Nociceptor neurons affect cancer immunosurveillance.

Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1-5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)-one such nociceptor-produced neuropeptide-directly increases the exhaustion of cytotoxic CD8+ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8+ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8+ T cells, Ramp1-/- CD8+ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8+ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8+ T cells.

FcεR1-expressing nociceptors trigger allergic airway inflammation.

BACKGROUND: Lung nociceptor neurons amplify immune cell activity and mucus metaplasia in response to an inhaled allergen challenge in sensitized mice. OBJECTIVE: We sought to identify the cellular mechanisms by which these sensory neurons are activated subsequent to allergen exposure. METHODS: We used calcium microscopy and electrophysiologic recording to assess whether vagal neurons directly respond to the model allergen ovalbumin (OVA). Next, we generated the first nociceptor-specific FcεR1γ knockdown (TRPV1Cre::FcεR1γfl/fl) mice to assess whether this targeted invalidation would affect the severity of allergic inflammation in response to allergen challenges. RESULTS: Lung-innervating jugular nodose complex ganglion neurons express the high-affinity IgE receptor FcεR1, the levels of which increase in OVA-sensitized mice. FcεR1γ-expressing vagal nociceptor neurons respond directly to OVA complexed with IgE with depolarization, action potential firing, calcium influx, and neuropeptide release. Activation of vagal neurons by IgE-allergen immune complexes, through the release of substance P from their peripheral terminals, directly amplifies TH2 cell influx and polarization in the airways. Allergic airway inflammation is decreased in TRPV1Cre::FcεR1γfl/fl mice and in FcεR1α-/- mice into which bone marrow has been transplanted. Finally, increased in vivo circulating levels of IgE following allergen sensitization enhances the responsiveness of FcεR1 to immune complexes in both mouse jugular nodose complex ganglion neurons and human induced pluripotent stem cell-derived nociceptors. CONCLUSIONS: Allergen sensitization triggers a feedforward inflammatory loop between IgE-producing plasma cells, FcεR1-expressing vagal sensory neurons, and TH2 cells, which helps to both initiate and amplify allergic airway inflammation. These data highlight a novel target for reducing allergy, namely, FcεR1γ expressed by nociceptors.

Closed Reduction and Immobilization of Pediatric Fifth Metacarpal Neck Fractures.

BACKGROUND: There is no clear consensus for the criteria for closed treatment of metacarpal neck fractures. Our objective was to determine whether closed reduction of pediatric fifth metacarpal neck fractures results in a clinically meaningful improvement in radiographic angulation. METHODS: We performed a retrospective cohort study of pediatric patients with fifth metacarpal neck fractures treated with closed reduction. Radiographs were examined for sagittal fracture angulation measured post-reduction, 2 to 14 days post-reduction, and 21 to 35 days post-reduction. We compared the angulation for open versus closed physes, initial fracture angulation greater than or less than 50°, and immobilization in extension versus intrinsic-plus position. RESULTS: Fifty-four subjects were included with an average age of 14.8 years at the time of injury and a mean initial fracture angulation of 42.7°. The improvement in fracture angulation was 8.3° (90% confidence interval [CI], 5.9-10.7) on post-reduction radiographs, 8.5° (90% CI, 6.1-10.9) at 2 to 14 days post-reduction, and 4.3° (90% CI, 1.4-7.2) at 21 to 35 days post-reduction. Subgroup analysis showed that patients with injury angle greater than or equal to 50° had significantly higher mean reductions than those with injury angle less than 50°. In this group, angulation improved 15.6° (90% CI, 8.5-22.7) post-reduction, 15.1° (90% CI, 10.1-20.1) at 2 to 14 days post-reduction, and 16.5° (90% CI, 10.4-22.6) at 21 to 35 days post-reduction. CONCLUSIONS: Closed reduction of pediatric fifth metacarpal neck fractures with initial fracture angulation less than 50° may not meaningfully improve sagittal alignment. For fractures with initial angulation greater than or equal to 50°, closed reduction resulted in clinically important, statistically significant, and lasting improvements of 16.5°.

The shifting demographics of birth-related brachial plexus injury: The impact of socio-economic status and ethnic groups.

INTRODUCTION: Many of the risk factors for birth-related brachial plexus injury (BRBPI), such as maternal gestational diabetes and macrosomia, are known to vary between demographic groups. Socio-economic differences are known to influence access to healthcare, including elective caesarean section rates and access to consultant obstetricians, which could impact the rates of BRBPI. This study aims to explore whether BRBPI is affected by demographic factors. METHOD: This retrospective study compares cohorts of BRBPI patients referred to the Royal National Orthopaedic Hospital in 2004, 2014 and 2017. N = 67 in 2004, N = 61 in 2014 and N = 71 in 2017. RESULTS: The risk of BRBPI for Black patients was 6 times higher than for White patients, and 2.7 times higher for Asian patients as compared to White patients (p < 0.001). There was an unequal distribution of BRBPI occurring in patients from lower socio-economic groups based on the index of multiple deprivation, with the highest level seen in those from the second lowest quintile. Neither of these risk factors have changed within the three years that they were examined. CONCLUSION: In this sample, the risk of BRBPI varies with ethnic groups; patients from non-White backgrounds are at a higher risk overall and are disproportionately represented in the BRBPI cohort as compared to White groups. Similarly, there seems to be a trend towards greater risk for those from lower socio-economic groups. These changes are consistent each year, suggesting that these inconsistencies are yet to be addressed. Further studies are warranted to explore why these demographic factors are significantly affecting health outcomes.