
Source: PubMed


To investigate the mechanism underlying neutrophil migration into the articular cavity in experimental arthritis and, by extension, human inflammatory synovitis.
Antigen-induced arthritis (AIA) was generated in mice with methylated bovine serum albumin (mBSA). Migration assays and histologic analysis were used to evaluate neutrophil recruitment to knee joints. Levels of inflammatory mediators were measured by enzyme-linked immunosorbent assay. Antibodies and pharmacologic inhibitors were used in vivo to determine the role of specific disease mediators. Samples of synovial tissue and synovial fluid from rheumatoid arthritis (RA) or osteoarthritis patients were evaluated for CXCL1 and CXCL5 expression.
High levels of CXCL1, CXCL5, and leukotriene B4 (LTB4) were expressed in the joints of arthritic mice. Confirming their respective functional roles, repertaxin (a CXCR1/CXCR2 receptor antagonist), anti-CXCL1 antibody, anti-CXCL5 antibody, and MK886 (a leukotriene synthesis inhibitor) reduced mBSA-induced neutrophil migration to knee joints. Repertaxin reduced LTB4 production in joint tissue, and neutrophil recruitment induced by CXCL1 or CXCL5 was inhibited by MK886, suggesting a sequential mechanism. Levels of both CXCL1 and CXCL5 were elevated in synovial fluid and were released in vitro by RA synovial tissues. Moreover, RA synovial fluid neutrophils stimulated with CXCL1 or CXCL5 released significant amounts of LTB4.
Our data implicate CXCL1, CXCL5, and LTB4, acting sequentially, in neutrophil migration in AIA. Elevated levels of CXCL1 and CXCL5 in the synovial compartment of RA patients provide robust comparative data indicating that this mechanism plays a role in inflammatory joint disease. Together, these results suggest that inhibition of CXCL1, CXCL5, or LTB4 may represent a potential therapeutic strategy in RA.

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Available from: Marcelo H Napimoga
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    • "The mBSA challenge induces a significant neutrophil migration which peaks at 24 hours and subsides by seven days after challenge [31,32]. Fc Receptors are involved in this activation [33,34], but – in contrast to exclusively antibody-mediated arthritis models – complement appears to play a minor role. This conclusion has been derived from findings which demonstrate that flare-up reactions of AIA are complement-independent, and that neutrophils occur in the synovial tissue of complement-depleted mice as well [35]. "
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    ABSTRACT: The role of endogenous glucocorticoids (GC) in the initiation and maintenance of rheumatoid arthritis (RA) remains unclear. We demonstrated previously that disruption of GC signalling in osteoblasts results in a profound attenuation of K/BxN serum-induced arthritis, a mouse model of RA. To determine whether or not the modulation of the inflammatory response by osteoblasts involves T cells, we studied the effects of disrupted osteoblastic GC-signalling in the T cell-dependent model of antigen-induced arthritis (AIA). Acute arthritis was induced in pre-immunised 11-week-old male 11beta-hydroxysteroid dehydrogenase type 2 transgenic (tg) mice and their wild-type (WT) littermates by intra-articular injection of methylated bovine serum albumine (mBSA) into one knee joint. Knee diameter was measured every 1-2 days until euthanasia on day 14 post injection. In a separate experiment, arthritis was maintained for 28 days by weekly reinjections of mBSA. Tissues were analysed by histology, histomorphometry and microfocal-computed tomography. Serum cytokines levels were determined by multiplex suspension array. In both short and long term experiments, arthritis developed in tg and WT mice with no significant difference between both groups. Histological indices of inflammation, cartilage damage and bone erosion were similar in tg and WT mice. Bone volume and turnover at the contralateral tibia and systemic cytokine levels were not different. Acute murine AIA is not affected by a disruption in osteoblastic GC signalling. These data indicate that osteoblasts do not modulate the T cell-mediated inflammatory response via a GC-dependent pathway.
