Transcriptome analysis of the human tibial nerve identifies sexually dimorphic expression of genes involved in pain, inflammation and neuro-immunity

Ray, Pradipta; Khan, Junaid Sarfraz; Wangzhou, Andi; Tavares‐Ferreira, Diana; Akopian, Armen N.; Dussor, Gregory; Price, Theodore J.

doi:10.1101/450197

Cited by 16 publications

(23 citation statements)

References 23 publications

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“…However, changes in neuronal genes in the mixed cultures following GM-CSF treatment indicate that it might be having an indirect effect on nociceptors via satellite cells or other non-neuronal cell types that make up the majority of the cells in the DRG, and indeed in the mixed DRG cultures. In order to obtain supporting evidence for the proposal that GM-CSF is incapable of directly stimulating nociceptor transcription, we reviewed recent publications that have made use of RNA sequencing to examine gene expression in mouse and human DRG ( Table 2, Thakur et al, 2014;Lopes et al, 2017;Zeisel et al, 2018;Flegel et al, 2015;Ray et al, 2018;Ray et al, 2019). The Table compares the expression of the two GM-CSF receptor chains to several control transcripts:…”

Section: Gm-csf Does Not Modulate Gene Expression In Purified Neuronsmentioning

confidence: 99%

“…It is evident the two transcripts coding for the receptor chains of the GM-CSF receptor, namely CSF2Rα and CSF2Rβ, are expressed at levels below our negative control transcript in the DRG -the CSF2Rβ gene, in particular, appears to be undetectable, even by a technique as sensitive as RNA-seq. In whole human tibial nerve, mRNA for both receptors can be detected at higher levels, presumably due to a contribution from non-neuronal cells (Ray et al, 2019).…”

Section: Gm-csf Does Not Modulate Gene Expression In Purified Neuronsmentioning

confidence: 99%

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Granulocyte-Macrophage Colony Stimulating Factor As an Indirect Mediator of Nociceptor Activation and Pain

et al. 2020

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Section: Gm-csf Does Not Modulate Gene Expression In Purified Neuronsmentioning

confidence: 99%

Section: Gm-csf Does Not Modulate Gene Expression In Purified Neuronsmentioning

confidence: 99%

Granulocyte-Macrophage Colony Stimulating Factor As an Indirect Mediator of Nociceptor Activation and Pain

et al. 2020

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“…Studies in both animals and humans demonstrate sexually dimorphic mechanisms controlling the development and resolution of chronic pain (Joseph et al, 2003; Sorge et al, 2015; Nasir et al, 2016; Taves et al, 2016; Lopes et al, 2017; Rosen et al, 2017; Mapplebeck et al, 2018; Paige et al, 2018; Dance, 2019; North et al, 2019; Patil et al, 2019b; Ray et al, 2019a; Rosen et al, 2019). Among these sex differences, several factors have been discovered that drive chronic pain specifically in males (Sorge et al, 2015; Taves et al, 2016; Mapplebeck et al, 2018; Megat et al, 2018; Paige et al, 2018; Shiers et al, 2018; Martin et al, 2019) but relatively little is known about such chronic pain mechanisms in females.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the apparent male-specific effect of microglia-driven P2X4 signaling in neuropathic pain can be conferred to females with testosterone treatment (Sorge et al, 2015). In humans, sex differences in tibial nerve transcriptomes also demonstrate a signature for gonadal hormone influence on sensory neuronal transcriptomes across the lifespan in females (Ray et al, 2019b). Experiments described here clearly demonstrate differential roles of gonadal hormones in development of chronicity in painful conditions with estrogen exacerbating priming effects and testosterone playing a protective role.…”

Section: Discussionmentioning

confidence: 99%

Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

Paige¹,

Barba-Escobedo

Mecklenburg

et al. 2020

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Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female but not male mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.Significance StatementFemales are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice – where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor.

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“…Strictly Standardized Mean Difference (Zhang et al, 2006;Ray et al, 2019) was used to estimate effect size between 2 different conditions under comparison, using the following formula:…”

Section: Strictly Standardized Mean Difference (Ssmd)mentioning

confidence: 99%

A pharmacological interactome platform for discovery of pain mechanisms and targets

Wangzhou

Paige

Neerukonda

et al. 2020

Preprint

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Smith for help with the colonic single neuron sequencing data, Dr. Brian Gulbransen and lab for help with the enteric glia TRAP data and Dr. Zhenyu Xuan for clarifying TCGA metadata formats. We thank all the authors of the papers from which we used their sequencing data for their exemplary transparency in sharing the details of their work with us. AbstractCells communicate with each other through ligand and receptor interactions. In the case of the peripheral nervous system, these ligand-receptor interactions shape sensory experience. In disease states, such as chronic pain, these ligand-receptor interactions can change the excitability of target neurons augmenting nociceptive input to the CNS. While the importance of these cell to neuron interactions are widely acknowledged, they have not been thoroughly characterized. We sought to address this by cataloging how peripheral cell types interact with sensory neurons in the dorsal root ganglion (DRG) using RNA sequencing datasets. Using single cell sequencing datasets from mouse we created a comprehensive interactome map for how mammalian sensory neurons interact with 42 peripheral cell types. We used this knowledge base to understand how specific cell types and sensory neurons interact in disease states. In mouse datasets, we created an interactome of colonic enteric glial cells in the naïve and inflamed state with sensory neurons that specifically innervate this tissue. In human datasets, we created interactomes of knee joint macrophages from rheumatoid arthritis patients and pancreatic cancer samples with human DRG. Collectively, these interactomes highlight ligandreceptor interactions in mouse models and human disease states that reflect the complexity of cell to neuron signaling in chronic pain states. These interactomes also highlight therapeutic targets, such as the epidermal growth factor receptor (EGFR), which was a common interaction point emerging from our studies.In this formula stands for distance, and stands for gene expression level across all cells in the first condition and second condition respectively, stands for standard deviation and stands for mean.

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Transcriptome analysis of the human tibial nerve identifies sexually dimorphic expression of genes involved in pain, inflammation and neuro-immunity

Abstract: = 220 words Main Text = 1904 words Captions = 174 words References = 22 references Figures = 2

Cited by 16 publications

References 23 publications

Granulocyte-Macrophage Colony Stimulating Factor As an Indirect Mediator of Nociceptor Activation and Pain

Granulocyte-Macrophage Colony Stimulating Factor As an Indirect Mediator of Nociceptor Activation and Pain

Neuroendocrine mechanisms governing sex-differences in chronic pain involve prolactin receptor sensory neuron signaling

A pharmacological interactome platform for discovery of pain mechanisms and targets

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