The pivotal role played by lipocalin-2 in chronic inflammatory pain.
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.
Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Mithilesh Kumar
MK
Jha
Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea; Department of Neurosurgery, Biological Chemistry, and Neuroscience, Neurosurgery Pain Research Institute, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Sangmin
S
Jeon
Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Myungwon
M
Jin
Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Jiyeon
J
Ock
Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Jong-Heon
JH
Kim
School of Life Sciences and Biotechnology, KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
Won-Ha
WH
Lee
Department of Pharmacology, Brain Science & Engineering Institute, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea. Electronic address: ksuk@knu.ac.kr.
Kyoungho
K
Suk
D000209:Acute-Phase Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D059350:Chronic Pain / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005620:Freund's Adjuvant / Q000494:pharmacology; D006930:Hyperalgesia / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D009619:Nociceptors / Q000276:immunology; D015513:Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D013116:Spinal Cord / Q000276:immunology
D000209:Acute-Phase Proteins; D000276:Adjuvants, Immunologic; D016207:Cytokines; D005620:Freund's Adjuvant; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C508313:Slc22a17 protein, mouse; C071332:Lcn2 protein, mouse
Chronic inflammatory pain; Glia; Hindpaw; Inflammation; Lipocalin-2; Macrophage; Neutrophil; Proalgesic mediators; Spinal cord