Research News

Nerves in cancer

Abstract: “The contribution of nerves to the pathogenesis of malignancies has emerged as an important component of the tumour microenvironment. Recent studies have shown that peripheral nerves (sympathetic, parasympathetic and sensory) interact with tumour and stromal cells to promote the initiation and progression of a variety of solid and haematological malignancies. Furthermore, new evidence suggests that cancers may reactivate nerve-dependent developmental and regenerative processes to promote their growth and survival. Here we review emerging concepts and discuss the therapeutic implications of manipulating nerves and neural signalling for the prevention and treatment of cancer.”

Zahalka AH, Frenette PS. Nerves in cancer. Nat Rev Cancer. 2020 Mar;20(3):143-157. doi: 10.1038/s41568-019-0237-2. Epub 2020 Jan 23. PMID: 31974491; PMCID: PMC7709871.

https://pubmed.ncbi.nlm.nih.gov/31974491/

and

Nociceptor neurons affect cancer immunosurveillance

Abstract: “Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems^1-5. 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.”

Balood M, Ahmadi M, Eichwald T, Ahmadi A, Majdoubi A, Roversi K, Roversi K, Lucido CT, Restaino AC, Huang S, Ji L, Huang KC, Semerena E, Thomas SC, Trevino AE, Merrison H, Parrin A, Doyle B, Vermeer DW, Spanos WC, Williamson CS, Seehus CR,Foster SL, Dai H, Shu CJ, Rangachari M, Thibodeau J, V Del Rincon S, Drapkin R, Rafei M, Ghasemlou N, Vermeer PD, Woolf CJ, Talbot S. Nociceptor neurons affect cancer immunosurveillance. Nature. 2022 Nov;611(7935):405-412. doi: 10.1038/s41586-022-05374-w. Epub 2022 Nov 2. PMID: 36323780; PMCID: PMC9646485.

https://pubmed.ncbi.nlm.nih.gov/36323780/

Abstract: “Mitochondrial dysfunction is a neurobiological phenomenon implicated in the pathophysiology of schizophrenia and bipolar disorder that can synergistically affect synaptic neurotransmission. We hypothesized that schizophrenia and bipolar disorder share molecular alterations at the mitochondrial and synaptic levels. Mitochondria DNA (mtDNA) copy number (CN), mtDNA common deletion (CD), mtDNA total deletion, complex I activity, synapse number, and synaptic mitochondria number were studied in the postmortem human dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus (STG), primary visual cortex (V1), and nucleus accumbens (NAc) of controls (CON), and subjects with schizophrenia (SZ), and bipolar disorder (BD). The results showed (i) the mtDNA CN is significantly higher in DLPFC of both SZ and BD, decreased in the STG of BD, and unaltered in V1 and NAc of both SZ and BD; (ii) the mtDNA CD is significantly higher in DLPFC of BD while unaltered in STG, V1, and NAc of both SZ and BD; (iii) The total deletion burden is significantly higher in DLPFC in both SZ and BD while unaltered in STG, V1, and NAc of SZ and BD; (iv) Complex I activity is significantly lower in DLPFC of both SZ and BD, which is driven by the presence of medications, with no alteration in STG, V1, and NAc. In addition, complex I protein concentration, by ELISA, was decreased across three cortical regions of SZ and BD subjects; (v) The number of synapses is decreased in DLPFC of both SZ and BD, while the synaptic mitochondria number was significantly lower in female SZ and female BD compared to female controls. Overall, these findings will pave the way to understand better the pathophysiology of schizophrenia and bipolar disorder for therapeutic interventions.”

Das SC, Hjelm BE, Rollins BL, Sequeira A, Morgan L, Omidsalar AA, Schatzberg AF, Barchas JD, Lee FS, Myers RM, Watson SJ, Akil H, Bunney WE, Vawter MP. Mitochondria DNA copy number, mitochondria DNA total somatic deletions, Complex I activity, synapse number, and synaptic mitochondria number are altered in schizophrenia and bipolar disorder. Transl Psychiatry. 2022 Aug 30;12(1):353. doi: 10.1038/s41398-022-02127-1. PMID: 36042222; PMCID: PMC9427957.

https://pubmed.ncbi.nlm.nih.gov/36042222/

also see:

https://pubmed.ncbi.nlm.nih.gov/29594135/

Summary: “Although mitochondria are often referred to as the powerhouses of the cell, these organelles can also act as signalling hubs that control physiological processes. One such signalling pathway controls inflammation. Writing in Nature, Zecchini et al. and Hooftman et al. report that fumarate (a molecule produced as an intermediate of metabolic processes in mitochondria) triggers the activation of specific inflammation-related pathways. Their findings have implications for cancer and inflammatory diseases.”

