Upregulation of CX3CL1 mediated by NF-κB activation in dorsal root ganglion contributes to peripheral sensitization and chronic pain induced by oxaliplatin administration

Abstract

Painful peripheral neuropathy is a severe side effect in oxaliplatin therapy that compromises cancer patients' quality of life. However, its underlying pathogenic mechanisms remain largely unknown. Here, we found that intraperitoneal consecutive administration of oxaliplatin significantly increased excitability of small diameter dorsal root ganglion neurons and induced thermal hyperalgesia in rats. Furthermore, the CX3CL1 expression was significantly increased after oxaliplatin treatment, and intrathecal injection of a neutralizing antibody against CX3CL1 markedly attenuated the enhanced excitability of dorsal root ganglion neurons and thermal hyperalgesia. Importantly, the upregulated CX3CL1 is mediated by the NF-κB signaling pathway, as inhibition of NF-κB p65 activation with pyrrolidine dithiocarbamate or p65 siRNA inhibited the upregulation of CX3CL1, the enhanced excitability of dorsal root ganglion neurons, and thermal hyperalgesia induced by oxaliplatin. Further studies with chromatin immunoprecipitation found that oxaliplatin treatment increased the recruitment of NF-κB p65 to the CX3Cl1 promoter region. Our results suggest that upregulation of CX3CL1 in dorsal root ganglion mediated by NF-κB activation contributes to the peripheral sensitization and chronic pain induced by oxaliplatin administration.

Transcriptomic sex differences in sensory neuronal populations of mice

“…These female-selective DEGs showed preferential expression in female DRG and TG, with notably larger differences in the TG neurons. In this cluster, the complement system 38 ; certain chemokines regulating monocyte, macrophage and NK cell migration/trafficking [40][41][42] ; IL-1, IL-6 and IL-33 cytokines; and the tumor necrosis factor super family members, such as Tnfrsf1a and Ntrk1 and their effector Nfkb2 24,38,42,43 are well documented contributors to nociception and pain development (Fig. 9B).…”

“…DEGs found enriched in female TG included members of the complement system (C1q and C3), which is part of the innate immune system and is involved in nociception regulation 38 . Both TG and DRG neurons contained female-selective DEGs belonging to the chemokine system (Cx3cl1, Cx3cr1, Ccl3, Cxcl12 and Cmklr1), which regulate monocyte, macrophage and natural killer (NK) cell migration/trafficking 39 and neuropathic pain [40][41][42] ; the www.nature.com/scientificreports/ cytokine system (IL6ra and IL33); the integrin system (Itga8, Itga3 and Itgam); the tumor necrosis factor super family members (Tnfrsf1a, Tnfrsf1b, Ltbr, Ngfr and Ntrk1) and their effectors (Nfkb2, Nfkbid, Tifab and Icam1), many of which are key regulators of pain chronicity 24,38,[42][43][44] ; and cluster differential factor (CD74 and CD93) ( Fig. 5A,B).…”

Genomewide Meta‐Analysis Validates a Role for S1PR1 in Microtubule Targeting Agent‐Induced Sensory Peripheral Neuropathy

“…Because the study focuses on sensory neuronal mechanisms involved in MTA-induced PN, five independent SNP associations with linkage disequilibrium support for association and whose nearest gene is expressed in human DRG 19 were prioritized for in silico functional analysis to determine if the SNP lies in a potential regulatory genomic region. Three of the five SNPs (rs74497159, rs10771973, and rs11076190) had the strongest in silico evidence for predicted functional activity and previous reports linking their annotated genes (S1PR1, 22,23 FGD4, 12,24 and CX3CL1 [25][26][27] ) to chemotherapy-induced neurotoxicity. Importantly, S1PR 1 function was linked to neurotoxicity of paclitaxel in iPSC-SNs in vitro.…”

“…25 Additionally, previous work suggests that increased recruitment of transcription factors (i.e., ΝF-κβ) to the CX3CL1 promoter region is heightened in CIPN in vivo models. 26 Two additional genomic regions warrant investigation of potential involvement in CIPN. rs2060717 lies in a highly predicted promoter site within an intronic region of CALU, a gene that encodes for calcium-binding protein calumenin, which localizes to the endoplasmic reticulum with potential roles in early neuronal development.…”

TNF-α Pretreatment Improves the Survival and Function of Transplanted Human Neural Progenitor Cells Following Hypoxic-Ischemic Brain Injury

“…By using RNA-seq analysis and qRT-PCR, we found that CX3CL1, an important factor for regulation of microglia, was increased in hNPCs by TNF-α treatment. Previous studies have shown that gene expression of CX3CL1 is regulated by TNF-α in other cell types [56], that CX3CL1 inhibits neuronal death by reducing the production of pro-inflammatory cytokine via inhibition of LPS-induced microglial activation [57][58][59], and that stem cells genetically modified to overexpress CX3CL1 exhibited enhanced neuroprotective effects, and reduced ischemia-induced cerebral infarct size and neurological deficits [60,61]. These findings suggest that, in this study, CX3CL1 contributed to the TNF-α-mediated neuroprotective effects.…”