The urokinase plasminogen activator receptor (uPAR) controls macrophage phagocytosis in intestinal inflammation

Genua, Marco; D’Alessio, Silvia; Cibella, Javier; Gandelli, Alessandro; Sala, Emanuela; Correale, Carmen; Spinelli, Antonino; Arena, Vincenzo; Malesci, Alberto; Rutella, Sergio; Ploplis, Victoria A.; Vetrano, Stefania; Danese, Silvio

doi:10.1136/gutjnl-2013-305933

Cited by 42 publications

(38 citation statements)

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“…Some earlier studies have indicated that components of the fibrinolytic system induce a proresolving phenotype in macrophages. [39][40][41][42] For example, it has been shown in 2 complementary studies that the urokinase-type plasminogen activator (uPA) contributes to the polarization of cardiac macrophages to an M2 phenotype associated with increased Arg activity, 39 and that Pla was sufficient to promote this skew. 40 In another study, 41 the skew of macrophages from an M1 toward an anti-inflammatory M2c subset was linked to increased uPA expression.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the uPA receptor is required to regulate the polarization of intestinal macrophages, as uPA receptor deficiency leads to increased M1 inflammatory phenotype. 42 Conversely, other studies suggest that the tissue-type plasminogen activator may promote the development of inflammatory macrophages. 43,44 In this study, we found that either Plg or Pla injected into the pleural cavity of mice did not change M1 macrophage numbers, but increased the number of M2 and Mres macrophages.…”

Section: Discussionmentioning

confidence: 99%

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Plasmin and plasminogen induce macrophage reprogramming and regulate key steps of inflammation resolution via annexin A1

Sugimoto

Ribeiro

Costa

et al. 2017

Blood

109

124

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Plasmin and plasminogen induce macrophage reprogramming and regulate key steps of inflammation resolution via annexin A1

Sugimoto

Ribeiro

Costa

et al. 2017

Blood

109

124

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show abstract

“…Nevertheless, further molecular studies are warranted, e.g. using uPAR -/- mice, to fully elucidate a potential tumorigenic function of suPAR [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Serum levels of soluble urokinase plasminogen activator receptor (suPAR) predict outcome after resection of colorectal liver metastases

et al. 2018

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BackgroundIn colorectal cancer (CRC), the liver is the most common site of metastasis. Surgical resection represents the standard therapy for patients with colorectal liver metastases (CRLM). However, 5-year survival rates after resection do not exceed 50%, and despite existing preoperative stratification algorithms it is still debated which patients benefit most from surgical treatment. The soluble urokinase plasminogen activator receptor (suPAR) has recently evolved as a promising biomarker for distinct clinical conditions. Here, we examined a potential role of suPAR as a biomarker in patients undergoing resection of CRLM.ResultsCorrelating with upregulated uPAR tissue expression in resected metastases, serum concentrations of suPAR were significantly elevated in CRLM patients compared to healthy controls. Importantly, patients with preoperative suPAR serum levels above the identified ideal cut-off value of 4.83 ng/ml showed a significantly reduced overall survival after resection of CRLM, both in right- and left-sided primary CRC. Moreover, multivariate Cox regression analysis revealed preoperative suPAR serum levels as a prognostic factor for mortality. Additionally, elevated preoperative suPAR but not creatinine levels were a predictor of acute kidney injury (AKI) after CRLM resection, correlating with a longer postoperative hospitalization.ConclusionSuPAR represents a promising novel biomarker in CRLM patients that might help to guide preoperative treatment decisions regarding patients’ outcome and to identify patients particularly susceptible to AKI.MethodsExpression levels of uPAR were analyzed in CRLM tissue using RT-PCR and immunohistochemistry. SuPAR serum levels were measured by ELISA in 104 CRC patients undergoing hepatic resection for CRLM and 50 healthy controls.

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“…Urokinase-type plasminogen activator receptor (uPAR) is a component of the plasminogen activator (PA) system. This system plays an important role in many physiological and pathological processes, including tissue remodelling [ 8 ], thrombosis [ 9 ], inflammation [ 10 ], and tumourigenesis [ 11 ]. The soluble form of uPAR (suPAR) can be detected in serum and other organic fluids [ 12 ]; its levels are increased in patients with HIV infection, malaria, tuberculosis, and sepsis, suggesting that it could serve as a useful prognostic biomarker [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Serum suPAR and syndecan-4 levels predict severity of community-acquired pneumonia: a prospective, multi-centre study

Luo

Zheng

et al. 2018

Crit Care

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BackgroundCommunity-acquired pneumonia (CAP) is a major cause of death worldwide and occurs with variable severity. There are few studies focused on the expression of soluble urokinase-type plasminogen activator receptor (suPAR) and syndecan-4 in patients with CAP.MethodsA prospective, multi-centre study was conducted between January 2014 and December 2016. A total of 103 patients with severe CAP (SCAP), 149 patients with non-SCAP, and 30 healthy individuals were enrolled. Clinical data were recorded for all enrolled patients. Serum suPAR and syndecan-4 levels were determined by quantitative enzyme-linked immunosorbent assay. The t test and Mann–Whitney U test were used to compare between two groups; one-way analysis of variance and the Kruskal–Wallis test were used to compare multiple groups. Correlations were assessed using Pearson and Spearman tests. Area under the curve (AUCs), optimal threshold values, sensitivity, and specificity were calculated. Survival curves were constructed and compared by log-rank test. Regression analyses assessed the effect of multiple variables on 30-day survival.ResultssuPAR levels increased in all patients with CAP, especially in severe cases. Syndecan-4 levels decreased in patients with CAP, especially in non-survivors. suPAR and syndecan-4 levels were positively and negatively correlated with severity scores, respectively. suPAR exhibited high accuracy in predicting SCAP among patients with CAP with an AUC of 0.835 (p < 0.001). In contrast, syndecan-4 exhibited poor diagnostic value for predicting SCAP (AUC 0.550, p = 0.187). The AUC for predicting mortality in patients with SCAP was 0.772 and 0.744 for suPAR and syndecan-4, respectively; the respective prediction threshold values were 10.22 ng/mL and 6.68 ng/mL. Addition of both suPAR and syndecan-4 to the Pneumonia Severity Index significantly improved their prognostic accuracy, with an AUC of 0.885. Regression analysis showed that suPAR ≥10.22 ng/mL and syndecan-4 ≤ 6.68 ng/mL were reliable independent markers for prediction of 30-day survival.ConclusionsuPAR exhibits high accuracy for both diagnosis and prognosis of SCAP. Syndecan-4 can reliably predict mortality in patients with SCAP. Addition of both suPAR and syndecan-4 to a clinical scoring method could improve prognostic accuracy.Trial registrationClinicalTrials.gov, NCT03093220. Registered on 28 March 2017 (retrospectively registered).

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The urokinase plasminogen activator receptor (uPAR) controls macrophage phagocytosis in intestinal inflammation

Abstract: These findings point to uPAR as an essential component of intestinal macrophage functions and unravel a new potential target to control mucosal inflammation in IBD.

Cited by 42 publications

References 39 publications

Plasmin and plasminogen induce macrophage reprogramming and regulate key steps of inflammation resolution via annexin A1

Plasmin and plasminogen induce macrophage reprogramming and regulate key steps of inflammation resolution via annexin A1

Serum levels of soluble urokinase plasminogen activator receptor (suPAR) predict outcome after resection of colorectal liver metastases

Serum suPAR and syndecan-4 levels predict severity of community-acquired pneumonia: a prospective, multi-centre study

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