Progranulin contributes to endogenous mechanisms of pain defense after nerve injury in mice
Hee-Young Lim
Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany
Search for more papers by this authorBoris Albuquerque
Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany
Search for more papers by this authorAnnett Häussler
Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany
Search for more papers by this authorThekla Myrczek
Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany
Search for more papers by this authorAihao Ding
Department of Microbiology and Immunology, Weill Cornell Medical College, NY, USA
Search for more papers by this authorCorresponding Author
Irmgard Tegeder
Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany
Irmgard TEGEDER, Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, Haus 74, 60590 Frankfurt am Main, Germany. Tel.: +49-69-6301-7621 Fax: +49-69-6301-7636 E-mail: [email protected]Search for more papers by this authorHee-Young Lim
Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany
Search for more papers by this authorBoris Albuquerque
Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany
Search for more papers by this authorAnnett Häussler
Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany
Search for more papers by this authorThekla Myrczek
Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany
Search for more papers by this authorAihao Ding
Department of Microbiology and Immunology, Weill Cornell Medical College, NY, USA
Search for more papers by this authorCorresponding Author
Irmgard Tegeder
Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany
Irmgard TEGEDER, Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, Haus 74, 60590 Frankfurt am Main, Germany. Tel.: +49-69-6301-7621 Fax: +49-69-6301-7636 E-mail: [email protected]Search for more papers by this authorAbstract
Progranulin haploinsufficiency is associated with frontotemporal dementia in humans. Deficiency of progranulin led to exaggerated inflammation and premature aging in mice. The role of progranulin in adaptations to nerve injury and neuropathic pain are still unknown. Here we found that progranulin is up-regulated after injury of the sciatic nerve in the mouse ipsilateral dorsal root ganglia and spinal cord, most prominently in the microglia surrounding injured motor neurons. Progranulin knockdown by continuous intrathecal spinal delivery of small interfering RNA after sciatic nerve injury intensified neuropathic pain-like behaviour and delayed the recovery of motor functions. Compared to wild-type mice, progranulin-deficient mice developed more intense nociceptive hypersensitivity after nerve injury. The differences escalated with aging. Knockdown of progranulin reduced the survival of dissociated primary neurons and neurite outgrowth, whereas addition of recombinant progranulin rescued primary dorsal root ganglia neurons from cell death induced by nerve growth factor withdrawal. Thus, up-regulation of progranulin after neuronal injury may reduce neuropathic pain and help motor function recovery, at least in part, by promoting survival of injured neurons and supporting regrowth. A deficiency in this mechanism may increase the risk for injury-associated chronic pain.
Supporting Information
Additional Supporting Information may be found in the online version of this article:
Fig S1 Schematic diagram of the modified lentiviral vector, pLL-3.7 used for overexpression of progranulin. The ubiquitin promoter-MCS (multiple cloning site) cassette was inserted in frame 5′ upstream of the U6 promoter of pLL-3.7 via SpeI and XhoI sites.
Fig S2 Representative images showing the automated identification of neurites (yellow) and neuronal body (red) from which neurite area, total length, number of central neurites, neurite thickness, and area, diameter and circumference of the soma were calculated.
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