Neutrophil-derived COX-2 has a key role during in�ammatory hyperalgesia

In�ammation is a vital process for the injured tissue restoration and one of its hallmarks is in�ammatory hyperalgesia. The cyclooxygenase (COX) pathway is strongly related to the in�ammatory and painful process. Usually, the COX-1 isoform is described as homeostatic, while COX-2 is characterized as inducible in in�ammatory conditions. Although it is well known that neutrophil cells are the �rst to arrive at the in�amed site and the major source of COX-2 is still unknown the speci�c role of neutrophil-derived Cox-2 in the pain process is. Thus, in the present study, we demonstrate for the �rst time that neutrophil-derived COX-2 plays a key role in peripheral in�ammatory hyperalgesia. Conditional knockout mice for Cox-2 in neutrophils (Cox-2 �/�: Mrp8cre+/− ) exhibited higher pain sensitivity after carrageenan (CG) injection and long-lasting IL-1β-induced hyperalgesia compared with the control group (COX-2 �/� ). Also, CG-induced in�ammation in Cox-2 �/�: Mrp8cre+/− mice showed Cox-1 overexpression, and increased neutrophil migration and pro-in�ammatory cytokines (e.g., IL-1β and CXCL1). These �ndings revealed that neutrophil Cox-2 has an important role in the regulation of in�ammatory hyperalgesia.

[1]  C. Cooper,et al.  Safety of Cyclooxygenase-2 Inhibitors in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis , 2019, Drugs & Aging.

[2]  M. Coluccia,et al.  Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature , 2018, Pharmaceuticals.

[3]  A. Basu,et al.  STAT3 and NF-κB are common targets for kaempferol-mediated attenuation of COX-2 expression in IL-6-induced macrophages and carrageenan-induced mouse paw edema , 2017, Biochemistry and biophysics reports.

[4]  R. Kaul,et al.  Role of Modulator of Inflammation Cyclooxygenase-2 in Gammaherpesvirus Mediated Tumorigenesis , 2017, Front. Microbiol..

[5]  Roderick V. Jensen,et al.  Genomic, Lipidomic and Metabolomic Analysis of Cyclooxygenase-null Cells: Eicosanoid Storm, Cross Talk, and Compensation by COX-1 , 2016, Genom. Proteom. Bioinform..

[6]  R. Casagrande,et al.  Pimaradienoic Acid Inhibits Carrageenan-Induced Inflammatory Leukocyte Recruitment and Edema in Mice: Inhibition of Oxidative Stress, Nitric Oxide and Cytokine Production , 2016, PloS one.

[7]  A. Rieger,et al.  Neutrophil contributions to the induction and regulation of the acute inflammatory response in teleost fish , 2016, Journal of leukocyte biology.

[8]  R. Alon,et al.  Leukocyte migration into inflamed tissues. , 2014, Immunity.

[9]  M. Cassatella,et al.  Neutrophil-Derived Cytokines: Facts Beyond Expression , 2014, Front. Immunol..

[10]  Robert J. Moots,et al.  The multifactorial role of neutrophils in rheumatoid arthritis , 2014, Nature Reviews Rheumatology.

[11]  W. Nauseef,et al.  Neutrophils at work , 2014, Nature Immunology.

[12]  J. Mitchell,et al.  Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system , 2012, Proceedings of the National Academy of Sciences.

[13]  Alberto Mantovani,et al.  Neutrophils in the activation and regulation of innate and adaptive immunity , 2011, Nature Reviews Immunology.

[14]  U. Dirnagl,et al.  IL-1β Stimulates COX-2 Dependent PGE2 Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells , 2011, PloS one.

[15]  N. Flamand,et al.  Characterization of prostaglandin E2 generation through the cyclooxygenase (COX)-2 pathway in human neutrophils. , 2007, Biochimica et biophysica acta.

[16]  L. Fick,et al.  Cytokine profiles during carrageenan-induced inflammatory hyperalgesia in rat muscle and hind paw. , 2007, The journal of pain : official journal of the American Pain Society.

[17]  W. Verri,et al.  Neutrophils: are they hyperalgesic or anti‐hyperalgesic? , 2006, Journal of leukocyte biology.

[18]  P. McNaughton,et al.  Inflammatory pain: the cellular basis of heat hyperalgesia. , 2006, Current neuropharmacology.

[19]  T. Ishikawa,et al.  Conditional knockout mouse for tissue‐specific disruption of the cyclooxygenase‐2 (Cox‐2) gene , 2006, Genesis.

[20]  J. Rask-Madsen,et al.  Systematic review: coxibs, non‐steroidal anti‐inflammatory drugs or no cyclooxygenase inhibitors in gastroenterological high‐risk patients? , 2006, Alimentary pharmacology & therapeutics.

[21]  F. Cunha,et al.  A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[22]  F. Fitzpatrick,et al.  Cyclooxygenase enzymes: regulation and function. , 2004, Current pharmaceutical design.

[23]  Charles N. Serhan,et al.  Lipid mediator class switching during acute inflammation: signals in resolution , 2001, Nature Immunology.

[24]  Adam Sapirstein,et al.  Interleukin-1β-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity , 2001, Nature.

[25]  J. Wallace,et al.  Cyclooxygenase 1 contributes to inflammatory responses in rats and mice: implications for gastrointestinal toxicity. , 1998, Gastroenterology.

[26]  G. Zimmerman,et al.  Inflammatory agonists induce cyclooxygenase type 2 expression by human neutrophils. , 1998, Journal of immunology.

[27]  W. Smith,et al.  Selective inhibition of prostaglandin endoperoxide synthase-1 (cyclooxygenase-1) by valerylsalicylic acid. , 1995, Archives of biochemistry and biophysics.

[28]  M. Zimmermann,et al.  Ethical guidelines for investigations of experimental pain in conscious animals , 1983, Pain.

[29]  D. Priebat,et al.  Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. , 1982, The Journal of investigative dermatology.

[30]  F. Camu,et al.  The Role of COX-2 Inhibitors in Pain Modulation , 2012, Drugs.

[31]  L. Ballou.  The regulation of cyclooxygenase-1 and -2 in knockout cells and mice. , 2002, Advances in experimental medicine and biology.

[32]  M. Giroux.  Cyclooxygenase-2 Expression in Macrophages: Modulation by Protein Kinase C-a , 2000 .

[33]  K. Ley,et al.  Fucoidin, but not yeast polyphosphomannan PPME, inhibits leukocyte rolling in venules of the rat mesentery. , 1993, Blood.