Sex differences in peripheral not central immune responses to pain-inducing injury

Lopes, Douglas M.; Małek, Natalia; Edye, Michelle E.; Jager, Sara Buskbjerg; McMurray, Sheridan; McMahon, Stephen B.; Denk, Franziska

doi:10.1038/s41598-017-16664-z

Cited by 95 publications

(99 citation statements)

References 21 publications

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“…Absolute event counts remained elevated up to 14 weeks after injury. As we observed previously in DRG 20 , nerve seemed to contain a large population of unidentified CD45+ cells that are non-myeloid (CD11b-) and not positive for αβTCR. They also do not appear to be positive for CD19 (B cells), and preliminary trials indicated that they are negative for γδ+ TCR or glutamine synthetase, a satellite glial cell marker (data not shown).…”

Section: Resultssupporting

confidence: 77%

“…Also in keeping with our cell count data, we found no striking main effect of sex at transcriptional level (Suppl . Table 6), at least not beyond X and Y-linked genes that are usually found associated with female and male sampling 20 . We could, however, detect clear differences in phenotype between macrophages from sciatic nerve and DRG.…”

Section: Resultsmentioning

confidence: 98%

“…We re-analysed our own data, as well as previously published data on relevant cell types that one might want to consider when examining the expression level of one's favourite gene in peripheral neuro-immune interactions, particularly after nerve injury. Specifically, we included naïve magnetically sorted sensory neurons (GSE62424) 25 , naïve FAC-sorted sensory neurons (GSE100035) 20 , magnetically sorted sensory neurons after nerve injury (GSE100035) 20 , Schwann cells sorted after sciatic nerve transection (GSE103039) 26 , macrophages after sciatic nerve transection (GSE106488) 27 , CCR2+Cx3cr1+ macrophages after sciatic nerve crush (GSE106927) 28 , and naïve macrophages associated with sympathetic nerve and ganglia in adipose tissue (GSE103847) 23 . To improve inter-study comparisons, we re-aligned our RNA-seq results using BioJupies 29 , to ensure all datasets were processed with the same kallisto settings.…”

Section: Resultsmentioning

confidence: 99%

“…n = 4 biological replicates) can yield false-positive findings when dealing with variable in vivo samples. It is a trap into which we ourselves seem to have fallen 20 . While it can be tricky to estimate power when faced with one-off, small scale, pre-clinical flow-cytometry experiments, it is easier to do so with big RNA sequencing datasets.…”

Section: Discussionmentioning

confidence: 98%

“…Figure 8). We previously detected sex differences in lymphocyte numbers when examining immune cells from DRG from a smaller number of mice (n = 4, male vs. female) at two time points (day 8 vs. day 28) 20 . Our current, more thorough exploration failed to replicate this.…”

Section: Figure 3: Partial Sciatic Nerve Ligation Induces a Long-lastmentioning

confidence: 99%

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A transcriptional toolbox for exploring peripheral neuro-immune interactions

Liang

Hore

Harley

et al. 2019

Preprint

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Correct communication between immune cells and peripheral neurons is crucial for the protection of our bodies. Its breakdown is observed in many common, often painful conditions, including arthritis, neuropathies and inflammatory bowel or bladder disease. Here, we have characterised the immune response in a mouse model of neuropathic pain using flow cytometry and cell-type specific RNA sequencing (RNA-seq). We found few striking sex differences, but a very persistent inflammatory response, with increased numbers of monocytes and macrophages up to 3½ months after the initial injury. This raises the question of whether the commonly used categorisation of pain into "inflammatory" and "neuropathic" is one that is mechanistically appropriate. Finally, we collated our data with other published RNA-seq datasets on neurons, satellite glial cells, macrophages and Schwann cells in naïve and nerve injury states. The result is a practical web-based tool for the transcriptional data-mining of peripheral neuroimmune interactions. Figure 8: At one week post PSNL, MHCII+/Ly6C-myeloid cells from sciatic nerve upregulate functions relating to interactions with other immune cells, in favour of more generic pro-inflammatory and homeostatic activities.A) STRING network analysis reveals that 77 of 186 genes upregulated in ipsilateral MHCII+ macrophages at adj. p < 0.05 are likely to be functionally connected with overrepresented processes including antigen presentation, regulation of lymphocytes and myeloid cell activation. B) Conversely, 41 of 93 significantly downregulated genes formed a network that includes transcripts relating to pro-inflammatory function (TNF, complements), regulation of angiogenesis and canonical macrophage markers, like CD163 typically found in resident macrophages. See Suppl. Table 5 for differential expression tables.

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Section: Resultssupporting

confidence: 77%

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Figure 3: Partial Sciatic Nerve Ligation Induces a Long-lastmentioning

confidence: 99%

See 3 more Smart Citations

A transcriptional toolbox for exploring peripheral neuro-immune interactions

Liang

Hore

Harley

et al. 2019

Preprint

Self Cite

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Sex‐specific transcriptome of spinal microglia in neuropathic pain due to peripheral nerve injury

Fiore

Yin

Güneykaya

et al. 2022

Glia

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Neuropathic pain is a prevalent and debilitating chronic disease that is characterized by activation in glial cells in various pain-related regions within the central nervous system. Recent studies have suggested a sexually dimorphic role of microglia in the maintenance of neuropathic pain in rodents. Here, we utilized RNA sequencing analysis and in vitro primary cultures of microglia to identify whether there is a common neuropathic microglial signature and characterize the sex differences in microglia in pain-related regions in nerve injury and chemotherapy-induced peripheral neuropa-

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Comparing axon regeneration in male and female mice after peripheral nerve injury

Jang

Bae

Yang

et al. 2021

J of Neuroscience Research

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Axons in the adult mammalian central nervous system fail to regenerate after injury. By contrast, spontaneous axon regeneration occurs in the peripheral nervous system (PNS) due to a supportive PNS environment and an increase in the intrinsic growth potential induced by injury via cooperative activation of multifaceted biological pathways. This study compared axon regeneration and injury responses in C57BL/6 male and female mice after sciatic nerve crush (SNC) injury. The extent of axon regeneration in vivo was indistinguishable in male and female mice when observed at 3 days after SNC injury, and primary dorsal root ganglion (DRG) neurons from injured, male and female mice extended axons to a similar length. Moreover, the induction of selected regeneration‐associated genes (RAGs), such as Atf3, Sprr1a, Gap43, Sox11, Jun, Gadd45a, and Smad1 were comparable in male and female DRGs when assessed by quantitative real‐time reverse transcription polymerase chain reaction. Furthermore, the RNA‐seq analysis of male and female DRGs revealed that differentially expressed genes (DEGs) in SNC groups compared to sham‐operated groups included many common genes associated with neurite outgrowth. However, we also found that a large number of genes in the DEGs were sex dependent, implicating the involvement of distinct gene regulatory network in the two sexes following peripheral nerve injury. In conclusion, we found that male and female mice mounted a comparable axon regeneration response and many RAGs were commonly induced in response to SNC. However, given that many DEGs were sex‐dependently expressed, future studies are needed to investigate whether they contribute to peripheral axon regeneration, and if so, to what extent.

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Sex differences in peripheral not central immune responses to pain-inducing injury

Cited by 95 publications

References 21 publications

A transcriptional toolbox for exploring peripheral neuro-immune interactions

A transcriptional toolbox for exploring peripheral neuro-immune interactions

Sex‐specific transcriptome of spinal microglia in neuropathic pain due to peripheral nerve injury

Comparing axon regeneration in male and female mice after peripheral nerve injury

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