Differential Role of Lipocalin 2 During Immune ComplexMediated Acute and Chronic Inflammation in Mice

• Type of Material: Article
• Authors: Rangaiah Shashidharamurthy, Philadelphia College of Osteopathic Medicine; Deepa Machiah, Yerkes National Primate Research Centre; Jesse D Aitken, Georgia State University; Kalyani Putty, Philadelphia College of Osteopathic Medicine; Gayathri Srinivasan, Georgia State University; Benoit Chassaing, Georgia State University; Charles A. Parkos, Emory University; Periasamy Selvaraj, Emory University; Matam Vijay-Kumar, Georgia State University
• Language: English
• Date: 2013-04-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 by the American College of Rheumatology.
• Final Published Version (URL): http://dx.doi.org/10.1002/art.37840
• Title of Journal or Parent Work: Arthritis and Rheumatism
• ISSN: 0004-3591
• Volume: 65
• Issue: 4
• Start Page: 1064
• End Page: 1073
• Grant/Funding Information: This work was supported by American Heart Association award (11SDG5710004) to R.S and NIH K01 (DK083275) award to M.V-K. DK072564, DK079392 to C.A.P
• Keywords: SYSTEMIC-LUPUS-ERYTHEMATOSUS; COMPLEX; Science & Technology; COLLAGEN-INDUCED ARTHRITIS; MAST-CELLS; FC-RECEPTORS; NGAL; Rheumatology; NEPHRITIS; Life Sciences & Biomedicine; IRON; ARTHUS REACTION; GELATINASE-ASSOCIATED LIPOCALIN
• Research Categories: Biology, Cell; Health Sciences, Immunology

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.