The pivotal role played by lipocalin-2 in chronic inflammatory pain

• Published in: Experimental neurology 2014-04, Vol.254, p.41-53
• Main Authors: Jha, Mithilesh Kumar, Jeon, Sangmin, Jin, Myungwon, Ock, Jiyeon, Kim, Jong-Heon, Lee, Won-Ha, Suk, Kyoungho
• Format: Article
• Language: English
• Subjects: Acute-Phase Proteins - genetics; Acute-Phase Proteins - immunology; Acute-Phase Proteins - pharmacology; Adjuvants, Immunologic - pharmacology; Animals; Biological and medical sciences; Cells, Cultured; Chronic inflammatory pain; Chronic Pain - genetics; Chronic Pain - immunology; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Cytokines - immunology; Disease Models, Animal; Female; Freund's Adjuvant - pharmacology; Glia; Hindpaw; Hyperalgesia - genetics; Hyperalgesia - immunology; Inflammation; Inflammation - chemically induced; Inflammation - genetics; Inflammation - immunology; Lipocalin-2; Lipocalins - genetics; Lipocalins - immunology; Lipocalins - pharmacology; Macrophage; Macrophages, Peritoneal - cytology; Macrophages, Peritoneal - immunology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Nervous system (semeiology, syndromes); Neurology; Neutrophil; Neutrophils - cytology; Neutrophils - immunology; Nociceptors - immunology; Oncogene Proteins - genetics; Oncogene Proteins - immunology; Oncogene Proteins - pharmacology; Proalgesic mediators; Receptors, Cell Surface - genetics; Receptors, Cell Surface - immunology; Recombinant Proteins - pharmacology; Spinal cord; Spinal Cord - immunology
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2014.01.009

Lipocalin-2 (LCN2) is an acute phase protein induced in response to injury, infection or other inflammatory stimuli. Based on the previously reported involvement of LCN2 in chemokine induction and in the recruitment of neutrophils at the sites of infection or tissue injury, we investigated the role of LCN2 in the pathogenesis of chronic/persistent inflammatory pain hypersensitivity. In the complete Freund's adjuvant (CFA)-induced chronic inflammatory pain model, LCN2 expression was strongly induced in the ipsilateral hindpaws, peaking at 12h after CFA injection and then gradually subsiding. In CFA-injected hindpaw tissues, LCN2 and its receptor 24p3R were mainly expressed in infiltrating neutrophils and macrophages. CFA-induced thermal hyperalgesia and mechanical allodynia were significantly diminished in Lcn2-deficient mice compared to wild-type animals. Furthermore, neutrophil infiltration, myeloperoxidase activity, expression of TNF-α, IL-1β and MIP-2 in CFA-injected hindpaws, and spinal glial activation were markedly reduced by Lcn2 deficiency. An intraplantar injection of recombinant LCN2 protein induced thermal and mechanical hypersensitivities in naïve mice, and this was accompanied by neutrophil and macrophage infiltration into the hindpaws and glial activation in the dorsal horn of the spinal cord. Taken together, our results show that inflammatory cell-derived LCN2 at the sites of inflammation plays important roles in central sensitization and the subsequent nociceptive behavior in the rodent model of chronic inflammatory pain. Suggested role of LCN2 in chronic inflammatory pain. LCN2 synthesized and released from neutrophils at inflammatory sites induces the expression of TNF-α, IL-1β, IL-8, and other pro-inflammatory mediators. LCN2, TNF-α, IL-1β, and IL-8 may then act in an autocrine and paracrine manner to activate and recruit neutrophils and macrophages to sites of injury or inflammation. These neutrophils and macrophages then further upregulate the expression of LCN2, TNF-α, IL-1β, IL-8 and other pro-inflammatory mediators, which activate nociceptors and spinal glia to cause peripheral and central sensitization. Taken together, our findings suggest that the neutrophil-derived LCN2 plays a pivotal role in the pathogenesis of chronic inflammatory pain hypersensitivity. [Display omitted] •The expression of LCN2 is upregulated in CFA-injected hindpaws of mice.•At inflammation site, LCN2 co-localizes with infiltrated neutrophils and macrophages.