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Lipocalin 2 Links Inflammation and Ankylosis in the Clinical Overlap of Inflammatory Bowel Disease (IBD) and Ankylosing Spondylitis (AS)

Author

Arthritis Res Ther. 2020 Mar 18;22(1):51.doi: 10.1186/s13075-020-02149-4.

Aifeng Lin 1 2 3, Robert D Inman 4 5 6, Catherine J Streutker 7 8, Zhenbo Zhang 5, Kenneth P H Pritzker 9 7, Hing Wo Tsui 5, Florence W L Tsui 9 6

Author Information

  • 1Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. fernaifenglin@gmail.com.
  • 2Krembil Research Institute, University Health Network, Toronto, Ontario, Canada. fernaifenglin@gmail.com.
  • 3KeyIntel Medical Inc, Toronto, Ontario, Canada. fernaifenglin@gmail.com.
  • 4Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
  • 5Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
  • 6Department of Immunology and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
  • 7Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • 8Li Ka Shing Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
  • 9KeyIntel Medical Inc, Toronto, Ontario, Canada.

Abstract

Background: Little is known about the mechanisms underlying the clinical overlap between gut inflammation and joint ankylosis, as exemplified by the concurrence of inflammatory bowel diseases (IBD) and ankylosing spondylitis (AS). As dysbiosis may serve as a common contributor, the anti-microbial pleiotropic factor lipocalin 2 could be a potential mediator due to its roles in inflammation and bone homeostasis.

Methods: Baseline colonic pathology was conducted in the ank/ank mouse model. Serum lipocalin 2 was analyzed by ELISA, in ank/ank mutants versus C3FeB6-A/Aw-jwt/wt, in patients with concurrent AS-IBD, AS alone, IBD alone, or mechanical back pain, and in healthy controls. In the ank/ank mouse model, the expression of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) was examined by real-time PCR. Intraperitoneal injection was done with the PPARγ agonist rosiglitazone or antagonist bisphenol A diglycidyl ether for four consecutive days. Serum levels of lipocalin 2 were examined on the sixth day.

Results: This study showed that the ank/ank mice with fully fused spines had concurrent colonic inflammation. By first using the ank/ank mouse model with progressive ankylosis and subclinical colonic inflammation, confirmed in patients with concurrent AS and IBD, elevated circulating lipocalin 2 levels were associated with the coexisting ankylosis and gut inflammation. The intracellular pathway of lipocalin 2 was further investigated with the ank/ank mouse model involving PPARγ. Colonic expression of PPARγ was negatively associated with the degree of gut inflammation. The PPARγ agonist rosiglitazone treatment significantly upregulated the serum levels of lipocalin 2, suggesting a potential regulatory role of PPARγ in the aberrant expression of lipocalin 2.

Conclusions: In summary, lipocalin 2 modulated by PPARγ could be a potential pathway involved in concurrent inflammation and ankylosis in AS and IBD.