 Nature 615, 401-402 (2023).

https://www.nature.com/articles/d41586-023-00596-y

Severe COVID-19 has been associated with cognitive impairment and changes in the frontal cortex. In a study published in Nature Aging, Mavrikaki, Lee et al. performed RNA sequencing on frontal cortex samples from 21 individuals with severe COVID-19, 22 age- and sex-matched uninfected controls, and 9 uninfected people who had received intensive care or ventilator treatment. The authors found almost 7,000 differentially expressed genes (DEGs) in the patient samples compared to controls. Upregulated DEGs were enriched for genes involved in immune-related pathways, and downregulated DEGs were enriched for genes involved in synaptic activity, cognition and memory — a profile of transcriptional changes that resembles those previously observed in aging brains. Direct comparisons between frontal cortex samples from young and old individuals confirmed this overlap. Application of tumor necrosis factor, interferon-β or interferon-γ to cultured human primary neurons induced transcriptional changes similar to those seen in patients with severe COVID-19. As no SARS-CoV-2 RNA was detected in the patient samples, these data suggest that the transcriptomic changes in frontal cortex of patients with severe COVID-19 were due to neuroinflammatory processes rather than a direct effect of the virus.

Welberg, L. COVID-19 and brain aging. Nat Neurosci 26, 1 (2023). https://doi.org/10.1038/s41593-022-01249-5

Abstract: There appear to be huge variations and aberrations in the reported data in COVID-19 two years now into the pandemic. Conflicting data exist at almost every level and also in the reported epidemiological statistics across different regions. It is becoming clear that COVID-19 is a polymorphic inflammatory spectrum of diseases and there is a wide range of inflammation-related pathology and symptoms in those infected with the virus. The host’s inflammatory response to COVID-19 appears to be determined by genetics, age, immune status, health status and stage of disease. The interplay of these factors may decide the magnitude, duration, types of pathology, symptoms, and prognosis in the spectrum of COVID-19 disorders, and whether neuropsychiatric disorders continue to be significant. Early and successful management of inflammation reduces morbidity and mortality in all stages of COVID-19.

Tang SW, Helmeste DM, Leonard BE. COVID-19 AS A POLYMORPHIC INFLAMMATORY SPECTRUM OF DISEASES: A REVIEW WITH FOCUS ON THE BRAIN. Acta Neuropsychiatr. 2023 Mar 2:1-70. doi: 10.1017/neu.2023.17. Epub ahead of print. PMID: 36861428.

https://pubmed.ncbi.nlm.nih.gov/36861428/

Certain selective serotonin reuptake inhibitors (SSRIs) have anti-inflammatory effects in preclinical models, and recent clinical studies suggest that fluvoxamine can prevent deterioration in patients with COVID-19, possibly through activating sigma 1 receptors (S1Rs). Here we examined potential mechanisms contributing to these effects of fluvoxamine and other SSRIs using a well-characterized model of pro-inflammatory stress in rat hippocampal slices. When hippocampal slices are exposed acutely to lipopolysaccharide (LPS), a strong pro-inflammatory stimulus, basal synaptic transmission in the CA1 region remains intact, but induction of long-term potentiation (LTP), a form of synaptic plasticity thought to contribute to learning and memory, is completely disrupted. Administration of low micromolar concentrations of fluvoxamine and fluoxetine prior to and during LPS administration overcame this LTP inhibition. Effects of fluvoxamine required both activation of S1Rs and local synthesis of 5-alpha reduced neurosteroids. In contrast, the effects of fluoxetine did not involve S1Rs but required neurosteroid production. The ability of fluvoxamine to modulate LTP and neurosteroid production was mimicked by a selective S1R agonist. Additionally, fluvoxamine and fluoxetine prevented learning impairments induced by LPS in vivo. Sertraline differed from the other SSRIs in blocking LTP in control slices likely via S1R inverse agonism. These results provide strong support for the hypothesis that S1Rs and neurosteroids play key roles in the anti-inflammatory effects of certain SSRIs and that these SSRIs could be beneficial in disorders involving inflammatory stress including psychiatric and neurodegenerative illnesses.

