Plasminogen Receptors and Fibrinolysis.

The ability of cells to promote plasminogen activation on their surfaces is now well recognized, and several distinct cell surface proteins have been demonstrated to function as plasminogen receptors. Here, we review studies demonstrating that plasminogen bound to cells, in addition to plasminogen directly bound to fibrin, plays a major role in regulating fibrin surveillance. We focus on the ability of specific plasminogen receptors on eukaryotic cells to promote fibrinolysis in the in vivo setting by reviewing data obtained predominantly in murine models. Roles for distinct plasminogen receptors in fibrin surveillance in intravascular fibrinolysis, immune cell recruitment in the inflammatory response, wound healing, and lactational development are discussed.

The plasminogen receptor, Plg-RKT, plays a role in inflammation and fibrinolysis during cutaneous wound healing in mice.

Wound healing is a complex physiologic process that proceeds in overlapping, sequential steps. Plasminogen promotes fibrinolysis and potentiates the inflammatory response during wound healing. We have tested the hypothesis that the novel plasminogen receptor, Plg-RKT, regulates key steps in wound healing. Standardized burn wounds were induced in mice and time dependence of wound closure was quantified. Healing in Plg-RKT-/- mice was significantly delayed during the proliferation phase. Expression of inflammatory cytokines was dysregulated in Plg-RKT-/- wound tissue. Consistent with dysregulated cytokine expression, a significant delay in wound healing during the proliferation phase was observed in mice in which Plg-RKT was specifically deleted in myeloid cells. Following wound closure, the epidermal thickness was less in Plg-RKT-/- wound tissue. Paradoxically, deletion of Plg-RKT, specifically in keratinocytes, significantly accelerated the rate of healing during the proliferation phase. Mechanistically, only two genes were upregulated in Plg-RKT-/- compared with Plg-RKT+/+ wound tissue, filaggrin, and caspase 14. Both filaggrin and caspase 14 promote epidermal differentiation and decrease proliferation, consistent with more rapid wound closure and decreased epidermal thickness during the remodeling phase. Fibrin clearance was significantly impaired in Plg-RKT-/- wound tissue. Genetic reduction of fibrinogen levels to 50% completely abrogated the effect of Plg-RKT deletion on the healing of burn wounds. Remarkably, the effects of Plg-RKT deletion on cytokine expression were modulated by reducing fibrinogen levels. In summary, Plg-RKT is a new regulator participating in different phases of cutaneous burn wound healing, which coordinately plays a role in the interrelated responses of inflammation, keratinocyte migration, and fibrinolysis.

Plasminogen is a master regulator and a potential drug candidate for the healing of radiation wounds.

Around 95% of cancer patients undergoing radiotherapy experience cutaneous side effects, and some develop radiation wounds or fibrosis. Currently, there is no effective treatment for these indications. We show here that plasminogen administration enhanced the healing of radiation wounds via pleiotropic effects on gene expression. Using RNA sequencing, we found that plasminogen downregulated the expression of genes in the TLR, TNF, WNT, MAPK, and TGF-ß signaling pathways, and enhanced the anti-inflammatory effect of arachidonic acid, leading to significantly decreased inflammation and improved remodeling of granulation tissue compared with placebo treatment. In addition, plasminogen induced metabolic changes, including decreased glycolysis. Importantly, many of the factors downregulated by plasminogen are pro-fibrotic. Therefore, in radiation wounds with excessive inflammation, plasminogen is able to enhance and redirect the healing process, such that it more closely resembles physiological healing with significantly reduced risk for developing fibrosis. This makes plasminogen an attractive drug candidate for the treatment of radiation wounds in cancer patients.

Disturbed Laminar Blood Flow Causes Impaired Fibrinolysis and Endothelial Fibrin Deposition In Vivo.

