Abstract
CD137L (4-1BBL) is a costimulatory molecule whose signaling can promote monocyte/macrophage functions; however, CD137L-mediated microglial response and its role in neuropathic pain remain unknown. We investigated CD137L following peripheral nerve injury-induced neuropathic pain using a spinal nerve L5 transection (L5Tx) murine model in both sexes. First, C57BL/6_CD137L knock-out (KO) mice displayed decreased mechanical and diminished heat hypersensitivity compared to wild-type (WT) controls, beginning on day 3 to up to day 35 post-L5Tx. Purified anti-mouse CD137L neutralizing monoclonal antibody (0.1 or 0.5 µg) was also used to identify CD137L’s window of action in BALB/c mice. Anti-CD137L antibody was intrathecally administered either from day 0 (before surgery) to day 7 (early treatment), or from day 6 to 13 post-L5Tx (late treatment), and nociceptive thresholds were assessed before surgery to up to day 35 post-surgery. Early treatment with anti-CD137L reduced L5Tx-induced mechanical but not heat hypersensitivity, while later treatment did not alter either sensitivity. Pro- versus anti-inflammatory responses within the lumbar spinal cord following L5Tx were further evaluated via quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) in time-course studies. Following L5Tx, female CD137L KO mice did not show increased iNOS mRNA and had reduced numbers of IL-1β+ cells compared to WT. At 21 d post-surgery, CD137L KO mice had higher total numbers of arginase (Arg)-1+ cells and Arg-1+ microglia. Altogether, results indicate that spinal cord CD137L contributes to the development of peripheral nerve injury-induced neuropathic pain, which may be in part mediated through CD137L’s modulation of the pro- and anti-inflammatory balance within the spinal cord.
Highlights
Neuropathic pain results from a lesion or disease of the somatosensory nervous system due to an insult to either the peripheral or central nervous system (IASP Taxonomy Working Group, 2011)
To examine the role of CD137L in neuropathic pain following peripheral nerve injury, hypersensitivity to both mechanical and heat stimuli was examined in CD137L KO and B6 WT mice following either a sham or L5Tx surgery
The current study demonstrates that CD137L plays a role in the development and maintenance of sensory hypersensitivity resulting from peripheral nerve injury using both BALB/c mice treated with different doses of a CD137L neutralizing antibody and B6_CD137L KO mice
Summary
Neuropathic pain results from a lesion or disease of the somatosensory nervous system due to an insult to either the peripheral or central nervous system (IASP Taxonomy Working Group, 2011). This damage disrupts homeostasis resulting in an assortment. Received June 1, 2018; accepted October 7, 2018; First published October 29, 2018. The authors declare no competing financial interests. It is estimated that 7– 8% of the general population suffer from a neuropathic pain disorder. Functioning for these individuals is severely impaired, making investigation of treatment options critical (IASP Taxonomy Working Group, 2011)
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