The Impact of Nerve Injury on the Immune System Across the Lifespan is Sexually Dimorphic

Abstract

Although nerve injury-associated neuroinflammation contributes to neuropathic pain, the long-term impact of such injury on systemic homeostasis and its potential role in pain remains elusive. In this study, we aim to understand the systemic changes that are present alongside chronic pain in nerve-injured male and female mice across their lifespan. We monitored mechanical and cold sensitivity in male and female mice starting at the age of 3–4 months old when they received spared nerve injury (SNI), up to 20-month post-injury. Alongside, we collected blood samples to track changes in immune cells with flow cytometry, and to assess inflammation-related serum proteome using a 111-target Proteome Profiler. We also transferred serum from sham/SNI mice to naïve mice to determine the potential of systemic contribution to pain. While nerve injury did not affect immune cell composition in the blood, it triggered a long-lasting disturbance of molecular profile in the serum of sham/SNI mice, in a sex-dependent manner. Compared to sham surgery, nerve injury amplified regulation of inflammatory proteins in males, but slightly reduced it in females. These changes in the serum occurred in parallel with long-lasting mechanical and cold hypersensitivity in the nerve-injured mice. Both male and female SNI serum induced hypersensitivity when transferred to naïve mice, regardless of a sex-matched or sex-crossed transfer. Our results highlight that a local nerve injury can have persistent systemic impact. Injury-associated systemic inflammation could contribute to neuropathic pain, but the underlying mechanisms may be sexually dimorphic.

Note:
Funding Information: This work was supported by funding from the Canadian Institutes for Health Research (CIHR) PJT-155929, PJT-185851 to JZ. WBSZ holds a PhD studentship from Louise and Alan Edwards Foundation.

Declaration of Interests: The authors have no conflict of interest to report.

Ethics Approval Statement: All protocols were approved by the McGill University Animal Care and Use Committee (protocol# 5775) and conducted according to the guidelines of the Canadian Council on Animal Care.

Keywords: nerve injury, serum transfer, systemic inflammation, sex difference, age, pain