Endothelial expression of tissue-type plasminogen activator (t-PA) is crucial for maintaining an adequate endogenous fibrinolysis. It is unknown how endothelial t-PA expression and fibrinolysis are affected by blood flow in vivo. In this study, we investigated the impact of different blood flow profiles on endothelial t-PA expression and fibrinolysis in the arterial vasculature. Induction of disturbed laminar blood flow (D-flow) in the mouse carotid artery potently reduced endothelial t-PA messenger ribonucleic acid and protein expression, and caused fibrin deposition. En face immunohistochemistry demonstrated that arterial areas naturally exposed to D-flow had markedly lower endothelial t-PA levels than areas with sustained laminar blood flow (S-flow), and displayed pronounced fibrin deposition despite an intact endothelium. In t-PA and plasminogen-deficient mice, fibrin deposition did not extend into S-flow areas, indicating that areas of D-flow and S-flow differ, not only in fibrinolytic capacity, but also in coagulation. Furthermore, plasminogen accumulation was found at D-flow areas, and infusion of recombinant t-PA activated fibrinolysis and significantly reduced the fibrin deposits. In conclusion, D-flow potently impairs the fibrinolytic capacity and causes endothelial fibrin deposition in vivo. Our data also indicate that t-PA is the limiting factor for efficient fibrinolysis at the thrombosis-prone D-flow areas in the arterial vasculature.

Plasminogen activation is required for the development of radiation-induced dermatitis.

Skin damage caused by radiation therapy (radiodermatitis) is a severe side effect of radiotherapy in cancer patients, and there is currently a lack of effective strategies to prevent or treat such skin damage. In this work, we show with several lines of evidence that plasminogen, a pro-inflammatory factor, is key for the development of radiodermatitis. After skin irradiation in wild-type (plg+/+) mice, the plasminogen level increased in the irradiated area, leading to severe skin damage such as ulcer formation. However, plasminogen-deficient (plg-/-) mice and mice lacking plasminogen activators were mostly resistant to radiodermatitis. Moreover, treatment with a plasminogen inhibitor, tranexamic acid, decreased radiodermatitis in plg+/+ mice and prevented radiodermatitis in plg+/- mice. Together with studies at the molecular level, we report that plasmin is required for the induction of inflammation after irradiation that leads to radiodermatitis, and we propose that inhibition of plasminogen activation can be a novel treatment strategy to reduce and prevent the occurrence of radiodermatitis in patients.

Novel diagnostic ELISA test for discrimination between infections with Yersinia enterocolitica and Yersinia pseudotuberculosis.

Yersiniosis is a foodborne infection caused by Yersinia enterocolitica or Yersinia pseudotuberculosis. Although yersiniosis is most often self-limiting, some patients develop chronic infections, such as reactive arthritis, glomerulonephritis, or myocarditis, which require an antibiotic treatment. Whereas early infections can be diagnosed by direct detection of bacteria, chronic infections can only be identified by serological tests. At this point, a serological method for differentiation between infections with the two Yersinia species is important since antibiotic susceptibility of these bacteria is different. Traditional immunoassays do not distinguish between infections with Y. enterocolitica and Y. pseudotuberculosis. The only test that allows for this differentiation is Mikrogen's strip test where discrimination between the two types of infection is based on two recombinant bacterial proteins, MyfA and PsaA (specific for Y. enterocolitica and Y. pseudotuberculosis, respectively). Here, we show that Y. enterocolitica and Y. pseudotuberculosis, cultured under the conditions that mimic the natural rout of infection, express surface antigens different from MyfA and PsaA that can also be used in a discrimination test. Further, we describe a new ELISA that is based on the whole bacteria and recombinant MyfA and PsaA as antigens, and that allows the differentiation between infections with Y. enterocolitica and Y. pseudotuberculosis and simultaneous detection of yersiniosis.

Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-ß-Slug signaling.

