Deletion of interleukin-6 signal transducer gp130 in small sensory neurons attenuates mechanonociception and down-regulates TRPA1 expression

Philipp Malsch, Manfred Andratsch, Christian Vogl, Andrea S Link, Christian Alzheimer, Stuart M Brierley, Patrick A Hughes, Michaela Kress, Philipp Malsch, Manfred Andratsch, Christian Vogl, Andrea S Link, Christian Alzheimer, Stuart M Brierley, Patrick A Hughes, Michaela Kress

Abstract

Glycoprotein 130 (gp130) is the signal transducing receptor subunit for cytokines of the interleukin-6 (IL-6) family, and it is expressed in a multitude of cell types of the immune and nervous system. IL-6-like cytokines are not only key regulators of innate immunity and inflammation but are also essential factors for the differentiation and development of the somatosensory system. Mice with a null mutation of gp130 in primary nociceptive afferents (SNS-gp130(-/-)) are largely protected from hypersensitivity to mechanical stimuli in mouse models of pathological pain. Therefore, we set out to investigate how neuronal gp130 regulates mechanonociception. SNS-gp130(-/-) mice revealed reduced mechanosensitivity to high mechanical forces in the von Frey assay in vivo, and this was associated with a reduced sensitivity of nociceptive primary afferents in vitro. Together with these findings, transient receptor potential ankyrin 1 (TRPA1) mRNA expression was significantly reduced in DRG from SNS-gp130(-/-) mice. This was also reflected by a reduced number of neurons responding with calcium transients to TRPA1 agonists in primary DRG cultures. Downregulation of Trpa1 expression was predominantly discovered in nonpeptidergic neurons, with the deficit becoming evident during stages of early postnatal development. Regulation of Trpa1 mRNA expression levels downstream of gp130 involved the classical Janus kinase family-signal transducer and activator of transcription pathway. Our results closely link proinflammatory cytokines to the expression of TRPA1, both of which have been shown to contribute to hypersensitive pain states. We suggest that gp130 has an essential role in mechanonociception and in the regulation of TRPA1 expression.

Keywords: Il-6 signal transducer; JAK/STAT signaling; cytokine; mechanonociceptor; mechanotransduction; pain.

Copyright © 2014 the authors 0270-6474/14/349845-12$15.00/0.

