Biology subjects

Chiu, I.

Publications and source records attributed to Chiu, I..

6 recordsLinked to original sources

bioRxiv2023

A DRG genetic toolkit reveals molecular, morphological, and functional diversity of somatosensory neuron subtypes

Mechanical and thermal stimuli acting on the skin are detected by morphologically and physiologically distinct sensory neurons of the dorsal root ganglia (DRG). Achieving a holistic view of how this diverse neuronal population relays sensory information from the skin to the central nervous system (CNS) has been challenging with existing tools. Here, we used transcriptomic datasets of the mouse DRG to guide development and curation of a genetic toolkit to interrogate transcriptionally defined DRG neuron subtypes. Morphological analysis revealed unique cutaneous axon arborization areas and branching patterns of each subtype. Physiological analysis showed that subtypes exhibit distinct thresholds and ranges of responses to mechanical and/or thermal stimuli. The somatosensory neuron toolbox thus enables comprehensive phenotyping of most principal sensory neuron subtypes. Moreover, our findings support a population coding scheme in which the activation thresholds of morphologically and physiologically distinct cutaneous DRG neuron subtypes tile multiple dimensions of stimulus space.

neuroscience↗

bioRxiv2022

Neuronal-immune Axis Alters Pain and Sensory Afferent Damage During Dental Pulp Injury

Dental pulp tissue is densely innervated by afferent fibers of the trigeminal ganglion. When bacteria cause dental decay near the pulpal tissue, a strong neuronal and immune response occur, creating pulpitis, which is associated with severe pain and pulp tissue damage. Neuro-immune interactions have the potential to modulate both the pain and pathological outcome of pulpitis. We first investigated the role of the neuropeptide calcitonin-gene related peptide (CGRP), released from peptidergic sensory afferents, in dental pain and immune responses by using calca knock out (calca-/-) and wild type (calca+/+) mice, in a model of pulpitis by creating a mechanical exposure of the dental pulp horn. While CGRP did not contribute to facial mechanical hypersensitivity, at an early time point, it did contribute to spontaneous pain-like behavior. We also found that CGRP contributed to recruitment of neutrophils and monocytes, while not clearly affecting the progression of pulpal pathology histologically. When we depleted neutrophils and monocytes, we found that there was more sensory afferent loss, tissue damage and deeper spread of bacteria into the pulp tissue, while there was a reduction in facial mechanical hypersensitivity compared to control animals at a later time point. Overall, we showed that there is a crosstalk between peptidergic neurons and neutrophils in the pulp, modulating the pain and inflammatory outcomes of the disease.

neuroscience↗

bioRxiv2022

Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration

Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. The frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME deficiency prolonged survival, ameliorated motor dysfunction, and rescued motor neuron loss in the SOD1G93A mouse model of ALS. GSDME knockdown also protected against neurite loss in ALS patient iPSC-derived motor neurons. Thus, we identify GSDME as an executioner of neuronal mitochondrial dysfunction that contributes to neurodegeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/513927v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@113c13dorg.highwire.dtl.DTLVardef@1f3c5caorg.highwire.dtl.DTLVardef@13e75adorg.highwire.dtl.DTLVardef@19fdc93_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIGSDME is expressed by neurons and activated by mitochondrial neurotoxins C_LIO_LIActivated GSDME drives axonal mitochondrial damage and neurite loss prior to cell death C_LIO_LIALS/FTD associated TDP-43 and PR-50 induces GSDME-driven neurite loss in mouse and human iPSC-derived neurons. C_LIO_LISOD1G93A mice show ameliorated disease progression and motor neuron loss in absence of GSDME C_LI

neuroscience↗

bioRxiv2022

Reprogramming brain immunosurveillance with engineered cytokines

Immune surveillance of the brain is regulated by resident non-neuronal cells and the blood-brain barrier.1 Dys-regulation of immunosurveillance is a hallmark feature of several diseases2-5 including brain tumors6 that interact with and rely heavily on immune cells,7 suggesting that disrupting the neuroimmunology of tumors could slow their progression. Yet few tools are available to control brain immunology in vivo with local precision, and fewer yet are used for therapeutic intervention. 2 Here, we propose engineered cytokines as a neuroimmune-modulation platform. We demonstrate that the residence time of cytokines in the brain can be tuned by binding them to the extracellular matrix or synthetic scaffolds. We then show that the aluminum hydroxide adjuvant (alum) is retained in the brain >2 weeks. Tethering of inflammatory cytokines such as interleukins (IL) 2 and 12 to alum yields extended neuroinflammation and brain immunosurveillance after intracranial administration, while avoiding systemic toxicity. In mouse models of both immunologically hot and cold brain tumors, the intracranial deposition of alum-tethered cytokines causes significant delay in tumor progression. RNA profiling reveals that engineered cytokines engage both innate and adaptive immunity in the brain. These findings suggest that engineered cytokines can reprogram brain immunosurveillance, informing the development of future therapies for neuroimmune diseases.

bioengineering↗

bioRxiv2021

On-person adaptive evolution of Staphylococcus aureus during atopic dermatitis increases disease severity

Genetic variation among bacterial strains can contribute to heterogeneity in the severity of chronic inflammatory diseases 1,2, but the degree of variation created by de novo mutation during colonization is not well understood. The inflamed skin of people with atopic dermatitis (AD) is frequently colonized with Staphylococcus aureus, an opportunistic pathogen associated with both asymptomatic colonization of nasal passages and invasive disease 3-6. While genetic risk and barrier disruption are critical to AD initiation 7,8, S. aureus colonization is thought to worsen disease severity by promoting skin damage9 1,4,5,10. Here we show, from tracking 23 children treated for AD over 9 months, that S. aureus adapts via de novo mutations during colonization. Patients S. aureus populations are typically dominated by a single lineage, with infrequent invasion by distant lineages. Variants emerge within each lineage with mutation accumulation rates similar to S. aureus in other contexts. Some of these variants replace their ancestors across the body within months, with signatures of adaptive, rather than neutral, forces. Most strikingly, the capsule synthesis gene capD obtained four parallel mutations within one patient and was involved in mutational sweeps in multiple patients. We confirm that selection for capD negativity is common in AD, but not in other contexts, via reanalysis of public S. aureus genomes from 276 people. Our finding of disease-specific selection raises the possibility that adaptation of pathobionts during colonization prolongs the positive feedback cycle of inflammation.

microbiology↗

bioRxiv2020

Allergen-induced dendritic cell migration is controlled through Substance P release by sensory neurons

Dendritic cells (DCs) of the cDC2 lineage are necessary for the initiation of the allergic immune response and in the dermis are marked by their expression of CD301b. CD301b+ dermal DCs respond to allergens encountered in vivo, but not in vitro. This suggests that another cell in the dermis may sense allergens and relay that information to activate and induce the migration of CD301b+ DCs to the draining lymph node. Using a model of cutaneous allergen exposure, we show that allergens directly activate TRPV1+ sensory neurons leading to itch and pain behaviors. Allergen-activated sensory neurons release the neuropeptide Substance P, which stimulates proximally located CD301b+ DCs through MRGPRA1. Substance P induces CD301b+ DC migration to the draining lymph node where they initiate Th2 differentiation. Thus, sensory neurons act as primary sensors of allergens, linking exposure to activation of allergic-skewing DCs and the initiation of the allergic immune response.

immunology↗