PAI-1 Inhibits Neutrophil Efferocytosis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2008 Aug 12

PMID 18689689

Citations 60

Authors

Young-Jun Park

Gang Liu

Emmanuel F Lorne

Xia Zhao

Jing Wang

Yuko Tsuruta

Jaroslaw Zmijewski

Edward Abraham

Affiliations

Soon will be listed here.

Abstract

Phagocytosis of apoptotic cells, also called efferocytosis, is an essential feature of immune responses and critical for the resolution of inflammation. Plasma and tissue levels of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, are elevated in inflammatory conditions, including sepsis and acute lung injury, in which activated neutrophils accumulate in tissues and contribute to organ dysfunction. In this study, we explored the potential involvement of PAI-1 in modulating neutrophil efferocytosis. We found enhanced phagocytosis of viable PAI-1 deficient (PAI-1(-/-)) and of wild-type neutrophils treated with anti-PAI-1 antibodies. PAI-1 levels were decreased on the surface of apoptotic neutrophils and the enhanced phagocytosis of apoptotic wild-type neutrophils or of viable PAI-1(-/-) neutrophils was diminished by preincubation with PAI-1. The increased phagocytosis associated with PAI-1 deficiency or blockade depended on both the lipoprotein receptor-related protein (LRP) and its ligand, calreticulin (CRT), because the LRP-mediated increase in phagocytosis of viable neutrophils induced by blockade of CD 47 was abrogated by PAI-1. CRT levels are increased on viable PAI-1(-/-) neutrophils. While CRT colocalizes with PAI-1 on viable neutrophils, markedly diminished colocalization of PAI-1 and CRT was present on apoptotic neutrophils. Our data therefore indicate that PAI-1 serves as a novel "don't eat me" signal for viable and apoptotic neutrophils.

Citing Articles

Unraveling the role of macrophages in diabetes: Impaired phagocytic function and therapeutic prospects.

Rong B, Jiang H, Zhu W, Yang G, Zhou X, Lyu Z Medicine (Baltimore). 2025; 104(8):e41613.

PMID: 39993124 PMC: 11856964. DOI: 10.1097/MD.0000000000041613.

The need for Cre-loci controls in conditional mouse experiments: Mrp8-cre transgene predisposes mice to antibody-induced arthritis.

Xu Z, Romero-Castillo L, Moreno-Giro A, Pandey R, Holmdahl R Genes Immun. 2024; .

PMID: 39632992 DOI: 10.1038/s41435-024-00313-3.

Cell Death in Liver Disease and Liver Surgery.

Stoess C, Choi Y, Onyuru J, Friess H, Hoffman H, Hartmann D Biomedicines. 2024; 12(3).

PMID: 38540172 PMC: 10968531. DOI: 10.3390/biomedicines12030559.

A bibliometric analysis of efferocytosis in cardiovascular diseases from 2001 to 2022.

Hu L, Lv Z, Gu Y, Zheng T, Kong Y, Mao W Medicine (Baltimore). 2023; 102(39):e34366.

PMID: 37773819 PMC: 10545234. DOI: 10.1097/MD.0000000000034366.

Cell death by phagocytosis.

Brown G Nat Rev Immunol. 2023; 24(2):91-102.

PMID: 37604896 DOI: 10.1038/s41577-023-00921-6.

References

Lupas A, Li H, Ecke M, Simmeth E, Gerisch G . Calreticulin and calnexin in the endoplasmic reticulum are important for phagocytosis. EMBO J. 2001; 20(23):6772-82. PMC: 125758. DOI: 10.1093/emboj/20.23.6772. View

Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y . Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science. 2004; 304(5674):1147-50. DOI: 10.1126/science.1094359. View

Marshall L, Ramdin L, Brooks T, DPhil P, Shute J . Plasminogen activator inhibitor-1 supports IL-8-mediated neutrophil transendothelial migration by inhibition of the constitutive shedding of endothelial IL-8/heparan sulfate/syndecan-1 complexes. J Immunol. 2003; 171(4):2057-65. DOI: 10.4049/jimmunol.171.4.2057. View

