Research News

“Compelling epidemiological evidence reveals a strong association between being overweight or obese and the risk of developing autoimmune diseases (1). From an immunological standpoint, the cellular and molecular mechanisms linked to this association include the overstimulation of T lymphocytes by nutrient- and energy-sensing pathways. The immunometabolic state of an individual is central to the modulation of immunological self-tolerance that suppresses self-reactivity to avoid autoimmunity. Adipose tissue is an immunologically active organ that influences systemic immune responses through the production of adipocytokines, and, in turn, immune cells affect adipocyte homeostasis and metabolism through the production of pro- and anti-inflammatory cytokines (2). This implies that metabolic overload from obesity can affect immunometabolism, which can alter susceptibility to autoimmune diseases….”

Matarese G. The link between obesity and autoimmunity. Science. 2023 Mar 31;379(6639):1298-1300. doi: 10.1126/science.ade0113. Epub 2023 Mar 30. PMID: 36996218.

https://pubmed.ncbi.nlm.nih.gov/36996218/

Abstract: “Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system underpinned by partially understood genetic risk factors and environmental triggers and their undefined interactions^1,2. Here we investigated the peripheral immune signatures of 61 monozygotic twin pairs discordant for MS to dissect the influence of genetic predisposition and environmental factors. Using complementary multimodal high-throughput and high-dimensional single-cell technologies in conjunction with data-driven computational tools, we identified an inflammatory shift in a monocyte cluster of twins with MS, coupled with the emergence of a population of IL-2 hyper-responsive transitional naive helper T cells as MS-related immune alterations. By integrating data on the immune profiles of healthy monozygotic and dizygotic twin pairs, we estimated the variance in CD25 expression by helper T cells displaying a naive phenotype to be largely driven by genetic and shared early environmental influences. Nonetheless, the expanding helper T cells of twins with MS, which were also elevated in non-twin patients with MS, emerged independent of the individual genetic makeup. These cells expressed central nervous system-homing receptors, exhibited a dysregulated CD25-IL-2 axis, and their proliferative capacity positively correlated with MS severity. Together, our matched-pair analysis of the extended twin approach allowed us to discern genetically and environmentally determined features of an MS-associated immune signature.”

Ingelfinger F, Gerdes LA, Kavaka V, Krishnarajah S, Friebel E, Galli E, Zwicky P, Furrer R, Peukert C, Dutertre CA, Eglseer KM, Ginhoux F, Flierl-Hecht A, Kümpfel T, De Feo D, Schreiner B, Mundt S, Kerschensteiner M, Hohlfeld R, Beltrán E, Becher B. Twin study reveals non-heritable immune perturbations in multiple sclerosis. Nature. 2022 Mar;603(7899):152-158. doi: 10.1038/s41586-022-04419-4. Epub 2022 Feb 16. PMID: 35173329; PMCID: PMC8891021.

https://pubmed.ncbi.nlm.nih.gov/35173329/

Abstract: “Growing evidences have suggested the association between coronavirus infection and neurodegenerative diseases. However, the molecular mechanism behind the association is complex and remains to be clarified. This study integrated human genes involved in infections of three coronaviruses including SARS-CoV-2, SARS-CoV and MERS-CoV from multi-omics data, and investigated the shared genes and molecular functions between coronavirus infection and two neurodegenerative diseases, namely Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). Seven genes including HSP90AA1, ALDH2, CAV1, COMT, MTOR, IGF2R and HSPA1A, and several inflammation and stress response-related molecular functions such as MAPK signaling pathway, NF-kappa B signaling pathway, responses to oxidative or chemical stress were common to both coronavirus infection and neurodegenerative diseases. These genes were further found to interact with more than 20 other viruses. Finally, drugs targeting these genes were identified. The study would not only help clarify the molecular mechanism behind the association between coronavirus infection and neurodegenerative diseases, but also provide novel targets for the development of broad-spectrum drugs against both coronaviruses and neurodegenerative diseases.”

Ding L, Ding L, Duan X, Peng Y. Shared molecular signatures between coronavirus infection and neurodegenerative diseases provide targets for broad-spectrum drug development. Sci Rep. 2023 Apr 4;13(1):5457. doi: 10.1038/s41598-023-29778-4. PMID: 37015947; PMCID: PMC10071237.

https://pubmed.ncbi.nlm.nih.gov/37015947/

Abstract: Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer’s disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy.

Koutsodendris, N., Blumenfeld, J., Agrawal, A. et al. Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat Aging 3, 275–296 (2023). https://doi.org/10.1038/s43587-023-00368-3.

https://www.nature.com/articles/s43587-023-00368-3

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/