TLR2 modulates inflammation in zymosan-induced arthritis in mice

The interplay between the innate and acquired immune systems in chronic inflammation is not well documented. We have investigated the mechanisms of inflammation in murine zymosan-induced arthritis (ZIA) in the light of recent data on the roles of Toll-like receptor 2 (TLR2) and Dectin-1 in the activation of monocyte/macrophages by zymosan. The severity of inflammation, joint histology, lymphocyte proliferation and antibody production in response to zymosan were analyzed in mice deficient in TLR2 and complement C3, and the effects of Dectin-1 inhibition by laminarin were studied. In comparison with wild-type animals, TLR2-deficient mice showed a significant decrease in the early (day 1) and late phases (day 24) of joint inflammation. C3-deficient mice showed no differences in technetium uptake or histological scoring. TLR2-deficient mice also showed a significant decrease in lymph node cell proliferation in response to zymosan and a lower IgG antibody response to zymosan at day 25 in comparison with wild-type controls, indicating that TLR2 signalling has a role in the development of acquired immune responses to zymosan. Although laminarin, a soluble β-glucan, was able to significantly inhibit zymosan uptake by macrophages in vitro, it had no effect on ZIA in vivo. These results show that ZIA is more prolonged than was originally described and involves both the innate and acquired immune pathways. C3 does not seem to have a major role in this model of joint inflammation

Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation

INTRODUCTION: Tissue factor (TF) activation of the coagulation proteases enhances inflammation in animal models of arthritis and endotoxemia, but the mechanism of this effect is not yet fully understood - in particular, whether this is primarily due to fibrin formation or through activation of protease activated receptors (PARs). METHODS: We induced extravascular inflammation by injection of recombinant soluble murine TF (sTF1-219) in the hind paw. The effects of thrombin inhibition, fibrinogen and platelet depletion were evaluated, as well as the effects of PAR deficiency using knockout mice deficient for each of the PARs. RESULTS: Injection of soluble TF provoked a rapid onset of paw swelling. Inflammation was confirmed histologically and by increased serum IL-6 levels. Inflammation was significantly reduced by depletion of fibrinogen (P < 0.05) or platelets (P = 0.015), and by treatment with hirudin (P = 0.04) or an inhibitor of activated factor VII (P < 0.001) compared with controls. PAR-4-deficient mice exhibited significantly reduced paw swelling (P = 0.003). In contrast, a deficiency in either PAR-1, PAR-2 or PAR-3 did not affect the inflammatory response to soluble TF injection. CONCLUSION: Our results show that soluble TF induces acute inflammation through a thrombin-dependent pathway and both fibrin deposition and platelet activation are essential steps in this process. The activation of PAR-4 on platelets is crucial and the other PARs do not play a major role in soluble TF-induced inflammation

Circulating CD26 Is Negatively Associated with Inflammation in Human and Experimental Arthritis

Dipeptidyl peptidase IV (DPPIV, CD26), a protease-cleaving N-terminal X-Pro dipeptide from selected proteins including some chemokines, is expressed both as a soluble form in plasma and on the cell surface of various immune and nonimmune cell types. To gain insights into the pathophysiological role of CD26 in arthritis, we explored DPPIV/CD26 expression during murine antigen-induced arthritis (AIA), an experimental model of arthritis. AIA induction led to reduced plasma DPPIV activity. In CD26-deficient mice, the severity of AIA was increased as assessed by enhanced technetium uptake and by increased histological parameters of inflammation (synovial thickness and exudate). We demonstrated that CD26 controls the in vivo half-life of the intact active form of the proinflammatory chemokine stromal cell-derived factor-1 (SDF-1). CD26-deficient mice exhibited increased levels of circulating active SDF-1, associated with increased numbers of SDF-1 receptor (CXCR4)-positive cells infiltrating arthritic joints. In a clinical study, plasma levels of DPPIV/CD26 from rheumatoid arthritis patients were significantly decreased when compared to those from osteoarthritis patients and inversely correlate with C-reactive protein levels. In conclusion, decreased circulating CD26 levels in arthritis may influence CD26-mediated regulation of the chemotactic SDF-1/CXCR4 axis

Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation-4

*= 0.001, Wilcoxon rank sum test. WT, wildtype; KO, knockout.<p><b>Copyright information:</b></p><p>Taken from "Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation"</p><p>http://arthritis-research.com/content/10/2/R42</p><p>Arthritis Research & Therapy 2008;10(2):R42-R42.</p><p>Published online 15 Apr 2008</p><p>PMCID:PMC2453761.</p><p></p

Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation-3

Ur different protease activated receptors (PARs). PAR-1-deficient mice. PAR-2-deficient mice. PAR-3-deficient mice. PAR-4-deficient mice. In each experiment, footpad swelling was assessed in the PAR-deficient mice and their littermates (+/+ or +/-) as controls.<p><b>Copyright information:</b></p><p>Taken from "Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation"</p><p>http://arthritis-research.com/content/10/2/R42</p><p>Arthritis Research & Therapy 2008;10(2):R42-R42.</p><p>Published online 15 Apr 2008</p><p>PMCID:PMC2453761.</p><p></p

Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation-2

or untreated mice (n = 7), were injected with 1 μg soluble tissue factor. Results from all treated groups were significantly reduced (< 0.05 by test) compared with the control group. Wildtype mice were treated with ancrod (n = 7) or with phosphate-buffered saline (n = 7) and then injected with 1 μg soluble tissue factor. Results from ancrod-treated mice are significantly different from the control group, at all time points (< 0.05 by test).<p><b>Copyright information:</b></p><p>Taken from "Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation"</p><p>http://arthritis-research.com/content/10/2/R42</p><p>Arthritis Research & Therapy 2008;10(2):R42-R42.</p><p>Published online 15 Apr 2008</p><p>PMCID:PMC2453761.</p><p></p

Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation-7

Hanges. Phosphate-buffered saline-injected mice showed minimal signs of inflammation. Staining for macrophages was strongly positive. CD3-positive T cells were also present. Staining specificity was confirmed using, as primary antibody, nonimmune isotype-matched antibodies. Fibrin deposition was assessed by fibrin immunohistochemistry.<p><b>Copyright information:</b></p><p>Taken from "Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation"</p><p>http://arthritis-research.com/content/10/2/R42</p><p>Arthritis Research & Therapy 2008;10(2):R42-R42.</p><p>Published online 15 Apr 2008</p><p>PMCID:PMC2453761.</p><p></p

Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation-0

) were detected using a polyclonal rabbit anti human TF antibody. Effect of sTF injected into the footpad: 1 μg sTF (in 10 μl phosphate-buffered saline) was injected into the intraplantar region of the right hindfootpad. The contralateral footpad was injected with the same volume of phosphate-buffered saline. Swelling was observed in the sTF-injected footpad after 2 hours and was sustained over 24 hours (photograph). Dose-dependent effect of sTF-induced inflammation: 0.2 to 5 μg sTF in 10 μl was administered into the hindfootpad. The contralateral footpad was injected with phosphate-buffered saline. Results expressed as the percentage increase in the right over left footpad thickness. *< 0.05, **< 0.01 and ***< 0.001, Wilcoxon rank sum test.<p><b>Copyright information:</b></p><p>Taken from "Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation"</p><p>http://arthritis-research.com/content/10/2/R42</p><p>Arthritis Research & Therapy 2008;10(2):R42-R42.</p><p>Published online 15 Apr 2008</p><p>PMCID:PMC2453761.</p><p></p

Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation-1

Hanges. Phosphate-buffered saline-injected mice showed minimal signs of inflammation. Staining for macrophages was strongly positive. CD3-positive T cells were also present. Staining specificity was confirmed using, as primary antibody, nonimmune isotype-matched antibodies. Fibrin deposition was assessed by fibrin immunohistochemistry.<p><b>Copyright information:</b></p><p>Taken from "Essential role of platelet activation via protease activated receptor 4 in tissue factor-initiated inflammation"</p><p>http://arthritis-research.com/content/10/2/R42</p><p>Arthritis Research & Therapy 2008;10(2):R42-R42.</p><p>Published online 15 Apr 2008</p><p>PMCID:PMC2453761.</p><p></p