Vimentin has been shown to be involved in wound healing, but its functional contribution to this process is poorly understood. Here we describe a previously unrecognized function of vimentin in coordinating fibroblast proliferation and keratinocyte differentiation during wound healing. Loss of vimentin led to a severe deficiency in fibroblast growth, which in turn inhibited the activation of two major initiators of epithelial-mesenchymal transition (EMT), TGF-ß1 signaling and the Zinc finger transcriptional repressor protein Slug, in vimentin-deficient (VIM(-/-)) wounds. Correspondingly, VIM(-/-) wounds exhibited loss of EMT-like keratinocyte activation, limited keratinization, and slow reepithelialization. Furthermore, the fibroblast deficiency abolished collagen accumulation in the VIM(-/-) wounds. Vimentin reconstitution in VIM(-/-) fibroblasts restored both their proliferation and TGF-ß1 production. Similarly, restoring paracrine TGF-ß-Slug-EMT signaling reactivated the transdifferentiation of keratinocytes, reviving their migratory properties, a critical feature for efficient healing. Our results demonstrate that vimentin orchestrates the healing by controlling fibroblast proliferation, TGF-ß1-Slug signaling, collagen accumulation, and EMT processing, all of which in turn govern the required keratinocyte activation.

Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori.

The Helicobacter pylori adhesin BabA binds mucosal ABO/Le(b) blood group (bg) carbohydrates. BabA facilitates bacterial attachment to gastric surfaces, increasing strain virulence and forming a recognized risk factor for peptic ulcers and gastric cancer. High sequence variation causes BabA functional diversity, but the underlying structural-molecular determinants are unknown. We generated X-ray structures of representative BabA isoforms that reveal a polymorphic, three-pronged Le(b) binding site. Two diversity loops, DL1 and DL2, provide adaptive control to binding affinity, notably ABO versus O bg preference. H. pylori strains can switch bg preference with single DL1 amino acid substitutions, and can coexpress functionally divergent BabA isoforms. The anchor point for receptor binding is the embrace of an ABO fucose residue by a disulfide-clasped loop, which is inactivated by reduction. Treatment with the redox-active pharmaceutic N-acetylcysteine lowers gastric mucosal neutrophil infiltration in H. pylori-infected Le(b)-expressing mice, providing perspectives on possible H. pylori eradication therapies.

Plasminogen is a critical regulator of cutaneous wound healing.

Wound healing is a complicated biological process that consist of partially overlapping inflammatory, proliferation and tissue remodelling phases. A successful wound healing depends on a proper activation and subsequent termination of the inflammatory phase. The failure to terminate the inflammation halts the completion of wound healing and is a known reason for formation of chronic wounds. Previous studies have shown that wound closure is delayed in plasminogen-deficient mice, and a role for plasminogen in dissection of extracellular matrix was suggested. However, our finding that plasminogen is transported to the wound by inflammatory cells early during the healing process, where it potentiates inflammation, indicates that plasminogen may also have other roles in the wound healing process. Here we report that plasminogen-deficient mice have extensive fibrin and neutrophil depositions in the wounded area long after re-epithelialisation, indicating inefficient debridement and chronic inflammation. Delayed formation of granulation tissue suggests that fibroblast function is impaired in the absence of plasminogen. Therefore, in addition to its role in the activation of inflammation, plasminogen is also crucial for subsequent steps, including resolution of inflammation and activation of the proliferation phase. Importantly, supplementation of plasminogen-deficient mice with human plasminogen leads to a restored healing process that is comparable to that in wild-type mice. Besides of being an activator of the inflammatory phase during wound healing, plasminogen is also required for the subsequent termination of inflammation. Based on these results, we propose that plasminogen may be an important future therapeutic agent for wound treatment.

Innate immunity. A Spaetzle-like role for nerve growth factor ß in vertebrate immunity to Staphylococcus aureus.

Many key components of innate immunity to infection are shared between Drosophila and humans. However, the fly Toll ligand Spaetzle is not thought to have a vertebrate equivalent. We have found that the structurally related cystine-knot protein, nerve growth factor ß (NGFß), plays an unexpected Spaetzle-like role in immunity to Staphylococcus aureus infection in chordates. Deleterious mutations of either human NGFß or its high-affinity receptor tropomyosin-related kinase receptor A (TRKA) were associated with severe S. aureus infections. NGFß was released by macrophages in response to S. aureus exoproteins through activation of the NOD-like receptors NLRP3 and NLRP4 and enhanced phagocytosis and superoxide-dependent killing, stimulated proinflammatory cytokine production, and promoted calcium-dependent neutrophil recruitment. TrkA knockdown in zebrafish increased susceptibility to S. aureus infection, confirming an evolutionarily conserved role for NGFß-TRKA signaling in pathogen-specific host immunity.

