Activation of colo‐rectal high‐threshold afferent nerves by Interleukin‐2 is tetrodotoxin‐sensitive and upregulated in a mouse model of chronic visceral hypersensitivity

Campaniello, Melissa A.; Harrington, Andrea M.; Martin, C. M.; Blackshaw, L. Ashley; Brierley, Stuart M.; Hughes, Patrick A.

doi:10.1111/nmo.12696

Cited by 14 publications

(15 citation statements)

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“…Visceral afferent firing to mechanical and chemical activation were unaffected following loss of, or antagonism of, Na V 1.7, but could be blocked by TTX as shown previously (Campaniello et al . ). As such, TTX‐S Na V s other than Na V 1.7 are involved in transducing noxious visceral stimuli.…”

Section: Discussionmentioning

confidence: 97%

Visceral and somatic pain modalities reveal Na_V1.7‐independent visceral nociceptive pathways

Hockley

González‐Cano

McMurray

et al. 2017

The Journal of Physiology

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Voltage-gated sodium channel Na 1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of Na 1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific Na 1.7 knockout mouse (Na 1.7 ) and selective small-molecule Na 1.7 antagonist PF-5198007. Na 1.7 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both Na 1.7 and littermate controls. Loss, or blockade, of Na 1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of Na 1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed Na 1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of Na 1.7 (in Na 1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective Na 1.7 antagonist PF-5198007. Our data demonstrate that Na 1.7 (in Na 1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of Na 1.7 alone in the viscera may be insufficient in targeting chronic visceral pain.

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Section: Discussionmentioning

confidence: 97%

Visceral and somatic pain modalities reveal Na_V1.7‐independent visceral nociceptive pathways

Hockley

González‐Cano

McMurray

et al. 2017

The Journal of Physiology

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“…Also, TNF‐α could be secreted by T cells, but is not T cell specific and can be secreted by many different cell types such as macrophages, adipocytes endothelial cells, cardiac myocytes, fibroblasts, and neurons. Interestingly, animal studies indicate that TNF‐α and IL‐2, a different T cell secreted cytokine, both activate colonic sensory afferent nerve endings, potentially indicating a role in abdominal pain in IBS. IL‐10 was not found to have any effect on these nerve populations .…”

Section: Discussionmentioning

confidence: 99%

Colonic immune cells in irritable bowel syndrome: A systematic review and meta‐analysis

Bashashati

Moossavi

Cremon

et al. 2017

Neurogastroenterology Motil

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133

118

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Background & Aims Increases in mucosal immune cells have frequently been observed in irritable bowel syndrome (IBS) patients. However, this finding is not completely consistent between studies, possibly due to a combination of methodological variability, population differences and small sample sizes. We performed a meta‐analysis of case–control studies that compared immune cell counts in colonic biopsies of IBS patients and controls. Methods PubMed and Embase were searched in February 2017. Results were pooled using standardized mean difference (SMD) and were considered significant when zero was not within the 95% confidence interval (CI). Heterogeneity was assessed based on I2 statistics where I2 ≤ 50% and I2 > 50% indicated fixed and random effect models, respectively. Key Results Twenty‐two studies on 706 IBS patients and 401 controls were included. Mast cells were increased in the rectosigmoid (SMD: 0.38 [95% CI: 0.06‐0.71]; P = .02) and descending colon (SMD: 1.69 [95% CI: 0.65‐2.73]; P = .001) of IBS patients. Increased mast cells were observed in both constipation (IBS‐C) and diarrhea predominant IBS (IBS‐D). CD3+ T cells were increased in the rectosigmoid (SMD: 0.53 [95% CI: 0.21‐0.85]; P = .001) and the descending colon of the IBS patients (SMD: 0.79, 95% CI [0.28‐1.30]; P = .002). This was possibly in relation to higher CD4+ T cells in IBS (SMD: 0.33 [95% CI: 0.01‐0.65]; P = .04) as there were no differences in CD8+ T cells. Conclusions & Inferences Mast cells and CD3+ T cells are increased in colonic biopsies of patients with IBS vs non‐inflamed controls. These changes are segmental and sometimes IBS‐subtype dependent. The diagnostic value of the quantification of colonic mucosal cells in IBS requires further investigation.

