Transcriptional Mechanisms Underlying Sensitization of Peripheral Sensory Neurons by Granulocyte-/Granulocyte-Macrophage Colony Stimulating Factors

Abstract

BackgroundCancer-associated pain is a major cause of poor quality of life in cancer patients and is frequently resistant to conventional therapy. Recent studies indicate that some hematopoietic growth factors, namely granulocyte macrophage colony stimulating factor (GMCSF) and granulocyte colony stimulating factor (GCSF), are abundantly released in the tumor microenvironment and play a key role in regulating tumor-nerve interactions and tumor-associated pain by activating receptors on dorsal root ganglion (DRG) neurons. Moreover, these hematopoietic factors have been highly implicated in postsurgical pain, inflammatory pain and osteoarthritic pain. However, the molecular mechanisms via which G-/GMCSF bring about nociceptive sensitization and elicit pain are not known.ResultsIn order to elucidate G-/GMCSF mediated transcriptional changes in the sensory neurons, we performed a comprehensive, genome-wide analysis of changes in the transcriptome of DRG neurons brought about by exposure to GMCSF or GCSF. We present complete information on regulated genes and validated profiling analyses and report novel regulatory networks and interaction maps revealed by detailed bioinformatics analyses. Amongst these, we validate calpain 2, matrix metalloproteinase 9 (MMP9) and a RhoGTPase Rac1 as well as Tumor necrosis factor alpha (TNFα) as transcriptional targets of G-/GMCSF and demonstrate the importance of MMP9 and Rac1 in GMCSF-induced nociceptor sensitization.ConclusionWith integrative approach of bioinformatics, in vivo pharmacology and behavioral analyses, our results not only indicate that transcriptional control by G-/GMCSF signaling regulates a variety of established pain modulators, but also uncover a large number of novel targets, paving the way for translational analyses in the context of pain disorders.

The relationship between synovial inflammation, structural pathology, and pain in post-traumatic osteoarthritis: differential effect of stem cell and hyaluronan treatment

“…There was evidence that Hymovis but not MSCs ameliorated later-stage OA-associated synovial Mmp9 upregulation. MMP9 is one of the key synovitis hub genes recently identified in human OA [50] and known to play a role in nociceptor sensitization [51]. In contrast, MSCs particularly when injected twice slowed the natural post-injury resolution of another of the key OA synovitis hub genes, Il6, which may in part explain their reduced effect on allodynia.…”

Painful, degenerating intervertebral discs up‐regulate neurite sprouting and CGRP through nociceptive factors

“…Conditioned media from degenerating, painful IVDs and healthy, pain-free IVDs were analysed using cytokine and chemokine protein arrays. Twenty factors were found to be up-regulated in degenerating, painful samples, of which 10 (IFN-c, IL-6 and -15, CCL2 and -7, CCL5, TNF-a, GRO and CXCL1, GCSF and GM-CSF) have been associated with increased nociception [10,11,[31][32][33][34][35][36][37][44][45][46][47][48][49][50]. Some of the 20 factors have been previously associated with IVD degeneration [12,15,[51][52][53][54], however 10 of the 20 factors (GCSF, GM-CSF, IL-3, IL-5, IL-13, IL-15, CCL8, TNF-b, GRO and CXCL1) have not previously been described in the IVD and two (CCL7 and CXCL9) [54] have not been described in degenerative disc disease.…”

Immune mediators of chronic pelvic pain syndrome

“…Mast cells contribute to rapidly occurring neuronal peripheral sensitization, 140 which is mediated by the neurotrophin nerve growth factor (NGF). 141–143 Mast cells are known to express TrkA receptors on their cell membrane and, therefore, NGF binding might cause degranulation, establishing a feedback mechanism that would promote sensitization mechanisms.…”