Critical Role of LTB4/BLT1 in IL-23-Induced Synovial Inflammation and Osteoclastogenesis via NF-κB.

Abstract

IL-23 activates the synthesis and production of leukotriene B4 (LTB4) in myeloid cells, which modulate inflammatory arthritis. In this study we investigated the role of LTB4 and its receptor LTB4R1 (BLT1) in synovial inflammation and osteoclast differentiation. Specifically, we used IL-23 in vivo gene transfer to induce arthritis in mice and showed that elevated serum LTB4 and synovial expression of 5-lipoxygenase correlated with increased disease severity by histological evaluation and paw swelling compared with GFP gene transfer controls. To further investigate the effect of the LTB4 pathway in bone loss, we performed osteoclast differentiation assays by stimulating with M-CSF and receptor activator of NF-κB ligand bone marrow cells derived from BLT1+/+ and/or BLT1-/- mice and used quantitative PCR for gene expression analysis in terminally differentiated osteoclasts. Deficiency in BLT1 resulted in the upregulation of osteoclast-related genes and an increase in the formation of giant, multinucleated TRAP+ cells capable of F-actin ring formation. Additionally, BLT1 deficiency showed an increase of phosphorylated NF-κB and phosphorylated IκB levels in osteoclasts. We also performed real-time calcium imaging to study the effect of BLT1 deficiency in receptor activator of NF-κ-B ligand-induced activation of intracellular calcium flux in vitro. Our data show that LTB4 and its receptor BLT1 exacerbate synovial inflammation in vivo and bone resorption in vitro, suggesting that LTB4 and BLT1 could be effectively targeted for the treatment of musculoskeletal diseases.

• Authors: Laura Bouchareychas, Eva M Grössinger, Mincheol Kang, Hong Qiu, Iannis E Adamopoulos
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 198 Issue 1 Pg. 452-460 (01 01 2017) ISSN: 1550-6606 [Electronic] United States
• PMID: 27895169 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 by The American Association of Immunologists, Inc.

Chemical References

• Interleukin-23
• Ltb4r1 protein, mouse
• NF-kappa B
• Receptors, Leukotriene B4
• Leukotriene B4

Topics

• Animals
• Arthritis, Experimental (metabolism, pathology)
• Arthritis, Rheumatoid (metabolism, pathology)
• Blotting, Western
• Flow Cytometry
• Immunohistochemistry
• Inflammation (metabolism, pathology)
• Interleukin-23 (immunology)
• Leukotriene B4 (metabolism)
• Male
• Mice
• Mice, Knockout
• NF-kappa B (metabolism)
• Oligonucleotide Array Sequence Analysis
• Osteoclasts (metabolism)
• Osteogenesis (physiology)
• Real-Time Polymerase Chain Reaction
• Receptors, Leukotriene B4 (metabolism)
• Synovial Membrane (metabolism, pathology)
• Transcriptome