Cell Surface Externalization of Annexin A1 as a Failsafe Mechanism Preventing Inflammatory Responses during Secondary Necrosis

Blume, Karin; Soeroes, Szabolcs; Waibel, Michaela; Keppeler, Hildegard; Wesselborg, Sebastian; Herrmann, Martin; Schulze‐Osthoff, Klaus; Lauber, Kirsten

doi:10.4049/jimmunol.0902250

Cited by 69 publications

(73 citation statements)

References 36 publications

(36 reference statements)

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“…Cells with positive annexin V FITC, but negative PI signal were considered apoptotic, whereas cells double positive for annexin V FITC and PI staining were considered necrotic (7).…”

Section: Mass Spectrometrymentioning

confidence: 99%

“…Phagocytosis was measured, as described previously (7,11). Briefly, 1 3 10 7 prey cells/ml were labeled with 2 mM PKH26 in diluent C (Sigma-Aldrich) for 5 min at room temperature, according to the manufacturer's instructions.…”

Section: Phagocytosis Assaymentioning

confidence: 99%

“…THP-1 cells were differentiated into macrophages with 10 nM PMA (Sigma-Aldrich) for 2.5 d, irradiated with 10 mJ/cm 2 UV-C to undergo apoptosis, or heated to 58˚C for 20 min to induce necrosis, respectively (7,8). Plasminogen, plasmin, thrombin, and plasminogen activator inhibitor-1 (PAI-1) were purchased from American Diagnostica (Heidelberg, Germany), plasminogen FITC was from Biomac (Leipzig, Germany), and plasmin-Cy2 was prepared with the Cy2-labeling kit (GE Healthcare), according to the manufacturer's instructions.…”

Section: Cells and Reagentsmentioning

confidence: 99%

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Serum-Derived Plasminogen Is Activated by Apoptotic Cells and Promotes Their Phagocytic Clearance

Rosenwald

Koppe

Keppeler

et al. 2012

The Journal of Immunology

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The elimination of apoptotic cells, called efferocytosis, is fundamentally important for tissue homeostasis and prevents the onset of inflammation and autoimmunity. Serum proteins are known to assist in this complex process. In the current study, we performed a multistep chromatographic fractionation of human serum and identified plasminogen, a protein involved in fibrinolysis, wound healing, and tissue remodeling, as a novel serum-derived factor promoting apoptotic cell removal. Even at levels significantly lower than its serum concentration, purified plasminogen strongly enhanced apoptotic prey cell internalization by macrophages. Plasminogen acted mainly on prey cells, whereas on macrophages no enhancement of the engulfment process was observed. We further demonstrate that the efferocytosis-promoting activity essentially required the proteolytic activation of plasminogen and was completely abrogated by the urokinase plasminogen activator inhibitor-1 and serine protease inhibitor aprotinin. Thus, our study assigns a new function to plasminogen and plasmin in apoptotic cell clearance.

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“…Cells with positive annexin V FITC, but negative PI signal were considered apoptotic, whereas cells double positive for annexin V FITC and PI staining were considered necrotic (7).…”

Section: Mass Spectrometrymentioning

confidence: 99%

Section: Phagocytosis Assaymentioning

confidence: 99%

Section: Cells and Reagentsmentioning

confidence: 99%

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Serum-Derived Plasminogen Is Activated by Apoptotic Cells and Promotes Their Phagocytic Clearance

Rosenwald

Koppe

Keppeler

et al. 2012

The Journal of Immunology

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“…It induces neutrophil apoptosis, 38 can promote phagocytosis 39 and efferocytosis, 40 and it acts as a fail-safe mechanism when released from secondary necrotic cells. 41 It was therefore natural to assess the ability of HDACIs in promoting phagocytosis. In macrophages, VPA, SB and TSA mobilized AnxA1 and increased the engulfment of zymosan particles or apoptotic neutrophils.…”

Section: (D) Representative Images Of Macrophages Engulfing Cfse-labementioning

confidence: 99%

Gene expression signature-based approach identifies a pro-resolving mechanism of action for histone deacetylase inhibitors