    Full-text · Article · Feb 2014 · BMC Musculoskeletal Disorders
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    • "AIA was induced according to Grespan et al. (2008) [16]. Fourteen BALB/c mice were sensitized by subcutaneous (s.c.) injected with 500 μg of mBSA (Sigma Aldrich, St. Louis/EUA) dissolved in 0.2 ml of an emulsion containing 0.1 ml of 0.9% saline and 0.1 ml of complete Freund’s adjuvant (Sigma Aldrich, St. Louis/USA) administered on day 0. Booster injections were administered for almost 2 weeks (7-14 days) using incomplete Freund’s adjuvant (Sigma Aldrich, St. Louis/USA). "
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    ABSTRACT: Equisetum giganteum is a plant used in traditional medicine as diuretic. From our knowledge this is the first time this plant is tested in an in vivo model of acute inflammation. To evaluate the effect of aqueous extract of giant horsetail (AEGH) as immunomodulatory therapy, antigen-induced arthritis (AIA) was generated in mice with methylated bovine serum albumin (mBSA). Inflammation was evaluated by articular nociception, leukocytes migration and lymphocyte proliferation. AEGH reduced nociception at 3, 6 and 24 h (P < 0.01), decreased leukocyte migration (P < 0.015), and inhibited lymphocyte proliferation stimulated with Concanavalin A and Lipopolysaccharide (P < 0.05). In conclusion, AEGH has an anti-inflammatory potential in acute model of inflammation, as well as immunomodulatory effect on both B and T lymphocytes, with an action independent of cytotoxicity.
    Full-text · Article · Dec 2013 · The Open Rheumatology Journal
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    • "For instance, CXCL1/KC is expressed at earlier time points, while CXCL2/MIP-2 predominates during the later phase (Endlich et al., 2002). Secondly, another possible explanation is that the earlier production of CXCL1/KC could be triggering a cascade of other chemotactic mediators, which, in turn, cause a maximal recruitment of neutrophils (Grespan et al., 2008; Vieira et al., 2009). Another important peripheral pronociceptive mediator involved in the genesis of post-incisional pain seems to be IL-1b (Wolf et al., 2008; Hu et al., 2010). "
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    ABSTRACT: Background: Neutrophil recruitment mediated by the CXCL1/KC chemokine and its receptors CXCR1/CXCR2 plays a critical role in inflammatory diseases. Recently, neutrophil migration and activation triggered by CXCL1-CXCR1/2 signalling was implicated in inflammatory nociception; however, their role in post-surgical pain has not been elucidated. In this study, we addressed the function of neutrophils in the genesis of post-incisional pain in an experimental model of post-surgical pain. Methods: Mechanical hyperalgesia was determined with an electronic von Frey test in a mouse hindpaw incisional model. Neutrophil accumulation and the level of CXCL1/KC in the plantar tissue were determined by myeloperoxidase activity assay and enzyme-linked immunosorbent assay, respectively. Results: An incision in the mouse hindpaw produces long-lasting mechanical hyperalgesia that persists for at least 72 h after surgery. Following surgery, there was an increase in both neutrophil accumulation and the CXCL1/KC level in the incised paws. The depletion of the mouse neutrophils by vinblastine sulphate or anti-neutrophil antibody treatments reduced the mechanical hyperalgesia after paw incision. Furthermore, the treatment of mice with ladarixin, an orally acting CXCR1/2 antagonist, also reduced both the mechanical hyperalgesia and the infiltration of neutrophils in the incised paws. Conclusion: In conclusion, it appears that after surgical processes, neutrophils are recruited by CXCL1-CXCR1/2 signalling and participate in the cascade of events, leading to mechanical hyperalgesia. These results suggest that blocking neutrophil migration through the inhibition of CXCL1-CXCR1/2 signalling might be a target to control post-surgical pain.
    Full-text · Article · May 2013 · European journal of pain (London, England)
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