Study reveals how glial cells respond to damage in neuron dendrites

 Ask your competent? doctor EXACTLY HOW THIS WILL GET YOU RECOVERED!  If it requires further research, is your doctor capable of getting it initiated? 

Study reveals how glial cells respond to damage in neuron dendrites

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Rockefeller UniversityJan 29 2025

Neurons may get all the glory, but they would be nothing without glial cells. While brain cells do the heavy lifting in the nervous system, it's the glia that provide nutrients, clean up waste, and protect neurons from harm.

Now, scientists have discovered a new mechanism by which these crucial supporting players detect and respond to neuron damage. Published in Nature Communications, the study describes how two key proteins allow glial cells to actively monitor the hair-like cilia that extend out of nematode dendrites, so that the glial cells can respond to injuries and prevent damage. The findings may have implications for treating diseases caused by defective cilia, such as polycystic kidney disease.

Fleshing out the pathway by which glia interact with dendrites was our major goal. An important next question is whether one could manipulate these cells to address diseases related to cilia."

Shai Shaham, head of the Laboratory of Developmental Genetics, Rockefeller University

Uncharted territory

Neurons rely on axons and dendrites for communication; axons send messages out, while dendrites receive those incoming, some with the help of cilia extending from their tips. Cilia detect odors, light, and other stimuli.

Scientists have studied how glial cells keep axons in shape. But comparatively few studies have investigated how glia protect and maintain dendrites and their delicate cilia. Knowing that dendrite structure changes correlate with learning and memory, and that dysfunctional cilia are at the heart of a family of disorders known as ciliopathies, Shaham and colleagues set out to fill that crucial knowledge gap .

"We knew essentially nothing about the interactions between glial cells and dendrites, but they matter just as much as axons," Shaham says. "You need something to receive signals, too."

The team chose to study glia, dendrites, and cilia in the nematode C. elegans, a model organism cherished by basic researchers for its straightforward genetics and well-studied biology. An additional advantage here was that nematodes have cilia only on the ends of their dendrites, simplifying the work of homing in on what happens to dendritic cilia when glia clock out. "C. elegans is a powerful model, because we can use it to explore everything from molecules to behavior," says Katherine Varandas, a postdoctoral fellow in Shaham's lab and lead author of the study. "Through studying nematodes we can decipher very specific dendrite and glia interactions."

Moving up the tree of life

For the study, the team used CRISPR to engineer nematodes with disrupted cilia or altered glial responses, and then tracked glia in-action using fluorescence microscopy. Then, to figure out how glia respond to normal and cilia-stunted nematodes, they employed RNA sequencing to monitor gene expression changes and electron microscopy to observe structural changes.

They found that glial cells respond to damaged cilia by accumulating excess extracellular matrix proteins and altering gene expression. Specifically, they discovered a new signaling pathway involving DGS-1, a neuronal protein, and FIG-1, a glial protein. These two proteins appear crucial to monitoring cilia integrity-mutations in either trigger glial responses even without cilia damage.

The findings broaden our understanding of glial functions, with potential implications extending far beyond nematodes. Indeed, the structural and functional similarities of sensory organs across species suggest that similar mechanisms for keeping cilia safe may exist in mammals, where glial cells have been shown to interact with similar dendritic structures. The present study could therefore lay the groundwork for exploring glia-dendrite interactions across species, with potential implications for humans suffering from ciliopathies.

"We hope to move these studies into mammals next," Varandas says. "Sensory organs, which include cilia-decorated dendrites surrounded by glia, are highly conserved across evolution and share striking similarities to one another, providing a fascinating direction for future research."

Source:

Rockefeller University

Journal reference:

Varandas, K. C., et al. (2025). Glia detect and transiently protect against dendrite substructure disruption in C. elegans. Nature Communications. doi.org/10.1038/s41467-024-55674-0.

Interleukin-2 Mediated Expansion of T-Regulatory Cells as an Ischemic Stroke Therapy

 You do expect your competent? doctor and hospital  to get human testing going? OF COURSE NOT! They are way too fucking incompetent to even know about this research, much less do something about it!

Interleukin-2 Mediated Expansion of T-Regulatory Cells as an Ischemic Stroke Therapy

David A. Hurst and

Farida Sohrabji

Originally published24 May 2024https://doi.org/10.1161/STROKEAHA.124.047357Stroke. 2024;55:e159–e160

The inflammatory cascade(Call it what is really is: the neuronal cascade of death! Which your doctors are doing nothing about, leaving millions to billions of neurons to die in the first week!) that ensues following an ischemic stroke has been increasingly recognized(Known since the Rockefeller University report in Jan. 2009! So you're that fucking out-of-date?) as a driving force in the long-term disability associated with the disease. This synopsis will highlight recent preclinical studies that aimed to promote a robust Treg (T-regulatory cell) response via interleukin-2 (IL-2) signaling following an experimental stroke.