Izumi Y, Reiersen AM, Lenze EJ, Mennerick SJ, Zorumski CF. SSRIs differentially modulate the effects of pro-inflammatory stimulation on hippocampal plasticity and memory via sigma 1 receptors and neurosteroids. Transl Psychiatry. 2023 Feb 3;13(1):39. doi: 10.1038/s41398-023-02343-3. PMID: 36737431; PMCID: PMC9897619.

https://pubmed.ncbi.nlm.nih.gov/36737431/

Abstract: “Epidemiological studies have provided compelling evidence that multiple sclerosis (MS) is a rare complication of infection with the Epstein–Barr virus (EBV), a herpesvirus that infects more than 90% of the global population. This link was long suspected because the risk of MS increases markedly after infectious mononucleosis (symptomatic primary EBV infection) and with high titres of antibodies to specific EBV antigens. However, it was not until 2022 that a longitudinal study demonstrated that MS risk is minimal in individuals who are not infected with EBV and that it increases over 30-fold following EBV infection. Over the past few years, a number of studies have provided clues on the underlying mechanisms, which might help us to develop more targeted treatments for MS. In this Review, we discuss the evidence linking EBV to the development of MS and the mechanisms by which the virus is thought to cause the disease. Furthermore, we discuss implications for the treatment and prevention of MS, including the use of antivirals and vaccines.”

Bjornevik, K., Münz, C., Cohen, J.I. et al. Epstein–Barr virus as a leading cause of multiple sclerosis: mechanisms and implications. Nature Reviews Neurol (2023). https://doi.org/10.1038/s41582-023-00775-5.

https://www.nature.com/articles/s41582-023-00775-5

Abstract: “Certain selective serotonin reuptake inhibitors (SSRIs) have anti-inflammatory effects in preclinical models, and recent clinical studies suggest that fluvoxamine can prevent deterioration in patients with COVID-19, possibly through activating sigma 1 receptors (S1Rs). Here we examined potential mechanisms contributing to these effects of fluvoxamine and other SSRIs using a well-characterized model of pro-inflammatory stress in rat hippocampal slices. When hippocampal slices are exposed acutely to Abstract:lipopolysaccharide (LPS), a strong pro-inflammatory stimulus, basal synaptic transmission in the CA1 region remains intact, but induction of long-term potentiation (LTP), a form of synaptic plasticity thought to contribute to learning and memory, is completely disrupted. Administration of low micromolar concentrations of fluvoxamine and fluoxetine prior to and during LPS administration overcame this LTP inhibition. Effects of fluvoxamine required both activation of S1Rs and local synthesis of 5-alpha reduced neurosteroids. In contrast, the effects of fluoxetine did not involve S1Rs but required neurosteroid production. The ability of fluvoxamine to modulate LTP and neurosteroid production was mimicked by a selective S1R agonist. Additionally, fluvoxamine and fluoxetine prevented learning impairments induced by LPS in vivo. Sertraline differed from the other SSRIs in blocking LTP in control slices likely via S1R inverse agonism. These results provide strong support for the hypothesis that S1Rs and neurosteroids play key roles in the anti-inflammatory effects of certain SSRIs and that these SSRIs could be beneficial in disorders involving inflammatory stress including psychiatric and neurodegenerative illnesses.“

Izumi Y, Reiersen AM, Lenze EJ, Mennerick SJ, Zorumski CF. SSRIs differentially modulate the effects of pro-inflammatory stimulation on hippocampal plasticity and memory via sigma 1 receptors and neurosteroids. Transl Psychiatry. 2023 Feb 3;13(1):39. doi: 10.1038/s41398-023-02343-3. PMID: 36737431; PMCID: PMC9897619.

https://pubmed.ncbi.nlm.nih.gov/36737431/

Abstract: “Although the new generation of vaccines and anti-COVID-19 treatment regimens facilitated the management of acute COVID-19 infections, concerns about post-COVID-19 syndrome or Long Covid are rising. This issue can increase the incidence and morbidity of diseases such as diabetes, and cardiovascular, and lung infections, especially among patients suffering from neurodegenerative disease, cardiac arrhythmias, and ischemia. There are numerous risk factors that cause COVID-19 patients to experience post-COVID-19 syndrome. Three potential causes attributed to this disorder include immune dysregulation, viral persistence, and autoimmunity. Interferons (IFNs) are crucial in all aspects of post-COVID-19 syndrome etiology. In this review, we discuss the critical and double-edged role of IFNs in post-COVID-19 syndrome and how innovative biomedical approaches that target IFNs can reduce the occurrence of Long Covid infection.”

