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

Sugimoto, Michelle A.; Ribeiro, Ana Luíza C.; Costa, Bruno Rocha Cordeiro; Vago, Juliana P.; Lima, Kátia M.; Carneiro, Fernanda S.; Ortiz, Mylena Maira O.; Lima, Graziele Letícia N.; Carmo, Aline A. F.; Rocha, Renata Maria; Perez, Denise; Reis, Alessandra; Pinho, Vanessa; Miles, Lindsey A.; Garcia, Cristiana C.; Teixeira, Mauro Martins; Sousa, Lirlândia P.

doi:10.1182/blood-2016-09-742825

Cited by 109 publications

(140 citation statements)

References 70 publications

(150 reference statements)

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“…Next, we validated the efferocytosis data using a different protocol in which apoptotic neutrophils are injected as prey into the peritoneal cavity of mice after the mice are injected with the drug, and we found that L‐cycloserine, FTY720, JTE013, or DTD increased the efferocytic ability of peritoneal macrophages (Fig. ).…”

Section: Resultsmentioning

confidence: 85%

Inhibition of the sphingosine‐1‐phosphate pathway promotes the resolution of neutrophilic inflammation

et al. 2019

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Sphingosine-1-phosphate (S1P) is an important sphingolipid derived from plasma membrane and has a known role in productive phase of inflammation, but its role in neutrophil survival and resolution phase of inflammation is unknown. Here, we investigated the effects of inhibition of S1P receptors and the blockade of S1P synthesis in BALB/c mice and human neutrophils. S1P and S1PR1-3 receptors expression were increased in cells from the pleural cavity stimulated with LPS. Using different antagonists of S1PRs and inhibitors of different steps of the metabolic pathway of S1P production, we show that S1P and its receptors are involved in regulating neutrophil survival and resolution of inflammation in the pleural cavity. Given the role of the S1P-S1PR axis in resolution of inflammation, we sought to identify whether blockade at different levels of the sphingosine-1-phosphate synthesis pathway could affect neutrophil survival in vitro. Inhibitors of the S1P pathway were also able to induce human neutrophil apoptosis. In addition, blockade of S1P synthesis or its receptor facilitated the efferocytosis of apoptotic neutrophil. Taken together, our data demonstrate a fundamental role for S1P in regulating the outcome of inflammatory responses, and position S1P-S1PR axis as a potential target for treatment of neutrophilic inflammation.

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Section: Resultsmentioning

confidence: 85%

Inhibition of the sphingosine‐1‐phosphate pathway promotes the resolution of neutrophilic inflammation

et al. 2019

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“…Others have shown that plasmin activates NF‐κB and induces expression of proinflammatory cytokines in monocytes and macrophages . Plasmin also may contribute to the resolution of inflammation . The protease activity of plasmin appears essential for its effects on cytokine expression.…”

Section: Introductionmentioning

confidence: 99%

“…The protease activity of plasmin appears essential for its effects on cytokine expression. Plasminogen receptors, such as annexin A2/S100A10 complex, annexin A1, α‐enolase, and plasminogen‐R TK , play a critical role in mediating the effects of plasmin in inflammation . One function of plasminogen receptors may be to facilitate plasminogen activation and then deliver plasmin to cell‐signaling receptors in the protease‐activated receptor (PAR) family .…”

Section: Introductionmentioning

confidence: 99%

Tissue-type plasminogen activator neutralizes LPS but not protease-activated receptor-mediated inflammatory responses to plasmin

Zalfa

Azmoon

Mantuano

et al. 2019

Journal of Leukocyte Biology

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Tissue‐type plasminogen activator (tPA) activates fibrinolysis and also suppresses innate immune system responses to LPS in bone marrow‐derived macrophages (BMDMs) and in vivo in mice. The objective of this study was to assess the activity of tPA as a regulator of macrophage physiology in the presence of plasmin. Enzymatically active and enzymatically inactive (EI) tPA appeared to comprehensively block the response to LPS in BMDMs, including expression of proinflammatory cytokines such as TNF‐α and IL‐1β and anti‐inflammatory cytokines such as IL‐10 and IL‐1 receptor antagonist. The activity of EI‐tPA as an LPS response modifier was conserved in the presence of plasminogen. By contrast, in BMDMs treated with tPA and plasminogen or preactivated plasmin, in the presence or absence of LPS, increased proinflammatory cytokine expression was observed and tPA failed to reverse the response. Plasmin independently activated NF‐κB, ERK1/2, c‐Jun N‐terminal kinase, and p38 mitogen‐activated protein kinase in BMDMs, which is characteristic of proinflammatory stimuli. Plasmin‐induced cytokine expression was blocked by ε‐aminocaproic acid, aprotinin, and inhibitors of the known plasmin substrate, Protease‐activated receptor‐1 (PAR‐1), but not by N‐methyl‐d‐aspartate receptor inhibitor, which blocks the effects of tPA on macrophages. Cytokine expression by BMDMs treated with the PAR‐1 agonist, TFLLR, was not inhibited by EI‐tPA, possibly explaining why EI‐tPA does not inhibit macrophage responses to plasmin and providing evidence for specificity in the ability of tPA to oppose proinflammatory stimuli. Regulation of innate immunity by the fibrinolysis system may reflect the nature of the stimulus and a balance between the potentially opposing activities of tPA and plasmin.

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“…Studies in the mouse have demonstrated that the Plg/plasmin system influences macrophages by transcriptional modulation of several genes to increase their efferocytosis activity and by promoting their reprogramming from the proinflammatory (M1) to the resolution (M2) type . However, these studies have not identified the Plg receptor on the phagocytes.…”

Section: Discussionmentioning

confidence: 99%

The mannose 6-phosphate/insulin-like growth factor 2 receptor mediates plasminogen-induced efferocytosis

Ohradanova‐Repic

Machacek

Donner

et al. 2019

Journal of Leukocyte Biology

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The plasminogen system is harnessed in a wide variety of physiological processes, such as fibrinolysis, cell migration, or efferocytosis; and accordingly, it is essential upon inflammation, tissue remodeling, wound healing, and for homeostatic maintenance in general. Previously, we identified a plasminogen receptor in the mannose 6‐phosphate/insulin‐like growth factor 2 receptor (M6P/IGF2R, CD222). Here, we demonstrate by means of genetic knockdown, knockout, and rescue approaches combined with functional studies that M6P/IGF2R is up‐regulated on the surface of macrophages, recognizes plasminogen exposed on the surface of apoptotic cells, and mediates plasminogen‐induced efferocytosis. The level of uptake of plasminogen‐coated apoptotic cells inversely correlates with the TNF‐α production by phagocytes indicating tissue clearance without inflammation by this mechanism. Our results reveal an up‐to‐now undetermined function of M6P/IGF2R in clearance of apoptotic cells, which is crucial for tissue homeostasis.

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

Abstract: Key Points Plg and Pla induce macrophage reprogramming and promote resolution of acute inflammation. Plg and Pla enhance the efferocytic capacity of macrophages and override the prosurvival effect of LPS on neutrophils via annexin A1.

Cited by 109 publications

References 70 publications

Inhibition of the sphingosine‐1‐phosphate pathway promotes the resolution of neutrophilic inflammation

Inhibition of the sphingosine‐1‐phosphate pathway promotes the resolution of neutrophilic inflammation

Tissue-type plasminogen activator neutralizes LPS but not protease-activated receptor-mediated inflammatory responses to plasmin

The mannose 6-phosphate/insulin-like growth factor 2 receptor mediates plasminogen-induced efferocytosis

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