Crosstalk between the plasminogen/plasmin system and inflammation resolution.

The plasminogen/plasmin (Plg/Pla) system, best known for its classical role in thrombolysis, has been recently highlighted as a regulator of other biological processes in mammals, including key steps involved in the resolution of inflammation. Inflammation resolution is a complex process coordinated by different cellular effectors, notably leukocytes, and active mediators, and is initiated shortly after the inflammatory response begins. Once the inflammatory insult is eliminated, an effective and timely engagement of proresolution programs prevents persistent inflammation, thereby avoiding excessive tissue damage, fibrosis, and the development of autoimmunity. Interestingly, recent studies demonstrate that Plg/Pla and their receptor, plasminogen receptor KT (Plg-RKT), regulate key steps in inflammation resolution. The number of studies investigating the involvement of the Plg/Pla system in these and other aspects of inflammation, including degradation of extracellular matrices, immune cell migration, wound healing, and skeletal growth and maintenance, highlights key roles of the Plg/Pla system during physiological and pathologic conditions. Here, we discuss robust evidence in the literature for the emerging roles of the Plg/Pla system in key steps of inflammation resolution. These findings suggest that dysregulation in Plg production and its activation plays a role in the pathogenesis of inflammatory diseases. Elucidating central mechanisms underlying the role of Plg/Pla in key steps of inflammation resolution either in preclinical models of inflammation or in human inflammatory conditions, can provide a rationale for the development of new pharmacologic interventions to promote resolution of inflammation, and open new pathways for the treatment of thromboinflammatory conditions.

Plasmin and plasminogen prevent sepsis severity by reducing neutrophil extracellular traps and systemic inflammation.

Sepsis is a lethal syndrome characterized by systemic inflammation and abnormal coagulation. Despite therapeutic advances, sepsis mortality remains substantially high. Herein, we investigated the role of the plasminogen/plasmin (Plg/Pla) system during sepsis. Plasma levels of Plg were significantly lower in mice subjected to severe compared with nonsevere sepsis, whereas systemic levels of IL-6, a marker of sepsis severity, were higher in severe sepsis. Plg levels correlated negatively with IL-6 in both septic mice and patients, whereas plasminogen activator inhibitor-1 levels correlated positively with IL-6. Plg deficiency render mice susceptible to nonsevere sepsis induced by cecal ligation and puncture (CLP), resulting in greater numbers of neutrophils and M1 macrophages, liver fibrin(ogen) deposition, lower efferocytosis, and increased IL-6 and neutrophil extracellular trap (NET) release associated with organ damage. Conversely, inflammatory features, fibrin(ogen), and organ damage were substantially reduced, and efferocytosis was increased by exogenous Pla given during CLP- and LPS-induced endotoxemia. Plg or Pla protected mice from sepsis-induced lethality and enhanced the protective effect of antibiotics. Mechanistically, Plg/Pla-afforded protection was associated with regulation of NET release, requiring Pla-protease activity and lysine binding sites. Plg/Pla are important host-protective players during sepsis, controlling local and systemic inflammation and collateral organ damage.

Annexin A1 Is Increased in the Plasma of Preeclamptic Women.

BACKGROUND: Preeclampsia (PE) is a pregnancy disease associated with exacerbated inflammatory response. Annexin A1 (AnxA1) is a glucocorticoid-regulated protein endowed with anti-inflammatory and proresolving properties that has been much studied in various animal models of inflammation but poorly studied in the context of human inflammatory diseases. The main objective of this study was to measure AnxA1 levels in PE women and to compare those levels in normotensive pregnant and non-pregnant women. We evaluated the association among AnxA1, ultrasensitive C reactive protein (us-CRP) and soluble tumor necrosis factor alpha receptor type 1 (sTNF-R1) plasma levels of the study participants. METHODS: This study included 40 non-pregnant, 38 normotensive pregnant and 51 PE women. PE women were stratified in early (N = 23) and late (N = 28) subgroups, according to gestational age (GA) at onset of clinical symptoms. Protein AnxA1 and us-CRP plasma levels were determined by ELISA and immunoturbidimetric assays, respectively. Transcript levels of AnxA1 in peripheral blood mononuclear cells (PBMC) were measured by real time RT-PCR. RESULTS: Increased levels of AnxA1 coincided with higher us-CRP levels in the plasma of PE women. Pregnant women with early PE had higher levels of AnxA1 and us-CRP than normotensive pregnant women with GA <34 weeks. No significant difference was found for AnxA1 and us-CRP, comparing late PE and normotensive pregnant women with GA ≥ 34 weeks. AnxA1 mRNA levels in PBMC were similar among the studied groups. AnxA1 was positively correlated with sTNF-R1, but not with us-CRP. CONCLUSIONS: Our data show that increased AnxA1 levels were associated with a systemic inflammatory phenotype in PE, suggesting AnxA1 deregulation in PE pathogenesis. However, more studies are needed to clarify the role of AnxA1 and other proresolving molecules in the context of the systemic inflammatory response in this intriguing disease.

