The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase.
Neuropathic pain is a major, intractable clinical problem and its pathophysiology is not well understood. Although recent gene expression profiling studies have enabled the identification of novel targets for pain therapy, classical study designs provide unclear results owing to the differential expression of hundreds of genes across sham and nerve-injured groups, which can be difficult to validate, particularly with respect to the specificity of pain modulation. To circumvent this, we used two outbred lines of rats, which are genetically similar except for being genetically segregated as a result of selective breeding for differences in neuropathic pain hypersensitivity. SerpinA3N, a serine protease inhibitor, was upregulated in the dorsal root ganglia (DRG) after nerve injury, which was further validated for its mouse homolog. Mice lacking SerpinA3N developed more neuropathic mechanical allodynia than wild-type (WT) mice, and exogenous delivery of SerpinA3N attenuated mechanical allodynia in WT mice. T lymphocytes infiltrate the DRG after nerve injury and release leukocyte elastase (LE), which was inhibited by SerpinA3N derived from DRG neurons. Genetic loss of LE or exogenous application of a LE inhibitor (Sivelastat) in WT mice attenuated neuropathic mechanical allodynia. Overall, we reveal a novel and clinically relevant role for a member of the serpin superfamily and a leukocyte elastase and crosstalk between neurons and T cells in the modulation of neuropathic pain.
Pharmacology Institute, University of Heidelberg, Heidelberg, Germany.
Lucas
L
Vicuña
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
David E
DE
Strochlic
1] F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
Alban
A
Latremoliere
Pharmacology Institute, University of Heidelberg, Heidelberg, Germany.
Kiran Kumar
0000000295031402
KK
Bali
Pharmacology Institute, University of Heidelberg, Heidelberg, Germany.
Manuela
M
Simonetti
Pharmacology Institute, University of Heidelberg, Heidelberg, Germany.
Dewi
D
Husainie
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Sandra
S
Prokosch
F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA.
Priscilla
P
Riva
Department of Anesthesiology (Pain Management), Hospital for Special Surgery, New York, New York, USA.
Robert S
RS
Griffin
Pharmacology Institute, University of Heidelberg, Heidelberg, Germany.
Christian
C
Njoo
Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, University of Heidelberg, Heidelberg, Germany.
Stefanie
S
Gehrig
Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, University of Heidelberg, Heidelberg, Germany.
Marcus A
MA
Mall
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Bernd
B
Arnold
Institute of Life Sciences and Center for Research on Pain, The Hebrew University of Jerusalem, Jerusalem, Israel.
Marshall
0000000182063301
M
Devor
1] F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
Clifford J
CJ
Woolf
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Stephen D
SD
Liberles
1] F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Anesthesia, Boston Children's Hospital, Boston, Massachusetts, USA.
Michael
M
Costigan
Pharmacology Institute, University of Heidelberg, Heidelberg, Germany.
Rohini
R
Kuner
D000209:Acute-Phase Proteins / Q000378:metabolism*; D000818:Animals; D002469:Cell Separation; D000229:Dependovirus / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D006930:Hyperalgesia / Q000503:physiopathology; D017403:In Situ Hybridization; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009437:Neuralgia; D009474:Neurons / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010146:Pain / Q000503:physiopathology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D051381:Rats; D015843:Serpins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology*; D015854:Up-Regulation
D000209:Acute-Phase Proteins; D004791:Enzyme Inhibitors; C516624:Serpina3n protein, mouse; C403317:Serpina3n protein, rat; D015843:Serpins; D019272:Leukocyte Elastase