Abstract
Peripheral nerve injury induces a myriad of immune-derived symptoms that negatively impacts pain, depression, and overall quality of life. Neuroimmune differences underlie sexual dimorphisms in various pain states. The innate immune system is a source of these sex differences, which promotes inflammation and pro-nociception through bidirectional signaling with the nervous system. Spatiotemporal interactions between leukocytes and sensory neurons could hold the key to explain ascribed differences between sexes. To date, studies have found it difficult to display these interactions. We are poised to answer important questions regarding the recruitment of peripheral leukocytes to key tissues of the pain system, the dorsal root ganglia (DRG) and sciatic nerve after nerve injury. We optically clear whole DRGs and sciatic nerves and concomitantly use multi-photon microscopy and transgenic reporter lines, to visualize leukocyte dynamics involved in neuropathic pain development following nerve injury. We observed robust sexual dimorphisms in leukocyte recruitment to the lumbar DRGs after nerve injury. We also assessed immune cell size and morphology to understand activation states in the context of nervous tissue inflammation. The altered mechanisms by which the male and female immune systems respond to nerve injury are still topics of further research, however; the continued use of next-generation imaging with advanced whole tissue image analysis remains an important tool in understanding the reciprocal interactions between neuronal and non-neuronal cells.
Highlights
Peripheral nerve injury often results in neuropathic pain, which is defined by trauma or lesions that disrupt the somatosensory systems
To improve our understanding of the dynamic immune response after peripheral nerve injury, we designed an interdisciplinary approach combining advanced multiphoton microscopy, ScaleS1 tissue clearing and a well-established nerve injury model (SNI) Using these techniques, we were able to address some of the limitations of previous studies investigating the macrophage response to nerve injury
We acquired high resolution Z-stack images of the cleared tissues using multiphoton microscopy and performed extensive analyses using Imaris Imaging Software to understand the dynamics of macrophage recruitment, activation, and morphology after injury
Summary
Peripheral nerve injury often results in neuropathic pain, which is defined by trauma or lesions that disrupt the somatosensory systems. Injury-induced neuropathic pain is estimated to occur in over 30% of patients following routine operations (Kehlet et al, 2006). The prevalence of chronic pain continues to rise, the number and effectiveness. Sex Differences in Neuroimmune Interactions of existing therapeutics remains limited (Finnerup, 2015). The increasing incidence of neuropathic pain has piqued interest in understanding the key immunologic processes involved. Previous studies have found a clinically observed difference in the prevalence and perception of pain in males vs females (Fillingim et al, 2009; Mogil, 2012). There is still a dearth of knowledge on the sexual dimorphisms observed in leukocyte trafficking, morphology, and neuroimmune interaction
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