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“…Myeloperoxidase activity in the distal colon was determined as previously described (15,16). Briefly, phosphate-buffered saline-washed tissue segments were homogenized in 0.5% hexadecyl-trimethylammonium bromide (Sigma-Aldrich) and reacted with o-dianisidine hydrochloride (Sigma-Aldrich).…”

Section: Myeloperoxidase Activitymentioning

confidence: 99%

Immuno-PET of Innate Immune Markers CD11b and IL-1β Detects Inflammation in Murine Colitis

et al. 2018

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Inflammatory bowel disease (IBD) is a chronic relapsing and remitting inflammatory disease of the gastrointestinal tract. The diagnosis and monitoring of IBD are reliant on endoscopy, which is invasive and does not provide information on specific mediators. Symptom flare in IBD is associated with increased activation of innate immune pathways. Immuno-PET approaches have previously demonstrated the ability to detect colitis; however, a direct comparison of antibodies targeted to innate immune mediators and cells has not been done. We aimed to compare immuno-PET of antibodies to IL-1β and CD11b against standard 18 F-FDG and MRI approaches to detect colonic inflammation. Methods: Colonic concentrations of IL-1β and myeloperoxidase were determined by ELISA, and colonic infiltration by CD11b-positive CD3-negative innate immune cells was determined by flow cytometry and compared between healthy and dextran sodium sulphate-treated colitic mice. PET of 89 Zr-lα-IL-1β, 89 Zr-α-CD11b, and 18 F-FDG was compared by volume-of-interest analysis and with MRI by region-of-interest analysis. Imaging results were confirmed by ex vivo biodistribution analysis. Results: Colonic inflammation was associated with impaired colonic epithelial barrier permeability, increased colonic IL-1β and myeloperoxidase concentrations, and increased CD11b-positive CD3-negative innate immune cell infiltration into the colon. 89 Zr-α-IL-1β and 89 Zr-α-CD11b immuno-PET detected colonic inflammation, as did 18 F-FDG, and all PET tracers were more sensitive than MRI. Although 18 F-FDG volumes of interest correlated with colitis severity and a strong trend was observed with 89 Zr-α-IL-1β, no correlation was observed for 89 Zr-α-CD11b or MRI. 89 Zr-α-IL-1β was distributed mainly to the gastrointestinal tract, whereas 89 Zr-α-CD11b was distributed to more tissue types. Conclusion: Immuno-PET using antibodies directed to innate immune markers detected colonic inflammation, with 89 Zr-α-IL-1β providing a more tissue-specific signal than 89 Zr-α-CD11b. Development of these technologies for human subjects will potentially provide a less invasive approach than endoscopy for diagnosing and monitoring IBD. Detects Inflammation inβ Immuno-PET of Innate Immune Markers CD11b and IL-1 http://jnm.snmjournals.org/content/60/6/858 This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml

show abstract

Activation of colo‐rectal high‐threshold afferent nerves by Interleukin‐2 is tetrodotoxin‐sensitive and upregulated in a mouse model of chronic visceral hypersensitivity

Abstract: IL-2, an immune mediator from the adaptive arm of the immune response, affects colo-rectal afferent function, indicating these effects are not restricted to innate immune mediators. Colo-rectal afferent sensitivity to IL-2 is increased long after healing from inflammation.

Cited by 14 publications

References 52 publications

Visceral and somatic pain modalities reveal Na_V1.7‐independent visceral nociceptive pathways

Visceral and somatic pain modalities reveal Na_V1.7‐independent visceral nociceptive pathways

Colonic immune cells in irritable bowel syndrome: A systematic review and meta‐analysis

Immuno-PET of Innate Immune Markers CD11b and IL-1β Detects Inflammation in Murine Colitis

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Activation of colo‐rectal high‐threshold afferent nerves by Interleukin‐2 is tetrodotoxin‐sensitive and upregulated in a mouse model of chronic visceral hypersensitivity

Abstract: IL-2, an immune mediator from the adaptive arm of the immune response, affects colo-rectal afferent function, indicating these effects are not restricted to innate immune mediators. Colo-rectal afferent sensitivity to IL-2 is increased long after healing from inflammation.

Cited by 14 publications

References 52 publications

Visceral and somatic pain modalities reveal NaV1.7‐independent visceral nociceptive pathways

Visceral and somatic pain modalities reveal NaV1.7‐independent visceral nociceptive pathways

Colonic immune cells in irritable bowel syndrome: A systematic review and meta‐analysis

Immuno-PET of Innate Immune Markers CD11b and IL-1β Detects Inflammation in Murine Colitis

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Visceral and somatic pain modalities reveal Na_V1.7‐independent visceral nociceptive pathways

Visceral and somatic pain modalities reveal Na_V1.7‐independent visceral nociceptive pathways