Differential Role of Lipocalin 2 During Immune Complex-mediated Acute and Chronic Inflammation in Mice

Overview

Journal Arthritis Rheum

Specialty Rheumatology

Date 2013 Jan 3

PMID 23280250

Citations 29

Authors

Rangaiah Shashidharamurthy

Deepa Machiah

Jesse D Aitken

Kalyani Putty

Gayathri Srinivasan

Benoit Chassaing

Charles A Parkos

Periasamy Selvaraj

Matam Vijay-Kumar

Affiliations

Soon will be listed here.

Abstract

Objective: Lipocalin 2 (LCN-2) is an innate immune protein that is expressed by a variety of cells and is highly up-regulated during several pathologic conditions, including immune complex (IC)-mediated inflammatory/autoimmune disorders. However, the function of LCN-2 during IC-mediated inflammation is largely unknown. Therefore, this study was undertaken to investigate the role of LCN-2 in IC-mediated diseases.

Methods: The up-regulation of LCN-2 was determined by enzyme-linked immunosorbent assay in 3 different mouse models of IC-mediated autoimmune disease: systemic lupus erythematosus, collagen-induced arthritis, and serum-transfer arthritis. The in vivo role of LCN-2 during IC-mediated inflammation was investigated using LCN-2-knockout mice and their wild-type littermates.

Results: LCN-2 levels were significantly elevated in all 3 of the autoimmune disease models. Further, in an acute skin inflammation model, LCN-2-knockout mice exhibited a 50% reduction in inflammation, with histopathologic analysis revealing notably reduced immune cell infiltration as compared to wild-type mice. Administration of recombinant LCN-2 to LCN-2-knockout mice restored inflammation to levels observed in wild-type mice. Neutralization of LCN-2 using a monoclonal antibody significantly reduced inflammation in wild-type mice. In contrast, LCN-2-knockout mice developed more severe serum-induced arthritis compared to wild-type mice. Histologic analysis revealed extensive tissue and bone destruction, with significantly reduced neutrophil infiltration but considerably more macrophage migration, in LCN-2-knockout mice compared to wild-type mice.

Conclusion: These results demonstrate that LCN-2 may regulate immune cell recruitment to the site of inflammation, a process essential for the controlled initiation, perpetuation, and resolution of inflammatory processes. Thus, LCN-2 may present a promising target in the treatment of IC-mediated inflammatory/autoimmune diseases.

Citing Articles

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References

Lee S, Kim J, Kim J, Seo J, Han H, Lee W . Lipocalin-2 Is a chemokine inducer in the central nervous system: role of chemokine ligand 10 (CXCL10) in lipocalin-2-induced cell migration. J Biol Chem. 2011; 286(51):43855-43870. PMC: 3243551. DOI: 10.1074/jbc.M111.299248. View

Sola A, Weigert A, Jung M, Vinuesa E, Brecht K, Weis N . Sphingosine-1-phosphate signalling induces the production of Lcn-2 by macrophages to promote kidney regeneration. J Pathol. 2011; 225(4):597-608. DOI: 10.1002/path.2982. View

Boilard E, Blanco P, Nigrovic P . Platelets: active players in the pathogenesis of arthritis and SLE. Nat Rev Rheumatol. 2012; 8(9):534-42. DOI: 10.1038/nrrheum.2012.118. View

Hazenbos W, Gessner J, Hofhuis F, Kuipers H, Meyer D, Heijnen I . Impaired IgG-dependent anaphylaxis and Arthus reaction in Fc gamma RIII (CD16) deficient mice. Immunity. 1996; 5(2):181-8. DOI: 10.1016/s1074-7613(00)80494-x. View

Goetz D, Holmes M, Borregaard N, Bluhm M, Raymond K, Strong R . The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell. 2002; 10(5):1033-43. DOI: 10.1016/s1097-2765(02)00708-6. View

