TY  - JOUR
AU  - Vicuña, Lucas
AU  - Strochlic, David E
AU  - Latremoliere, Alban
AU  - Bali, Kiran Kumar
AU  - Simonetti, Manuela
AU  - Husainie, Dewi
AU  - Prokosch, Sandra
AU  - Riva, Priscilla
AU  - Griffin, Robert S
AU  - Njoo, Christian
AU  - Gehrig, Stefanie
AU  - Mall, Marcus A
AU  - Arnold, Bernd
AU  - Devor, Marshall
AU  - Woolf, Clifford J
AU  - Liberles, Stephen D
AU  - Costigan, Michael
AU  - Kuner, Rohini
TI  - The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase.
JO  - Nature medicine
VL  - 21
IS  - 5
SN  - 1546-170X
CY  - New York, NY
PB  - Nature America Inc.
M1  - DKFZ-2017-03729
SP  - 518 - 523
PY  - 2015
AB  - 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.
KW  - Acute-Phase Proteins (NLM Chemicals)
KW  - Enzyme Inhibitors (NLM Chemicals)
KW  - Serpina3n protein, mouse (NLM Chemicals)
KW  - Serpina3n protein, rat (NLM Chemicals)
KW  - Serpins (NLM Chemicals)
KW  - Leukocyte Elastase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25915831
C2  - pmc:PMC4450999
DO  - DOI:10.1038/nm.3852
UR  - https://inrepo02.dkfz.de/record/127706
ER  -