Responses of injured nerve in CD137L knockout mice following sciatic nerve crush-induced neuropathic pain

Abstract

Abstract Previously, we showed that CD137L, a costimulatory molecule is involved in the development of neuropathic pain following sciatic nerve crush (SNC). CD137L knockout (KO) mice displayed reduced SNC-induced pain-like behaviors and faster recovery following SNC. To determine the responses at the nerve crush site, we further examined the phenotypic and inflammatory changes of injured sciatic nerve in both CD137L KO mice and wild type (WT) C57BL/6 mice. Both CD137L KO and WT mice underwent either SNC or sham surgery. Sample collection occurred at days 0 (naïve), 3, 7, 14, 28, and 56 post-surgery. First, the femur-level segment of sciatic nerve containing the injury site was analyzed via whole mount immunohistochemistry. At the baseline, CD137L KO mice showed higher staining intensity for IB4 (non-peptidergic c-fibers) compared to WT mice. In WT mice but not CD137L KO mice, SNC significantly increased staining intensity for CGRP (all times; peptidergic c-fibers) and IB4 (Days 3 and 28). These increases were not observed in the corresponding CD137L KO mice. Second, selected inflammatory markers were measured via real time qRT-PCR. At baseline, CD137L KO mice expressed significantly lower levels of TNFα, yet higher levels of IL-10. SNC induced higher levels of elevation of IL-6, CCL3, CCL4, and Arg-1 (all peaked at day 3) in CD137L KO mice compared to WT mice. WT but not CD137L KO mice, showed significant up-regulation of CCL5 (throughout the time course) and CXCL1 (peaked at day 14). Therefore, we propose that CD137L-mediated local inflammatory responses may contribute to SNC induced pain-like behaviors in part by affecting the phenotype of injured nerve. Supported by NIH/NINDS R01NS098426 (Cao), COBRE Histology and Imaging Core funded by NIH/NIGMS P20GM103643 (Meng), and the Kahn Family Foundation through the Carmen Pettapiece Student Research Fellowship (Souza Di Nucci).