Enhanced neutrophil extravasation and rapid progression of proteoglycan‐induced arthritis in TSG‐6–knockout mice

Abstract

Objective. To gain insight into the mechanisms of the antiinflammatory effect of tumor necrosis factor ␣ (TNF␣)-induced protein 6 (Tnfip6) in arthritis, using Tnfip6-deficient animals.Methods. TNF␣-stimulated gene 6 (TSG-6) coding for Tnfip6 was disrupted. Tnfip6-deficient mice were backcrossed into proteoglycan-induced arthritis (PGIA)-susceptible BALB/c mice, and arthritis was induced by systemic immunization with cartilage proteoglycan (PG). Thioglycollate-induced sterile peritonitis was also assessed, to monitor the early events of neutrophil extravasation in wild-type and Tnfip6-deficient mice in the presence or absence of treatment with recombinant murine Tnfip6.Results. The onset of PGIA was similar, but progression and severity were significantly greater, in Tnfip6-deficient mice compared with wild-type BALB/c mice. However, this was not associated with enhanced T or B cell responses to cartilage PGs, but rather, an early and more extensive infiltration of the synovium with neutrophil leukocytes was the most prominent histopathologic feature of PGIA in Tnfip6-deficient mice. This was accompanied by elevated serum levels of interleukin-6 and amyloid A, and significantly increased activities of the enzymes plasmin, myeloperoxidase, and neutrophil elastase in the inflamed paw joints of Tnfip6-null mice, when compared with that of the wild-type littermates. Loss of control over several components of inflammation resulted in extensive and rapid cartilage degradation, bone erosion, joint ankylosis, and deformities in Tnfip6-null animals. In support of the antiinflammatory effect of Tnfip6 via the inhibition of polymorphonuclear (PMN) cell efflux, neutrophil invasion during thioglycollate-induced peritonitis was 2-fold higher in Tnfip6-deficient animals than in wild-type animals, but was dramatically suppressed by intravenous injection of recombinant murine Tnfip6.Conclusion. Tnfip6 is a multifunctional antiinflammatory protein that is produced at the site of inflammation and can be retained by the hyaluronanrich extracellular matrix. A major effect of Tnfip6 is the inhibition of the extravasation of PMN cells, predominantly neutrophils, into the site of inflammation, most likely via a CD44/hyaluronan/Tnfip6-mediated blocking mechanism.

Hyaluronan cross-linking: a protective mechanism in inflammation?

“…The formation of cross-linked HA networks at the surface of synovium and cartilage could serve to protect these tissues during inflammation by providing a barrier to prevent the loss of matrix components and perhaps acting as a temporary scaffold to direct and enhance formation of new matrix. This hypothesis, although speculative, is consistent with the anti-inflammatory properties of TSG-6, which has been shown to be highly protective of cartilage matrix and enhances its repair in mouse models of rheumatoid arthritis [19,28]. Although this protective activity also involves other functions of TSG-6 (i.e.…”

TSG-6 Protein Is Crucial for the Development of Pulmonary Hyaluronan Deposition, Eosinophilia, and Airway Hyperresponsiveness in a Murine Model of Asthma

“…We have shown that TSG-6 deficiency leads to decreased airway eosinophilia. In contrast, other investigators have shown that TSG-6 deficiency has an enhancing effect on neutrophil migration into peripheral joints of mice undergoing a murine model of proteoglycan-induced arthritis (46). Reciprocally, exogenous TSG-6 inhibits neutrophil extravasation in a murine model of acute inflammation (47).…”

TNFα-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury

“…Veterinary care of the mice and the related animal experiments was approved by the University of Illinois Animal Resources Center. The TSG6 knockout mice originally generated on a BALB/c background (30) were obtained from Jackson Laboratory. Age-matched TSG6 +/+ and TSG6…”

“…Human and murine TSG6 proteins are ∼94% identical (4). Transgenic mice overexpressing TSG6 were resistant to collageninduced arthritis (CIA) (9), whereas inactivation of the TSG6 gene enhanced inflammation and increased the susceptibility to arthritis (30). Intravenous administration of MSCs in mice also prevented endotoxin-mediated ALI, apparently by reducing the expression of proinflammatory cytokines and neutrophil sequestration in lungs (13); however, siRNA-mediated suppression of TSG6 expression in MSCs prevented these protective effects, indicating the involvement of TSG6 in this protection.…”