Figures

Figure 1.
Figure 1.
SNS-gp130−/− mice were less sensitive to mechanical stimulation. A, SNS-gp130−/− mice responded with significantly lower frequencies to mechanical stimulation with von Frey hairs than control gp130fl/fl mice (N = 9, two-way ANOVA, genotype: p < 0.001, forces: p < 0.001, genotype × forces: p = 0.084). B, Stimulus–response relationship of SNS-gp130−/− mice in the von Frey test was shifted toward stronger forces as SNS-gp130−/− mice exhibited significantly higher mechanical thresholds than gp130fl/fl mice. Boxes represent median as well as lower and upper quartile; whiskers represent the 10th and 90th percentiles. C, In vitro, the distribution of mechanical thresholds was significantly shifted toward stronger stimuli for unmyelinated mechanosensitive afferents obtained from SNS-gp130−/− (black columns) compared with those from gp130fl/fl mice (white columns; gp130fl/fl: median: 32 mN, n = 63, N = 30; black columns: SNS-gp130−/−: median: 128 mN, n = 35, N = 23; Mann–Whitney U test, p < 0.05). D, The cumulative distribution showed that a significantly lower percentage of fibers responded to medium to high mechanical forces in SNS-gp130−/− mice. *p < 0.05. **p < 0.01.
Figure 2.
Figure 2.
Genome-wide mRNA expression profiling assay. A, Average ion channel expression intensities in SNS-gp130−/− compared with gp130fl/fl DRG explants (N = 5). Depicted are the means of the quantile-normalized signals. The linear values are shown in a log2 scaling. FDR-adjusted p values for deregulated genes: Scn5a, p = 0.162797384; Kcnh1, p = 0.309818818; Chrnb4, p = 0.112616368; Kcnj11, p = 0.36698117; Scn3b, p = 0.396426446; Trpc7, p = 0.378056322; Cacna1f, p = 0.5246788; Trpa1, p = 0.363034703; LOC637107, p = 0.31986923. B, Heat map showing ion channel gene expression in SNS-gp130−/− versus gp130fl/fl DRG explants. Genes, which are upregulated (green, left) or downregulated (magenta, right), are sorted by their unadjusted p value. Only genes with p < 0.05 are shown. C, Expressed ion channels with a putative function in mechanotransduction. Expression levels are shown as log2 quantile-normalized signal values for each candidate and genotype (open circles represent gp130fl/fl; filled circles represent SNS-gp130−/−), and variation between individuals is minimal. Among the 14 genes, Trpa1 is the only deregulated ion channel. For fold change in expression levels, see Table 1.
Figure 3.
Figure 3.
Neuronal gp130 was essential for Trpa1 mRNA expression in DRG. A, TaqMan mRNA analysis revealed significantly lower Trpa1 mRNA levels in DRG explants and primary neuronal cultures of SNS-gp130−/− mice (DRG from thoracic and lumbar levels). B, Trpa1 mRNA expression was significantly reduced in lumbar DRG explants from SNS-gp130−/− mice compared with gp130fl/fl and SNS-Cre, which were not significantly different. Furthermore, Trpv1 and Trpv4 mRNA levels were similar between gp130fl/fl and SNS-gp130−/− mice. C, Trpa1 mRNA expression of lumbar DRG explants within the first 14 postnatal days. In SNS-gp130−/− mice, Trpa1 mRNA expression was already reduced at P1–P14. Expression levels are normalized to adult gp130fl/fl mice. *p < 0.05. **p < 0.01. ***p < 0.001.
Figure 4.
Figure 4.
Reduced Trpa1 mRNA levels in DRG sections of SNS-gp130−/− mice. A, ISH with Trpa1 antisense riboprobe produced a selective staining of Trpa1-expressing neurons, whereas sense probes did not show specific staining in the lumbar DRG sections. Scale bar, 50 μm. B, Samples of gp130fl/fl and SNS-gp130−/− lumbar DRG sections with Trpa1 antisense riboprobe display reduced Trpa1 mRNA labeling in SNS-gp130−/− sections. Scale bar, 50 μm. C, Quantification of the ISH labeling in lumbar gp130fl/fl and SNS-gp130−/− sections. SNS-gp130−/− sections reveal significantly lower numbers of Trpa1 expressing neurons. *p < 0.05.
Figure 5.
Figure 5.
Trpa1 deficiency was predominantly observed in IB4-binding nociceptive neurons. A, B, Staining for IB4+ neurons in gp130fl/fl and SNS-gp130−/− DRG sections. Scale bar, 50 μm. C, The percentage of IB4-binding neurons was similar in both genotypes. D, E, FISH for Trpa1 mRNA in gp130fl/fl and SNS-gp130−/− DRG sections. Scale bar, 50 μm. F, Quantification of FISH shows that the number of Trpa1 mRNA-expressing neurons (Trpa1+) was significantly reduced in SNS-gp130−/− mice. G, H, Colabeling of Trpa1 mRNA expressing (magenta) and IB4-binding (green) neurons in both genotypes. Scale bar, 50 μm. I, In control mice, Trpa1 mRNA was predominantly expressed in IB4-positive neurons. In SNS-gp130−/− mice, reduction of Trpa1 was most noticeable in the IB4-positive population. n.s., Not significant (p > 0.05). *p < 0.05. **p < 0.01.
Figure 6.
Figure 6.
Expression of Trpa1 mRNA was controlled by the JAK-STAT pathway. TaqMan mRNA analysis revealed significantly reduced Trpa1 expression levels in DRG neurons incubated with a selective JAK inhibitor I (JAKI, 1 μm) or a STAT inhibitor, with selectivity for STAT3 (Stattic, 1.5 μm). *p < 0.05. **p < 0.01.
Figure 7.
Figure 7.
Functional TRPA1 expression was reduced in cultured primary DRG neurons of SNS-gp130−/− mice. A, Calcium imaging sample traces of primary neurons stimulated with the TRPA1-agonist CA (200 μm), high potassium chloride (KCl, 25 mm) and TRPV1-agonist capsaicin (0.3 μm). B, The percentage of neurons responding to CA was significantly decreased in SNS-gp130−/− cultures. In contrast, the responsiveness to capsaicin (Caps) was unchanged. C, Calcium imaging sample traces of primary neurons stimulated with NPPB (100 μm) and KCl (25 mm). Responses to NPPB were greatly diminished in TRPA1−/− neurons. Magnitude of ratio increase in response to stimulation with 100 μm NPPB in TRPA1+/+ (n = 53, N = 2) and TRPA1−/− (n = 101, N = 3) neuronal cultures. The highest ratio increase in TRPA1−/− cultures was considered as threshold for TRPA1-mediated responses to NPPB. TRPA1+/+ and TRPA1−/−: boxes represent median as well as lower and upper quartile; whiskers represent the 10th and 90th percentiles. D, Percentage and ratio increase of neurons responding to NPPB with a suprathreshold ratio increase in gp130fl/fl and SNS-gp130−/− neuron cultures. In SNS-gp130−/− cultures, the number of neurons responding to NPPB was significantly decreased, and NPPB-responsive cells showed a significantly lower ratio increase to the stimulus. *p < 0.05. **p < 0.01. ***p < 0.001.
Figure 8.
Figure 8.
Attenuated CA-induced nocifensive behavior in SNS-gp130−/− mice. SNS-gp130−/− mice displayed a significantly shorter licking duration and reduced number of licks of their hindpaws in response to an injection of 20 μl 1% CA during the 5 min observation period. *p < 0.05. **p < 0.01.

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