The role and effects of glucocorticoid-induced leucine zipper in the context of inflammation resolution.

Glucocorticoid (GC)-induced leucine zipper (GILZ) has been shown to mediate or mimic several actions of GC. This study assessed the role of GILZ in self-resolving and GC-induced resolution of neutrophilic inflammation induced by LPS in mice. GILZ expression was increased during the resolution phase of LPS-induced pleurisy, especially in macrophages with resolving phenotypes. Pretreating LPS-injected mice with trans-activator of transcription peptide (TAT)-GILZ, a cell-permeable GILZ fusion protein, shortened resolution intervals and improved resolution indices. Therapeutic administration of TAT-GILZ induced inflammation resolution, decreased cytokine levels, and promoted caspase-dependent neutrophil apoptosis. TAT-GILZ also modulated the activation of the survival-controlling proteins ERK1/2, NF-κB and Mcl-1. GILZ deficiency was associated with an early increase of annexin A1 (AnxA1) and did not modify the course of neutrophil influx induced by LPS. Dexamethasone treatment resolved inflammation and induced GILZ expression that was dependent on AnxA1. Dexamethasone-induced resolution was not altered in GILZ(-/-) mice due to compensatory expression and action of AnxA1. Our results show that therapeutic administration of GILZ efficiently induces a proapoptotic program that promotes resolution of neutrophilic inflammation induced by LPS. Alternatively, a lack of endogenous GILZ during the resolution of inflammation is compensated by AnxA1 overexpression.

Soluble endoglin, transforming growth factor-Beta 1 and soluble tumor necrosis factor alpha receptors in different clinical manifestations of preeclampsia.

BACKGROUND: Despite intensive research, the etiopathogenesis of preeclampsia (PE) remains uncertain. Inflammatory and angiogenic factors are thought to play considerable roles in this disease. The objective of this study was to investigate the association between soluble endoglin (sEng), transforming growth factor beta-1 (TGF-ß1) and tumor necrosis factor alpha soluble receptors (sTNF-Rs) and the clinical manifestations of PE. METHODS: Plasma levels of sEng, TGF-ß1 and sTNF-Rs were determined by ELISA in 23 non-pregnant, 21 normotensive pregnant and 43 PE women. PE women were stratified into subgroups according to the severity [mild (n = 12) and severe (n = 31)] and onset-time of the disease [early (n = 19) and late (n = 24)]. RESULTS: Pregnancy was associated with higher levels of sEng, sTNF-R1 and sTNF-R2 than the non-pregnant state. Moreover, PE women had higher levels of sEng and sTNF-R1 than normotensive pregnant women. No difference was found in TGF-ß1 levels, comparing the three study groups. Late PE had higher levels of sTNF-R1 and sTNF-R2 than early PE. No significant differences were found in sEng and TGF-ß1 comparing early and late PE. sEng levels were higher in severe PE than in mild PE and no difference was found for TGF-ß1, sTNF-R1 and sTNF-R2 levels. There was a positive correlation among sEng, TNF-R1 and sTNF-2 levels. Logistic regression analysis revealed that primiparity and sEng levels are independently associated with the development of PE. Furthermore, sEng levels are independently associated with the disease severity. CONCLUSIONS: These results suggest that pregnancy is a condition associated with higher levels of anti-angiogenic and pro-inflammatory factors than the non-pregnant state and that PE is associated with an imbalance of these factors in the maternal circulation.