Ishimoto Y, Ohashi K, Mizuno K, Nakano T . Promotion of the uptake of PS liposomes and apoptotic cells by a product of growth arrest-specific gene, gas6. J Biochem. 2000; 127(3):411-7. DOI: 10.1093/oxfordjournals.jbchem.a022622. View

Serhan C, Savill J . Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005; 6(12):1191-7. DOI: 10.1038/ni1276. View

Brown S, Heinisch I, Ross E, Shaw K, Buckley C, Savill J . Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature. 2002; 418(6894):200-3. DOI: 10.1038/nature00811. View

Savill J, Dransfield I, Gregory C, Haslett C . A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol. 2002; 2(12):965-75. DOI: 10.1038/nri957. View

Determann R, Millo J, Garrard C, Schultz M . Bronchoalveolar levels of plasminogen activator inhibitor-1 and soluble tissue factor are sensitive and specific markers of pulmonary inflammation. Intensive Care Med. 2006; 32(6):946-7. DOI: 10.1007/s00134-006-0167-9. View

Myohanen H, Vaheri A . Regulation and interactions in the activation of cell-associated plasminogen. Cell Mol Life Sci. 2004; 61(22):2840-58. DOI: 10.1007/s00018-004-4230-9. View

10.

Arndt P, Young S, Worthen G . Regulation of lipopolysaccharide-induced lung inflammation by plasminogen activator Inhibitor-1 through a JNK-mediated pathway. J Immunol. 2005; 175(6):4049-59. DOI: 10.4049/jimmunol.175.6.4049. View

11.

Degryse B, Neels J, Czekay R, Aertgeerts K, Kamikubo Y, Loskutoff D . The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1. J Biol Chem. 2004; 279(21):22595-604. DOI: 10.1074/jbc.M313004200. View

12.

Henson P, Bratton D, Fadok V . Apoptotic cell removal. Curr Biol. 2001; 11(19):R795-805. DOI: 10.1016/s0960-9822(01)00474-2. View

13.

Xu Z, Balsara R, Gorlatova N, Lawrence D, Castellino F, Ploplis V . Conservation of critical functional domains in murine plasminogen activator inhibitor-1. J Biol Chem. 2004; 279(17):17914-20. DOI: 10.1074/jbc.M314197200. View

14.

El Solh A, Bhora M, Pineda L, Aquilina A, Abbetessa L, Berbary E . Alveolar plasminogen activator inhibitor-1 predicts ARDS in aspiration pneumonitis. Intensive Care Med. 2005; 32(1):110-5. DOI: 10.1007/s00134-005-2847-2. View

15.

Andreasen P, Egelund R, Petersen H . The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci. 2000; 57(1):25-40. PMC: 11146824. DOI: 10.1007/s000180050497. View

16.

Lazar M, Christensen P, Du M, Yu B, Subbotina N, Hanson K . Plasminogen activator inhibitor-1 impairs alveolar epithelial repair by binding to vitronectin. Am J Respir Cell Mol Biol. 2004; 31(6):672-8. DOI: 10.1165/rcmb.2004-0025OC. View

17.

Renckens R, Roelofs J, Bonta P, Florquin S, de Vries C, Levi M . Plasminogen activator inhibitor type 1 is protective during severe Gram-negative pneumonia. Blood. 2006; 109(4):1593-601. DOI: 10.1182/blood-2006-05-025197. View

18.

Prabhakaran P, Ware L, White K, Cross M, Matthay M, Olman M . Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2003; 285(1):L20-8. DOI: 10.1152/ajplung.00312.2002. View

19.

Henson P, Tuder R . Apoptosis in the lung: induction, clearance and detection. Am J Physiol Lung Cell Mol Physiol. 2008; 294(4):L601-11. DOI: 10.1152/ajplung.00320.2007. View

20.

Zhou A . Functional structure of the somatomedin B domain of vitronectin. Protein Sci. 2007; 16(7):1502-8. PMC: 2206693. DOI: 10.1110/ps.072819107. View