Systemic inflammatory perturbations triggered by neuropathic pain in L5 compressed mouse and rat model

Neuropathic pain is caused by lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Unresolvable inflammation is one of the main causes of the difficulty in managing prolonged pain. Although neuropathic pain is characterized by local inflammatory infiltration at the lesion site, whether neuropathic pain can induce systemic inflammation and the underlying mechanisms remain unknown.

The systematically effects of neuropathic pain was we investigated by using lumbar 5 (L5) nerve compression mouse and rat model and performed multi-omic analysis on multiple organ systems at three levels: (1) local compressed nerves (L4-6), (2) brain and bone marrow, and (3) major indirect organs (including heart, liver, lung, kidney, colon, small intestine, spine and spleen).

Bulk RNA sequencing of nerves (L4-6) revealed L5 compression resulted in inflammatory response, metabolic disorders, neuron regeneration. Single-cell RNA sequencing of bone marrow and brain cells identified perturbations in neutrophils and macrophages within the bone marrow, and in microglia within the brain, highlighting the upregulation of inflammatory and immune response pathways. Further ATAC sequencing of bone marrow-derived macrophages revealed upregulation of Rho protein signal transduction and small GTPase-mediated signal transduction. Bulk RNA sequencing of major organs (heart, liver, lung, kidney, colon, small intestine, spine and spleen) revealed activated immune and dysregulated lipid metabolism, with macrophages playing a key role in the process through the activation of different pathways.

Our study reveals that nerve compression-induced neuropathic pain triggers systemic inflammation, characterized by upregulated expression of pro-inflammatory genes (IL13 and Csf3 in bone marrow and brain; TNF-α in the compressed nerve), altered chromatin accessibility in bone marrow macrophages, increased aerobic respiration and energy metabolism in the lungs, hepatic metabolic dysfunction, and renal lipid accumulation. Additionally, ligand-receptor networks facilitate cross-organ inflammation. This atlas redefines neuropathic pain as a multi-organ disorder and identifies myeloid-immune signaling pathways as potential therapeutic targets.

Our study identifies key genes and signaling pathways that may contribute to systemic inflammation in nerve compression-induced neuropathic pain. We sorted out potential intervention targets to modulate the inflammatory process in neuropathic pain, such as inhibitors of Csf3 and IL13, as well as targeting the IL6/TNF-α pathway. However, further functional validation is necessary to confirm their therapeutic efficacy.