Plasminogen initiates and potentiates the healing of acute and chronic tympanic membrane perforations in mice.

BACKGROUND: Most tympanic membrane (TM) perforations heal spontaneously, but approximately 10-20% remain open as chronic TM perforations. Chronic perforations can lead to an impaired hearing ability and recurrent middle ear infections. Traditionally, these perforations must be surgically closed, which is costly and time consuming. Therefore, there is a need for simpler therapeutic strategies. Previous studies by us have shown that plasminogen (plg) is a potent pro-inflammatory regulator that accelerates cutaneous wound healing in mice. We have also shown that the healing of TM perforations is completely arrested in plg-deficient (plg(-/-)) mice and that these mice develop chronic TM perforations. In the present study, we investigated the therapeutic potential of local plg injection in acute and chronic TM perforation mice models. METHODS: Plg(-/-) mice and wild-type mice were subjected to standardized TM perforations followed by local injection of plg into the soft tissue surrounding the TM. TM perforations with chronic characteristics were induced by leaving TM perforations in plg(-/-) mice untreated for 9 days before treatment. The healing process was observed through otomicroscope and finally confirmed by immunostaining. The quality of TM healing was evaluated based on the morphology of the TM. RESULT: Daily local injections of plg into the soft tissue surrounding the TM restored the ability to heal TM perforations in plg-/- mice in a dose-dependent manner, and potentiated the healing rate and quality in wild-type mice. A single local injection of plg initiated the healing of the chronic-like TM perforations in these mice, resulting in a closed TM with a continuous but rather thick outer keratinocyte layer. However, three plg injections led to a completely healed TM with a thin keratinizing squamous epithelium covering a connective tissue layer. CONCLUSION: Our data suggests that plg is a promising drug candidate for the treatment of chronic TM perforations in humans.

Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations.

Mice deficient in plasminogen, the precursor of plasmin, show completely arrested healing of tympanic membrane (TM) perforations, indicating that plasmin plays an essential role in TM healing. The activation of plasminogen to plasmin is performed by two plasminogen activators (PAs), urokinase-type PA (uPA) and tissue-type PA (tPA). To elucidate the functional roles of PAs in the healing of TM perforations, we investigated the phenotypes of single gene-deficient mice lacking uPA (uPA(-/-)) or tPA (tPA(-/-)) after TM perforation. Delayed healing of TM perforations was observed in uPA(-/-) mice but not tPA(-/-) mice. The migration of keratinocytes was clearly delayed and seemed to be misoriented in uPA(-/-) mice. Furthermore, fibrin deposition and the inflammatory response were persistent in these mice. Our findings demonstrate that uPA plays a role in the healing of TM perforations. The observed phenotypes in uPA(-/-) mice are most likely due to the reduced generation of plasmin.

Plasminogen is a key proinflammatory regulator that accelerates the healing of acute and diabetic wounds.

Despite decades of research on wound healing, effective biologic agents for the treatment of chronic wounds, especially diabetic wounds, are still lacking. In the present study, we report that the inert plasma protein plasminogen (plg) acts as a key regulatory molecule that potentiates wound healing in mice. Early in the healing process, plg bound to inflammatory cells is transported to the wound area, where the level of plg is increased locally, leading to the induction of cytokines and intracellular signaling events and to a potentiation of the early inflammatory response. Systemic administration of additional plg not only accelerates the healing of acute burn wounds in wild-type mice, but also improves the healing of chronic diabetic wounds in a mouse model of diabetes. Our results suggest that the administration of plg may be a novel therapeutic strategy to treat many different types of wounds, especially chronic wounds such as those caused by diabetes.

Beneficial and detrimental effects of plasmin(ogen) during infection and sepsis in mice.

