teasing-out-interplay-between-natural-killer-cells-nociceptor

Teasing Out the Interplay Between Natural Killer Cells and Nociceptor Neurons

Somatosensory neurons have evolved to detect noxious stimuli and activate defensive reflexes. By sharing means of communication, nociceptor neurons also ...

Université de Montréal

Raphiodon echinus (R. echinus) is used in Brazilian folk medicine for the treatment of inflammation, coughs, and infectious diseases. However, no information is available on the potential antioxidant, cytotoxicity and genotoxicity of this plant. In this study, the polyphenolic constituents, antioxidant capacity and potential toxic effects of aqueous and ethanolic extracts of R. echinus on human erythrocytes and leukocytes were investigated for the first time. R. echinus extracts showed the presence of Gallic, chlorogenic, caffeic and ellagic acids, rutin, quercitrin and quercetin. Aqueous and ethanolic extracts of R. echinus exhibited antioxidant activity in DPPH radical scavenging with IC50 = 111.9 μg/mL (EtOH extract) and IC50 = 227.9 μg/mL (aqueous extract). The extracts inhibited Fe(2+) (10 μM) induced thiobarbituric acid reactive substances (TBARS) formation in rat brain and liver homogenates. The extracts (30-480 μg/mL) did not induce genotoxicity, cytotoxicity or osmotic fragility in human blood cells. The findings of this present study therefore suggest that the therapeutic effect of R. echinus may be, in part, related to its antioxidant potential. Nevertheless, further in vitro and in vivo studies are required to ascertain the safety margin of its use in folk medicine. 

Polyphenolic Composition and Evaluation of Antioxidant Activity, Osmotic Fragility and Cytotoxic Effects of Raphiodon echinus (Nees &amp; Mart.) Schauer.

Cell bioprinting technologies aim to fabricate tissuelike constructs by delivering biomaterials layer-by-layer. Bioprinted constructs can reduce the use of animals in drug development and hold promise for addressing the shortage of organs for transplants. Here, we sought to validate the feasibility of bioprinting primary adult sensory neurons using a newly developed laser-assisted cell bioprinting technology, known as Laser-Induced Side Transfer (LIST). We used dorsal root ganglion neurons (DRG; cell bodies of somatosensory neurons) to prepare our bioink. DRG-laden- droplets were printed on fibrin-coated coverslips and their viability, calcium kinetics, neuropeptides release, and neurite outgrowth were measured. The transcriptome of the neurons was sequenced. We found that LIST-printed neurons maintain high viability (Printed: 86%, Control: 87% on average) and their capacity to release neuropeptides (Printed CGRP: 130 pg/mL, Control CGRP: 146 pg/mL). In addition, LIST-printed neurons do not show differences in the expressed genes compared to control neurons. However, in printed neurons, we found compromised neurite outgrowth and lower sensitivity to the ligand of the TRPV1 channel, capsaicin. In conclusion, LIST-printed neurons maintain high viability and marginal functionality losses. Overall, this work paves the way for bioprinting functional 2D neuron assays.

Bioprinting of Adult Dorsal Root Ganglion (DRG) Neurons Using Laser-Induced Side Transfer (LIST).

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1-2% of the population aged 65 and over. Additionally, non-motor symptoms such as pain and gastrointestinal dysregulation are also common in PD. These impairments might stem from a dysregulation within the gut-brain axis that alters immunity and the inflammatory state and subsequently drives neurodegeneration. There is increasing evidence linking gut dysbiosis to the severity of PD's motor symptoms as well as to somatosensory hypersensitivities. Altogether, these interdependent features highlight the urgency of reviewing the links between the onset of PD's non-motor symptoms and gut immunity and whether such interplays drive the progression of PD. This review will shed light on maladaptive neuro-immune crosstalk in the context of gut dysbiosis and will posit that such deleterious interplays lead to PD-induced pain hypersensitivity.

Neuro-Immunity and Gut Dysbiosis Drive Parkinson's Disease-Induced Pain.

Dendritic cells (DCs) excel at cross-presenting antigens, but their effectiveness as cancer vaccine is limited. Here, we describe a vaccination approach using mesenchymal stromal cells (MSCs) engineered to express the immunoproteasome complex (MSC-IPr). Such modification instills efficient antigen cross-presentation abilities associated with enhanced major histocompatibility complex class I and CD80 expression,  production of interleukin-12, and higher chemokine secretion. This cross-presentation capacity of MSC-IPr is highly dependent on their metabolic activity. Compared with DCs, MSC-IPr hold the ability to cross-present a vastly different epitope repertoire, which translates into potent re-activation of T cell immunity against EL4 and A20 lymphomas and B16 melanoma tumors. Moreover, therapeutic vaccination of mice with pre-established tumors efficiently controls cancer growth, an effect further enhanced when combined with antibodies targeting PD-1, CTLA4, LAG3, or 4-1BB under both autologous and allogeneic settings. Therefore, MSC-IPr constitute a promising subset of non-hematopoietic antigen-presenting cells suitable for designing universal cell-based cancer vaccines.

Engineering immunoproteasome-expressing mesenchymal stromal cells: A potent cellular vaccine for lymphoma and melanoma in mice.

The sensory nervous and immune systems work in concert to preserve homeostasis. While this endogenous interplay protects from danger, it may drive chronic pathologies. Currently, genetic engineering of neurons remains the primary approach to interfere selectively with this potentially deleterious interplay. However, such manipulations are not feasible in a clinical setting. Here, this work reports a nanotechnology-enabled concept to silence subsets of unmodified nociceptor neurons that exploits their ability to respond to heat via the transient receptor potential vanilloid type 1 (TRPV1) channel. This strategy uses laser stimulation of antibody-coated gold nanoparticles to heat-activate TRPV1, turning this channel into a cell-specific drug-entry port. This delivery method allows transport of a charged cationic derivative of an N-type calcium channel blocker (CNCB-2) into targeted sensory fibers. CNCB-2 delivery blocks neuronal calcium currents and neuropeptides release, resulting in targeted silencing of nociceptors. Finally, this work demonstrates the ability of the approach to probe neuro-immune crosstalk by targeting cytokine-responsive nociceptors and by successfully preventing nociceptor-induced CD8 T-cells polarization. Overall, this work constitutes the first demonstration of targeted silencing of nociceptor neuron subsets without requiring genetic modification, establishing a strategy for interfering with deleterious neuro-immune interplays.

Article	Year
Polyphenolic Composition and Evaluation of Antioxidant Activity, Osmotic Fragility and Cytotoxic Effects of Raphiodon echinus (Nees & Mart.) Schauer. Molecules (Basel, Switzerland)\| PubMed ID: 26729080	2015
Bioprinting of Adult Dorsal Root Ganglion (DRG) Neurons Using Laser-Induced Side Transfer (LIST). Micromachines\| PubMed ID: 34442487	2021
Neuro-Immunity and Gut Dysbiosis Drive Parkinson's Disease-Induced Pain. Frontiers in immunology\| PubMed ID: 34868000	2021
Engineering immunoproteasome-expressing mesenchymal stromal cells: A potent cellular vaccine for lymphoma and melanoma in mice. Cell reports. Medicine\| PubMed ID: 35028603	2021
Nanophotonics Enable Targeted Photothermal Silencing of Nociceptor Neurons. Small (Weinheim an der Bergstrasse, Germany)\| PubMed ID: 35195345	2022

Katiane Roversi

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