To elucidate the mechanism by which an expansion in Tregs following experimental ischemic injury promotes white matter integrity and functional recovery, Yuan et al (Regulatory T cell expansion promotes white matter repair after stroke. Neurobiol Dis. 2023;179:106063. doi: 10.1016/j.nbd.2023.106063) demonstrated that Treg augmentation via direct intravenous transfer of Tregs isolated from donor mice 2 hours after transient middle cerebral artery occlusion (tMCAO) resulted in improved white matter recovery when compared with splenocyte-treated mice poststroke. To determine whether promoting an endogenous Treg expansion poststroke would similarly result in a neuroprotective(Don't ever use the milquetoast word, neuroprotection. It doesn't signal urgency at all! Whereas your doctor telling you they failed to stop the neuronal cascade of death in the first week might engender a few medical malpractice suits. I suggest a payment of $1000 a dead neuron; in my case that would come to 5.571 billion dead neurons; Only 55 trillion dollars!) phenotype, wild-type mice were treated with either a consecutive intraperitoneal administration of IL-2/IL-2 antibody complexes (IL-2/IL-2Ab) or equal concentrations of isotype-matched antibody (IgG) at 6 hours, 1 day, 2 days, 3 days, 10 days, 20 days, and 30 days after stroke. At 14 days after stroke, IL-2/IL-2Ab mice displayed a significant increase in the CD25⁺CD4⁺Foxp3⁺ Treg cell population in the blood, spleen, and brain parenchyma when compared with IgG-treated controls. Importantly, IL-2/IL-2Ab treatment mitigated sensorimotor dysfunction at 35 days, but not at 7 days after stroke. To evaluate white matter integrity, longitudinal in vivo diffusion tensor imaging scans 14 and 28 days after tMCAO coupled with ex vivo diffusion tensor imaging scanning of brains 35 days after stroke were used to construct fractional anisotropy maps. Fractional anisotropy mapping showed that IL-2/IL-2Ab–treated mice exhibited improved white matter integrity at 28 and 35 days after stroke, indicating that Treg expansion promotes white matter integrity in the late phase of stroke. Delayed IL-2/IL-2Ab treatment remained protective even when administered as late as 5 days after stroke, as Luxol fast blue staining of coronal brain slices of treated mice showed increased myelin in the external capsule and striatum 21 days after tMCAO in IL-2/IL-2Ab–treated mice compared with IgG-treated mice.

To determine a precise signaling mechanism through which Tregs promote long-term tissue repair following ischemic stroke, Shi et al (Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke. Immunity. 2021;54:1527–1542.e8. doi: 10.1016/j.immuni.2021.04.022) utilized single-cell RNA sequencing and flow cytometry to verify that Tregs are among the immune cell populations that infiltrate the brain poststroke at 3, 5, 7, 14, and 35 days after stroke. To confirm their role in improving white matter integrity after stroke, Tregs were selectively depleted via diphtheria toxin (DT) injections in Foxp3^DTR (DTR) transgenic mice that express the DT receptor under the control of the Foxp3 promoter. Treg depletion resulted in diminished functional recovery and drastically aggravated white matter lesions following an ischemic stroke. Comparative transcriptomic analysis of sorted CD4⁺CD25⁺Foxp3(GFP)⁺ Treg cells from the ischemic brain and blood of stroke and sham DTR mice identified differentially expressed genes between brain-infiltrating Treg cells and peripheral Treg cells; several genes upregulated in brain-infiltrating Treg cells encoded trophic factors known to stimulate oligodendrocyte precursor cell differentiation, such as Igf1, IL-1a, and Osm. Additionally, brain-infiltrating Treg cells displayed higher levels of transcripts encoding cytokines such as Spp1, Il1b, Il1a, and Il10, suggesting that Treg cell-mediated white matter repair may rely on immunomodulatory signals and cell-cell interactions. Treg-derived osteopontin was identified as a potential signaling molecule driving microglial-mediated white matter repair, as protein-protein interaction enrichment analysis via STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) identified interactions between Spp1, which encodes osteopontin, and Itgb1, Itga5, and Itgav, which encode the integrin subunits of the osteopontin receptor on microglia. To confirm the role of osteopontin signaling in vivo, Treg cells derived from wild-type or Spp1^−/− mice into DTR+DT mice 6 hours after tMCAO, and myelination was assessed via Luxol fast blue staining. Importantly, Spp1^−/− Treg cell-treated mice displayed a reduction in myelination when compared with wild-type Treg cell-treated mice. Lastly, this study showed that IL-2/IL-2Ab treatment boosted the number of osteopontin+ Treg cells in the ischemic brain 3 days after tMCAO, improved sensorimotor function, spatial learning, and mitigated white matter injury (fractional anisotropy mapping and dual staining for myelin basic protein).

Observing the capacity of IL-2 to drive Treg recruitment and infiltration into the brain following stroke resulting in improved functional recovery and white matter repair, Yshii et al (Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation. Nat Immunol. 2022;23:878–891. doi: 10.1038/s41590-022-01208-z) aimed to develop and validate a central nervous system–specific therapeutic strategy. The adeno-associated virus–based therapeutic delivery system detailed in this study utilized the GFAP (glial fibrillary acidic protein) promoter to drive IL-2 expression in astrocytes specifically while simultaneously avoiding expression in both the peripheral immune systems and astrocytes. The ability of the delivery system to drive astrocyte-specific expression of IL-2 and increase recruit of Tregs to the central nervous system was validated using ELISA, flow cytometry, immunofluorescent staining, and single-cell RNA-seq. The efficacy of the gene delivery was evaluated in various models of central nervous system injury, such as the controlled cortical impact model for traumatic brain injury, a distal middle cerebral artery occlusion model, the photothrombotic model stroke, and the experimental autoimmune encephalomyelitis model of multiple sclerosis. Cognitive recovery was then assessed 15 days after injury using the Morris water maze test and the novel object recognition test. Comparative assessments of tissue injury and lesion size were conducted using immunofluorescence staining of the cortical tissue and MRI 14 days after injury. Importantly, PHP.GFAP-IL-2 treatment before injury mitigated neuroinflammation and improved functional recovery in all models of central nervous system injury, including traumatic brain injury, stroke, and multiple sclerosis, and did not impact the peripheral immune system.

While preclinical studies have shown promising results in the use of IL-2 to amplify Tregs to mitigate white matter injury following ischemic stroke, the application of this method in clinical settings remains sparse. One major hurdle in applying IL-2–mediated Treg expansion in clinical trials is to do so without inadvertently activating other immune cells or causing broader side effects that come with IL-2 treatments.