Plasmin has been proposed to be an important mediator during inflammation/infection. In this study, by using mice lacking genes for plasminogen, tissue-type plasminogen activator (tPA), and urokinase-type PA (uPA), we have investigated the functional roles of active plasmin in infection and sepsis. Two models were used: an infection model by intravenous injection of 1×107 CFU of S. aureus, and a sepsis model by intravenous injection of 1.6×108 CFU of S. aureus. We found that in the infection model, wild-type (WT) mice showed significantly higher survival rates than plasminogen-deficient (plg⁻/⁻) mice. However, in the sepsis model, plg⁻/⁻ or tPA⁻/⁻/uPA⁻/⁻ mice showed the highest survival rate whereas WT and tPA⁺/⁻/uPA⁺/⁻ mice showed the lowest survival rate, and plg⁺/⁻, tPA⁻/⁻, and uPA⁻/⁻ mice had an intermediate survival rate. These results indicate that the levels of active plasmin are critical in determining the survival rate in the sepsis, partly through high levels of inflammatory cytokines and enhanced STAT3 activation. We conclude that plasmin is beneficial in infection but promotes the production of inflammatory cytokines in sepsis that may cause tissue destruction, diminished neutrophil function, and an impaired capacity to kill bacteria which eventually causes death of these mice.

Plasmin is essential in preventing periodontitis in mice.

Periodontitis involves bacterial infection, inflammation of the periodontium, degradation of gum tissue, and alveolar bone resorption, which eventually leads to loss of teeth. To study the role of the broad-spectrum protease plasmin in periodontitis, we examined the oral health of plasminogen (Plg)-deficient mice. In wild-type mice, the periodontium was unaffected at all time points studied; in Plg-deficient mice, periodontitis progressed rapidly, within 20 weeks. Morphological study results of Plg-deficient mice revealed detachment of gingival tissue, resorption of the cementum layer, formation of necrotic tissue, and severe alveolar bone degradation. IHC staining showed massive infiltration of neutrophils in the periodontal tissues. Interestingly, doubly deficient mice, lacking both tissue- and urokinase-type plasminogen activators, developed periodontal disease similar to that in Plg-deficient mice; however, mice lacking only tissue- or urokinase-type plasminogen activator remained healthy. Supplementation by injection of Plg-deficient mice with human plasminogen for 10 days led to necrotic tissue absorption, inflammation subsidence, and full regeneration of gum tissues. Notably, there was also partial regrowth of degraded alveolar bone. Taken together, our results show that plasminogen is essential for the maintenance of a healthy periodontium and plays an important role in combating the spontaneous development of chronic periodontitis. Moreover, reversal to healthy status after supplementation of Plg-deficient mice with plasminogen suggests the possibility of using plasminogen for therapy of periodontal diseases.

Lack of plasminogen does not alter the early inflammatory response following a tympanic membrane perforation: a study in plasminogen-deficient mice.

CONCLUSIONS: The results of the present study show that the early inflammatory response in plasminogen (plg)-deficient mice is not altered compared to that in wild-type (wt) mice. Therefore the chronicity of the perforation in the long-term healing experiment cannot be explained by an impairment of the early inflammatory response, but rather by an impairment in activation of the inflammatory cells. These findings give further insight into the mechanisms resulting in a clinically seen chronic tympanic membrane (TM) perforation and thus possible therapeutic strategies to replace today's conventional surgical treatment of these perforations. OBJECTIVES: Plg has been shown to play an essential role in the healing of TM perforations. In plg-deficient mice a completely arrested healing reaction was seen, resulting in a chronic TM perforation. The mechanisms involved seem to be an abundant neutrophil recruitment, an accumulation of macrophages, an arrested keratinocyte migration, and a massive deposition of fibrin along the TM tissue. However, the exact functional role of plg in the early inflammatory response during healing of TM perforation remains unclear. This study aimed to evaluate the early inflammatory response, mainly the occurrence of macrophages and neutrophils, during the first 48 h following a perforation in the pars tensa (PT) of the TM, in mice lacking the plasminogen gene compared to the corresponding response in wt mice. MATERIALS AND METHODS: The TMs were perforated in 45 plg-deficient and 39 wt mice. Otomicroscopic evaluation was performed at 3, 6, 9, 12, 18, 24, and 48 h after the perforation was made. Mice were harvested at all time points and prepared for morphology including immunohistochemistry (IHC). IHC was performed with antibodies targeting macrophages, neutrophils, T and B cells, cytokeratin, and fibrin(ogen). Morphometry was performed regarding the volume percentage of TM tissue occupied by the different inflammatory cells. RESULTS: Perforation of the TM resulted in early otomicroscopic changes of the pars flaccida (PF) in both genotypes. Infiltration of inflammatory cells to PF and the presence of edema occurred as early as 6 h after the perforation was made, in both plg-deficient and wt mice. Morphometry did not reveal any significant differences between the genotypes concerning the occurrence of inflammatory cells. In contrast to the PF, the PT showed only sparse reactions during the experimental period. Furthermore, the migration pattern of keratinocytes did not differ between the genotypes throughout the experimental period.