Karbalaeimahdi M, Farajnia S, Bargahi N, Ghadiri-Moghaddam F, Rasouli Jazi HR, Bakhtiari N, Ghasemali S, Zarghami N. The Role of Interferons in Long Covid Infection. J Interferon Cytokine Res. 2023 Feb;43(2):65-76. doi: 10.1089/jir.2022.0193. PMID: 36795973.

https://pubmed.ncbi.nlm.nih.gov/36795973/

Multiple sclerosis (MS) is a neuro-inflammatory and degenerative disease with substantial heterogeneity in presentation, clinical course, and immunopathology. In addition to genetic background, several environmental risk factors are critical mediators of the onset and course of MS (1). Disease heterogeneity dictates the therapeutic efficacy of treatment with disease- modifying therapies. Since environmental factors are known to affect the disease trajectory, it is urgent to identify their specific impact on disease heterogeneity as well as their mechanisms of action. Therefore, this Research Topic was focused on the effects of environmental factors on MS and the identification of their mechanisms of action.

Among others, sex, vitamin D status, and body mass index (BMI) determine the environment in which genetic determinants act, which has been addressed in several contributions to this Research Topic. Genome-wide association studies in MS identified a large number of risk-associated single nucleotide polymorphisms (SNP) (2). Additionally, combinations of SNP genotypes can be associated with specific biological traits, and hereby be exploited to investigate associations of these biological traits with specific disease endpoints in case-control designs (3). Vandebergh et al. showed in their Mendelian randomization study, that SNPs associated with higher BMI and increased IL-6 signaling are enriched in MS. The effect of BMI on MS was partly mediated by IL-6 signaling, elaborating further on the well know interaction between these biological factors (4).

Leffler et al. reviewed the importance of the interaction between sex and MS disease mechanisms. They make a case for taking into account sex when investigating the effect of other environmental risk factors on MS, including female-specific characteristics of anti-viral responses. In particular, the effect of sex hormones on immune function and pathology of MS is highlighted. Along this line, Koetzier et al. report on the synergism between corticosteroids, vitamin D, and sex steroids in the control of potentially pathogenic CD4⁺ T cell activation in MS. This group earlier showed Th17.1 cells (IL17^lowIFNγ^highGMCSF^high) to be a major contributor to the CNS-homing T cell pool in MS, which show resistance towards suppression by corticosteroids (5). In their current contribution, the authors show that this resistance can be partly overcome in vitro by adding 1,25-dihydroxy vitamin D and sex steroids.

Infection with Epstein Barr Virus (EBV) is one of the most consolidated risk factors for developing MS (6), and may even be a prerequisite (7). Márquez et al. report mechanistic studies on the influence of type I interferons on the role of the murine homolog of EBV (murine gammaherpesvirus 68, γHV-68) in the experimental autoimmune encephalomyelitis (EAE) model of neuroinflammation. They extend on their earlier work in which they showed that latent γHV-68 infection results in amplified CNS-infiltration of CD4⁺ and CD8⁺ T cells in EAE (8). The authors now report that in knockout mice for interferon alpha receptor (IFNAR^-/-), EAE is more severe with a preserved profound infiltration of CD8⁺ T cells in the case of latent γHV-68 infection likewise the wild-type mice. Contrastingly, the adoptive transfer of γHV-68 infected IFNAR^-/-mice to wild-type recipients did not result in an amplification of CD8⁺ T cell infiltration. These results suggest that type I interferons could be important for the in situ interaction of B and CD8⁺ T cells in neuroinflammation, as has been postulated in MS (9). Herewith, the current study of Márquez et al. helps to understand how the interaction between EBV and type I interferons could contribute to the formation of CD4⁺and CD8⁺ T cell populations that characterize the pathology of MS (10). In addition, Gottlieb et al. report that T cell responsiveness to brain antigens is another factor relevant in this perspective. They studied the proliferative response of peripheral blood mononuclear cells to denatured, organic-extracted brain homogenate with Carboxyfluorescein succinimidyl ester (CFSE)-labelling, and compared the transcriptome and T cell receptor (TCR) clonality of FACS-sorted proliferated vs. non-proliferated T cells. Brain antigen-responsive cells were enriched for mRNA encoding chemokine receptors and cytokines relevant for neuroinflammation, yet TCR sequences did not overlap with EBV, influenza virus, or varicella zoster virus-responsive cells. These findings support the case that EBV-infection may affect a detrimental cellular response to brain antigens (11), which should be the subject of further study.

Smolders J, Steelman AJ, Inoue M. Editorial: Environmental factors influencing the immune functions during multiple sclerosis. Front Immunol. 2023 Jan 20;14:1141014. doi: 10.3389/fimmu.2023.1141014. PMID: 36793707; PMCID: PMC9923231.

https://pubmed.ncbi.nlm.nih.gov/36793707/