2012

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Despite several therapies are currently available to treat inflammatory diseases, new drugs to treat chronic conditions with less side effects and lower production costs are still needed. An innovative approach to drug discovery, the Connectivity Map (CMap), shows how integrating genome-wide gene expression data of drugs and diseases can accelerate this process. Comparison of genome-wide gene expression data generated with Annexin A1 (AnxA1) with the CMap revealed significant alignment with gene profiles elicited by histone deacetylase inhibitors (HDACIs), what made us to hypothesize that AnxA1 might mediate the anti-inflammatory actions of HDACIs. Addition of HDACIs (valproic acid, sodium butyrate and thricostatin A) to mouse macrophages caused externalization of AnxA1 with concomitant inhibition of cytokine gene expression and release, events that occurred independently since this inhibition was retained in AnxA1 null macrophages. However, novel AnxA1-mediated functions for HDACIs could be unveiled, including promotion of neutrophil apoptosis and macrophage phagocytosis, both steps crucial for effective resolution of inflammation. In a model of acute resolving inflammation, administration of valproic acid and sodium butyrate to mice at the peak of disease accelerated resolution processes in wild type, but much more modestly in AnxA1 null mice. Deeper analyses revealed a role for endogenous AnxA1 in the induction of neutrophil death in vivo by HDACIs. In summary, interrogation of the CMap revealed an unexpected association between HDACIs and AnxA1 that translated in mechanistic findings with particular impact on the processes that regulate the resolution of inflammation. We propose non-genomic modulation of AnxA1 in immune cells as a novel mechanism of action for HDACIs, which may underlie their reported efficacy in models of chronic inflammatory pathologies.

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“…This has physiological significance during inflammation, since secondary necrosis can lead to the release of chemotactic peptides, which, in turn, may induce recruitment of monocytes into inflamed tissue. Moreover, proteins released from necrotic cells can opsonise apoptotic cells and thus facilitate their phagocytic uptake, which contributes to the resolution of inflammation (Blume et al 2009;Blume et al 2012).…”

Section: Discussionmentioning

confidence: 99%

Sladek Z, Rysanek D: CD14 expression, apoptosis and necrosis in resident and inflammatory macrophages from virgin bovine mammary gland

Sládek¹,

Rysanek²

2014

Vet. Med. - Czech

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This paper investigates the association between expression of CD14 and occurrence of apoptosis in blood monocytes, resident ( RES MAC) and inflammatory macrophages from heifer mammary glands after infusion of PBS ( INF MAC PBS ) or LPS ( INF MAC LPS ). Resident macrophages ( RES MAC) were obtained before, and inflammatory macrophages ( INF MAC PBS and INF MAC LPS ) 24 h after, induction of an inflammatory response using phosphate buffered saline (PBS) and lipopolysaccharide (LPS) in mammary glands of unbred heifers. Cell samples were analysed for differential counts, CD14 expression, apoptosis and necrosis using flow cytometry. In vitro cultivation led to a decrease in the proportion of living cells and to an increase in the proportion of apoptotic and necrotic cells in all macrophages and blood monocytes. In CD14 + macrophages, the proportions of live cells increased and proportions of apoptotic and necrotic cells decreased after in vitro cultivation. We observed in CD14 − macrophages and monocytes that the proportions of live cells decreased and proportions of apoptotic and necrotic cells increased after in vitro cultivation. Our experiments confirm that the expression of CD14 in bovine mammary gland macrophages and blood monocytes is associated with cell viability.

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Cell Surface Externalization of Annexin A1 as a Failsafe Mechanism Preventing Inflammatory Responses during Secondary Necrosis

Abstract: Material

Cited by 69 publications

References 36 publications

Serum-Derived Plasminogen Is Activated by Apoptotic Cells and Promotes Their Phagocytic Clearance

Serum-Derived Plasminogen Is Activated by Apoptotic Cells and Promotes Their Phagocytic Clearance

Gene expression signature-based approach identifies a pro-resolving mechanism of action for histone deacetylase inhibitors

Sladek Z, Rysanek D: CD14 expression, apoptosis and necrosis in resident and inflammatory macrophages from virgin bovine mammary gland

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