Mok C, Lau C . Pathogenesis of systemic lupus erythematosus. J Clin Pathol. 2003; 56(7):481-90. PMC: 1769989. DOI: 10.1136/jcp.56.7.481. View

Devireddy L, Gazin C, Zhu X, Green M . A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell. 2005; 123(7):1293-305. DOI: 10.1016/j.cell.2005.10.027. View

Xu S, Venge P . Lipocalins as biochemical markers of disease. Biochim Biophys Acta. 2000; 1482(1-2):298-307. DOI: 10.1016/s0167-4838(00)00163-1. View

Nielsen B, Borregaard N, Bundgaard J, Timshel S, Sehested M, Kjeldsen L . Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel diseases. Gut. 1996; 38(3):414-20. PMC: 1383072. DOI: 10.1136/gut.38.3.414. View

10.

Ravetch J, Bolland S . IgG Fc receptors. Annu Rev Immunol. 2001; 19:275-90. DOI: 10.1146/annurev.immunol.19.1.275. View

11.

Bao G, Clifton M, Hoette T, Mori K, Deng S, Qiu A . Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex. Nat Chem Biol. 2010; 6(8):602-9. PMC: 2907470. DOI: 10.1038/nchembio.402. View

12.

Biezeveld M, van Mierlo G, Lutter R, Kuipers I, Dekker T, Hack C . Sustained activation of neutrophils in the course of Kawasaki disease: an association with matrix metalloproteinases. Clin Exp Immunol. 2005; 141(1):183-8. PMC: 1809423. DOI: 10.1111/j.1365-2249.2005.02829.x. View

13.

Zhang Y, Ramos B, Jakschik B . Augmentation of reverse arthus reaction by mast cells in mice. J Clin Invest. 1991; 88(3):841-6. PMC: 295470. DOI: 10.1172/JCI115385. View

14.

Hemdahl A, Gabrielsen A, Zhu C, Eriksson P, Hedin U, Kastrup J . Expression of neutrophil gelatinase-associated lipocalin in atherosclerosis and myocardial infarction. Arterioscler Thromb Vasc Biol. 2005; 26(1):136-42. DOI: 10.1161/01.ATV.0000193567.88685.f4. View

15.

Wu H, Santoni-Rugiu E, Ralfkiaer E, Porse B, Moser C, Hoiby N . Lipocalin 2 is protective against E. coli pneumonia. Respir Res. 2010; 11:96. PMC: 2912245. DOI: 10.1186/1465-9921-11-96. View

16.

Shashidharamurthy R, Machiah D, Bozeman E, Srivatsan S, Patel J, Cho A . Hydrodynamic delivery of plasmid DNA encoding human FcγR-Ig dimers blocks immune-complex mediated inflammation in mice. Gene Ther. 2011; 19(9):877-85. PMC: 3296821. DOI: 10.1038/gt.2011.175. View

17.

Flower D, North A, Sansom C . The lipocalin protein family: structural and sequence overview. Biochim Biophys Acta. 2000; 1482(1-2):9-24. DOI: 10.1016/s0167-4838(00)00148-5. View

18.

Vinuesa E, Sola A, Jung M, Alfaro V, Hotter G . Lipocalin-2-induced renal regeneration depends on cytokines. Am J Physiol Renal Physiol. 2008; 295(5):F1554-62. DOI: 10.1152/ajprenal.90250.2008. View

19.

Brunner H, Mueller M, Rutherford C, Passo M, Witte D, Grom A . Urinary neutrophil gelatinase-associated lipocalin as a biomarker of nephritis in childhood-onset systemic lupus erythematosus. Arthritis Rheum. 2006; 54(8):2577-84. DOI: 10.1002/art.22008. View

20.

Pitashny M, Schwartz N, Qing X, Hojaili B, Aranow C, Mackay M . Urinary lipocalin-2 is associated with renal disease activity in human lupus nephritis. Arthritis Rheum. 2007; 56(6):1894-903. DOI: 10.1002/art.22594. View