Protective effects of plasmin(ogen) in a mouse model of Staphylococcus aureus–induced arthritis

Abstract

Objective. To assess the functional roles of plasmin in a murine model of Staphylococcus aureus-induced bacterial arthritis.Methods. Bacterial arthritis was induced in plasminogen-deficient (Plg -/-) and wild-type (Plg ؉/؉ ) littermates by local injection of 1 ؋ 10 6 colony-forming units of S aureus into the knee joints. Human plasminogen was administered to Plg -/-mice on days 0-7 or days 7-14. Antibiotic treatment was administered to Plg -/-mice on days 7-14. Bacteria counts and histologic, immunohistochemical, and Western blot analyses were performed.Results. In Plg ؉/؉ mice, S aureus counts had declined within 2 days, and by day 28 the bacteria had been completely eliminated. However, S aureus was still detectable in all injected joints from Plg -/-mice, and bacteria counts were 27 times higher than the amount injected on day 0. The extent of macrophage and neutrophil recruitment to the infected joints was comparable for Plg ؉/؉ and Plg -/-mice on days 1, 7, and 14. The activation of these inflammatory cells appeared to be impaired in Plg -/-mice, however. Treatment of Plg -/-mice with antibiotic (cloxacillin) resulted in successful killing of the bacteria, but the necrotic tissue remained in the infected joints. When human plasminogen was given intravenously to Plg -/-mice daily for 7 days, bacterial clearance was greatly improved as compared with their untreated counterparts, and the amount of necrotic tissue in the joint cavity was dramatically reduced. The expression of interleukin 6 (IL-6) and IL-10 was higher in Plg ؉/؉ mice than in Plg -/-mice during bacterial arthritis.Conclusion. Our findings indicate that plasmin plays a pluripotent role in protecting against S aureusinduced arthritis by activating inflammatory cells, killing bacteria, removing necrotic tissue, and enhancing cytokine expression.Staphylococcus aureus is the microorganism most frequently associated with bacterial arthritis (1,2), which results in synovial inflammation, cartilage and bone destruction, and eventually, joint deformity (3). The plasminogen activator (PA) system is a general proteolytic system that has been suggested to play an important role in the development of different types of arthritis (4-6). Plasminogen can be activated to the broadspectrum protease plasmin by either of the 2 physiologic PAs, tissue-type PA (tPA) or urokinase-type PA (uPA). In addition to its function in fibrinolysis, plasmin(ogen) plays a role in degradation of the extracellular matrix (ECM) and in tissue remodeling during many physiologic and pathologic processes, such as wound healing (7), tumor cell invasion, angiogenesis, and rheumatoid arthritis (RA) (8). There is some evidence that plasmin can also induce proinflammatory responses independently of its proteolytic properties (9).A number of pathogenic microorganisms have been shown to bind plasminogen (10-12). The subsequent activation of plasminogen to plasmin may contribute to the virulence of these microorganisms (13). However, during bacterial arthritis, plasmin may also be of importance...

Plasminogen activator/plasmin system in arthritis and inflammation: Friend or foe?

“…The findings by Guo et al (16) in Plg Ϫ/Ϫ mice with septic arthritis add to the complexity of the function of the PA/plasmin system in arthritis and in host defense. More sophisticated gene targeting of the various components in mice, such as by tissue-specific and conditional targeting strategies, is needed to probe more selectively as to what the PA/plasmin system is actually doing in conditions of pathology.…”

“…Given the results reported by Guo et al (16), it seems as though septic arthritis has now to be included in the biology of this system. What has to be considered is that the PA/ plasmin system can be involved potentially in several processes, such as fibrinolysis, tissue remodeling involving many substrates, cell migration, cell activation via PARs, complement (for example, C3 and C5) activation, and latent cytokine activation (1).…”

“…In this issue of Arthritis & Rheumatism, Guo et al (16) describe the findings of their examination of septic arthritis progression in Plg Ϫ/Ϫ mice following intraarticular injection of Staphylococcus aureus, the microorganism frequently associated with bacterial arthritis (17). Just to add to the complexity, it is interesting and perhaps surprising, given the literature on the contribution to bacterial virulence of plasminogen activation to plasmin by bacterial enzymes, possibly via fibrin dissolution (see, for example, refs.…”

“…It was concluded by Guo et al (16) that plasmin protects against S aureus-induced arthritis by activating inflammatory cells, killing bacteria, removing necrotic tissue, and enhancing cytokine (IL-6 and IL-10) expression. It was further concluded that fibrin deposition was not a major factor that caused the difference in arthritis severity between the wild-type and Plg Ϫ/Ϫ mice, since it was increased to similar levels in the joints of the two strains.…”

“…What has to be considered is that the PA/ plasmin system can be involved potentially in several processes, such as fibrinolysis, tissue remodeling involving many substrates, cell migration, cell activation via PARs, complement (for example, C3 and C5) activation, and latent cytokine activation (1). Another consideration is that for the arthritis studies with gene-deficient mice, monarticular models, including now a monarticular model of septic arthritis (16), and the systemic CIA model have been used, the former models likely making a contribution from trauma due to injection of the arthritogen directly into the joint (1,8,9,21). At least in the widely used systemic CIA model of RA, which does not involve such local irritation, the results from the depletion of the individual PAs using gene-deficient mice point toward some nonredundant functions of uPA and tPA and with even opposite consequences, suggesting the possibility of selective targeting (1,9).…”