Expression and localization of the serine proteases high-temperature requirement factor A1, serine protease 23, and serine protease 35 in the mouse ovary.

Proteolytic degradation of extracellular matrix components has been suggested to play an essential role in the occurrence of ovulation. Recent studies in our laboratory have indicated that the plasminogen activator and matrix metalloproteinase systems, which were previously believed to be crucial for ovulation, are not required in this process. In this study we have used a microarray approach to identify new proteases that are involved in ovulation. We found three serine proteases that were relatively highly expressed during ovulation: high-temperature requirement factor A1 (HtrA1), which was not regulated much during ovulation; serine protease 23 (PRSS23), which was down-regulated by gonadotropins; and serine protease 35 (PRSS35), which was up-regulated by gonadotropins. We have further investigated the expression patterns of these proteases during gonadotropin-induced ovulation in immature mice and in the corpus luteum (CL) of pseudopregnant mice. We found that HtrA1 was highly expressed in granulosa cells throughout follicular development and ovulation, as well as in the forming and regressing CL. PRSS23 was highly expressed in atretic follicles, and it was expressed in the ovarian stroma and theca tissues just before ovulation. PRSS35 was expressed in the theca layers of developing follicles. It was also highly induced in granulosa cells of preovulatory follicles. PRSS35 was also expressed in the forming and regressing CL. These data suggest that HtrA1 and PRSS35 may be involved in ovulation and CL formation and regression, and that PRSS23 may play a role in follicular atresia.

Expression patterns of neurotrophins and neurotrophin receptors in articular chondrocytes and inflammatory infiltrates in knee joint arthritis.

BACKGROUND: It is likely that neurotrophins (NTs) are of great importance for the articular cartilage and the inflammation process in arthritis. METHODS: The immunohistochemical expression of the NTs nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and the associated receptors p75, TrkA and TrkB was examined in the knee joint of arthritic and healthy mice. RESULTS: Immunoreactions for NGF and BDNF were detected in cells and nerve fiber varicosities in the inflammatory infiltrates of the synovial tissue of arthritic joints but not in synovial tissue of controls. p75-immunoreactive nerve fiber-like strands were detected in inflammatory infiltrates. Immunostaining for NGF, BDNF, p75, TrkA and TrkB was noted in articular chondrocytes. There was a statistically significant decrease in reactions for NGF (p < 0.001), TrkA (p = 0.001) and p75 (p < 0.001) in articular chondrocytes in joints exhibiting severe arthritis. CONCLUSION: The findings show that an NT system develops in inflammatory infiltrates of the synovial tissue. Furthermore, most interestingly, autocrine/paracrine effects appear to exist concerning NTs for the articular chondrocytes. The downregulated expression of NGF and NT receptors in articular chondrocytes in arthritis is a new aspect concerning the involvement of NTs in cartilage.

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

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 x 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 aureus-induced arthritis by activating inflammatory cells, killing bacteria, removing necrotic tissue, and enhancing cytokine expression.