Biology subjects

McIlvried, L. A.

Publications and source records attributed to McIlvried, L. A..

4 recordsLinked to original sources

bioRxiv2025

Cancer-induced Nerve Injury Unveils a Sympathetic-to-Sensory Nerve Axis in Head and Neck Cancer

Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, with patients frequently reporting spontaneous, neuropathic-like pain. While sympathetic and sensory nerves have been individually implicated in cancer progression, whether and how these systems interact to drive pain and tumor growth has remained unclear. Here, we integrate prospective human data with reverse-translational mouse models to reveal that cancer-induced nerve injury unveils crosstalk between sympathetic postganglionic neurons and trigeminal sensory afferents in the tumor microenvironment. In patients, circulating norepinephrine (NE) correlated with spontaneous pain and perineural invasion, identifying a potential sympathetic contribution to disease burden. In mice, aggressive non-immunogenic OSCC tumors evoked spontaneous nociceptive behaviors, elevated tumoral NE, and sensory nerve injury marked by ATF3 expression and hyperexcitability. Tumor-associated sensory neurons acquired adrenergic sensitivity through 1-adrenergic receptor plasticity, while sympathetic neurons exhibited plasticity characterized by sprouting, altered gene expression, and heightened excitability, creating a maladaptive feed-forward loop that amplified nociceptive signaling. Disrupting this sympathetic-sensory communication by sympathectomy or selective ablation of TRPV1 sensory fibers reduced tumor growth, sympathetic tone, and spontaneous pain like behaviors, although sensory adrenergic sensitivity persisted. Together, these findings establish that reciprocal sympathetic-sensory plasticity and crosstalk in the tumor may fuel both OSCC progression and neuropathic like pain. Targeting this peripheral neuroplasticity may offer a translational strategy to limit tumor growth and alleviate pain. One Sentence SummaryReciprocal plasticity and crosstalk between sympathetic and sensory nerves drive both tumor progression and neuropathic-like pain in oral squamous cell carcinoma, suggesting peripheral neuroplasticity as a therapeutic target.

neuroscience↗

bioRxiv2023

Harmonized cross-species cell atlases of trigeminal and dorsal root ganglia

Peripheral sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG) are specialized to detect and transduce diverse environmental stimuli including touch, temperature, and pain to the central nervous system. Recent advances in single-cell RNA-sequencing (scRNA-seq) have provided new insights into the diversity of sensory ganglia cell types in rodents, non-human primates, and humans, but it remains difficult to compare transcriptomically defined cell types across studies and species. Here, we built cross-species harmonized atlases of DRG and TG cell types that describe 18 neuronal and 11 non-neuronal cell types across 6 species and 19 studies. We then demonstrate the utility of this harmonized reference atlas by using it to annotate newly profiled DRG nuclei/cells from both human and the highly regenerative axolotl. We observe that the transcriptomic profiles of sensory neuron subtypes are broadly similar across vertebrates, but the expression of functionally important neuropeptides and channels can vary notably. The new resources and data presented here can guide future studies in comparative transcriptomics, simplify cell type nomenclature differences across studies, and help prioritize targets for future pain therapy development.

neuroscience↗

bioRxiv2019

Transcriptomic analysis of native versus cultured human and mouse dorsal root ganglia focused on pharmacological targets

Dorsal root ganglion (DRG) neurons detect sensory inputs and are crucial for pain processing. They are often studied in vitro as dissociated cell cultures with the assumption that this reasonably represents in vivo conditions. However, to our knowledge, no study has ever directly compared genome-wide transcriptomes of DRG tissue in vivo versus in vitro, or between different labs and culturing protocols. We extracted bilateral lumbar DRG from C57BL6/J mice and human organ donors, and acutely froze one side and processed the other side as a dissociated cell culture, which was then maintained in vitro for 4 days. RNA was extracted and sequenced using the NextSeq Illumina platform. Comparing native to cultured human or mouse DRG, we found that the overall expression level of many ion channels and GPCRs specifically expressed in neurons is markedly lower in culture, but still expressed. This suggests that most pharmacological targets expressed in vivo are present in culture conditions. However, there are changes in expression levels for these genes. The reduced relative expression for neuronal genes in human DRG cultures is likely accounted for by increased expression of genes in fibroblast-like and other proliferating cells, consistent with the mitotic status of many cells in these cultures. We did find a subset of genes that are typically neuronally expressed, increased in human and mouse DRG cultures, including genes associated with nerve injury and/or inflammation in preclinical models such as BDNF, MMP9, GAL, and ATF3. We also found a striking upregulation of a number of inflammation-associated genes in DRG cultures, although many were different between mouse and human. Our findings suggest an injury-like phenotype in DRG cultures that has important implications for the use of this model system for pain drug discovery.

neuroscience↗

bioRxiv2017

Macrophage-to-sensory neuron crosstalk mediated by Angiotensin II type-2 receptor elicits neuropathic pain

Peripheral nerve damage initiates a complex series of cellular and structural processes that culminate in chronic neuropathic pain. Our study defines local angiotensin signaling via activation of the Angiotensin II (Ang II) type-2 receptor (AT2R) on macrophages as the critical trigger of neuropathic pain. An AT2R-selective antagonist attenuates neuropathic, but not inflammatory pain hypersensitivity in mice, and requires the cell damage-sensing ion channel transient receptor potential family-A member-1 (TRPA1). Mechanical and cold pain hypersensitivity that are characteristic of neuropathic conditions can be attenuated by chemogenetic depletion of peripheral macrophages and AT2R-null hematopoietic cell transplantation. Our findings show no AT2R expression in mouse or human sensory neurons, rather AT2R expression and activation in macrophages triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on sensory neurons. Our study defines the precise neuro-immune crosstalk underlying nociceptor sensitization at the site of nerve injury. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic neuropathic pain, and therefore identifies multiple analgesic targets.

neuroscience↗