Biology subjects

Sanchez, K.

Publications and source records attributed to Sanchez, K..

6 recordsLinked to original sources

bioRxiv2026

The role of the NLRP3 inflammasome in a CLN2 mouse model of neuroinflammation

Neuronal ceroid lipofuscinoses, or Batten disease, comprises a group of inherited pediatric neurodegenerative disorders, and is characterized by the lysosomal accumulation of the fluorescent storage material lipofuscin. The human classical late-infantile form of the disorder (CLN2) is caused by mutations in the CLN2/Tripeptidyl peptidase 1 (TPP1) gene. Comparable to human CLN2, a knockout of the Tpp1 gene (Tpp1 -/-) in the mouse leads to progressive vision loss, ataxia, motor atrophy, seizures, and premature death. While we previously showed using bulk RNA-seq analysis that reactive gliosis develops between 3 and 4 months in this animal model, the role of the inflammasome in CLN2 remains unexplored. The inflammasome is a multiprotein complex formed through pattern recognition receptor engagement, which culminate in the cleavage and release of interleukin-1 beta. Here we report that while some inflammasome-associated genes are upregulated as early as 1-month in the Tpp1 -/- cerebellum, it is not until 3-months-old that all gene transcripts necessary for inflammasome assembly and function are upregulated, leading to IL1{beta} release. In Tpp1 -/- slice cultures, we demonstrated that MCC950, an inhibitor of inflammasome assembly, downregulates transcriptional expression of genes associated with reactive microglia and inflammasome function. Furthermore, prophylactic administration of MCC950 in drinking water of Tpp1 -/- animals for two months is sufficient to lower the expression of these same genes in the forebrain and cerebellum, suggesting that inflammasome inhibitors are promising therapeutics for CLN2 and neurodegeneration broadly.

cell biology↗

bioRxiv2026

Vagus nerve stimulation limits colonic inflammation through distinct neuroimmune circuitry shaped by inflammatory history

Bidirectional communication between the nervous and immune systems has been demonstrated to limit or enhance immune cell function across organ systems and conditions. Although these neuroimmune circuits can become activated as an anti-inflammatory reflex, vagus nerve stimulation (VNS) reduces inflammation in models of endotoxemia, rheumatoid arthritis, and intestinal inflammation. In the spleen during endotoxemia, VNS activates a "cholinergic anti-inflammatory pathway" (CAIP), whereby choline acetyltransferase (ChAT)-expressing T cells release acetylcholine to reduce macrophage activation. VNS can also drive CAIP-independent pathways to reduce inflammation in the spleen and intestinal tract, although the circuitry modulating colonic inflammation remains underexplored. Here, we demonstrate that left cervical VNS reduces acute LPS-induced inflammation, evidenced by reduced Tnfa expression in colon and spleen and decreased circulating TNF. In the colon, these protective effects required efferent but not afferent VNS and were independent of ChAT+ T cells, IL10, {beta}-adrenergic signaling, and colonic sympathetic innervation. Critically, the ability of VNS to modulate colonic inflammation depended on prior tissue-specific inflammation. Mice recovering from DSS colitis, despite near-complete histological recovery, were refractory to the protective effects of VNS in the colon. This lack of efficacy in the colon was not reflected in measures of inflammation in the spleen or serum, highlighting the need for target-organ-specific monitoring. This loss of efficacy after colonic inflammation was transient, with restoration occurring upon complete recovery. These findings demonstrate that VNS efficacy in colonic inflammation depends on circuitry distinct from canonical systemic anti-inflammatory pathways, and that tissue responsiveness is shaped by anatomical site and inflammatory history. Key PointsO_LIElectrical stimulation of the left cervical vagus nerve reduces LPS-induced inflammation in the mouse colon. C_LIO_LIThis colonic anti-inflammatory effect requires vagal efferents but not afferent signaling. C_LIO_LIUnlike canonical splenic anti-inflammatory pathways, the colonic response does not require ChAT+ T cells, IL-10, {beta}-adrenergic signaling, or local sympathetic innervation. C_LIO_LIRecent DSS colitis abolishes colonic responsiveness to VNS despite preserved splenic and systemic anti-inflammatory effects. C_LIO_LIRecovery of VNS anti-inflammatory efficacy after colitis shows that neuroimmune responsiveness in the colon is dynamically shaped by inflammatory history. C_LI

immunology↗

bioRxiv2025

Tac1 Deficiency Reduces the Severity of Enteric Bacterial Infection

BackgroundInfection with enteric bacterial pathogens continues to cause significant morbidity and mortality throughout the world. These pathogens include enterohemorrhagic and enteropathogenic Escherichia coli, which transit the intestinal tract, efface microvilli, and attach firmly to intestinal epithelial cells predominantly in the colon. Investigation of these human-adapted pathogens has been greatly aided by mouse models of infection. The mouse-adapted attaching and effacing pathogen Citrobacter rodentium utilizes many similar mechanisms of pathogenesis, including the use of a type III secretion system, and virulence factors encoded in a locus of enterocyte effacement. Although this model has allowed for assessing the complexity of the host response, the complex interplay between the nervous and immune systems in response to infection remains incomplete. MethodsWe assessed the role of sensory neurotransmitters encoded by the Tac1 gene in the host response to C. rodentium. ResultsTac1-deficient mice had significantly reduced pathogen shedding and colonic bacterial burden, accompanied by decreased expression of inflammatory cytokines and chemokines. In accordance with reduced chemokine production, we observed reduced colonic recruitment of specific immune cell populations in Tac1-/- compared to WT mice. ConclusionsSensory neuropeptides regulate key aspects of enteric bacterial infection and may serve as unique targets in the treatment of enteric disease.

immunology↗

bioRxiv2025

Pathological tau activates inflammatory nuclear factor-kappa B (NF-κB) and pT181-Qβ vaccine attenuates NF-κB in PS19 tauopathy mice

Tau regulates neuronal integrity. In tauopathy, phosphorylated tau detaches from microtubules and aggregates, and is released into the extracellular space. Microglia are the first responders to the extracellular tau, a danger/damage-associated molecular pattern (DAMP), which can be cleared by proteostasis and activate innate immune response gene expression by nuclear factor-kappa B (NF-{kappa}B). However, longitudinal NF-{kappa}B activation in tauopathies and whether pathological tau (pTau) contributes to NF-{kappa}B activity is unknown. Here, we tau oligomers from human Alzheimers disease brain (AD-TO) activate NF-{kappa}B in mouse microglia and macrophages reducing the I{kappa}B via promoting its secretion in the extracellular space. NF-{kappa}B activity peaks at 9- and 11-months age in PS19Luc+ and hTauLuc+ mice, respectively. Reducing pTau via pharmacological (DOX), genetic (Mapt-/-) or antibody-mediated neutralization (immunization with pT181-Q{beta} vaccine) reduces NF-{kappa}B activity, and together suggest pTau is a driver of NF-{kappa}B and chronic neuroinflammation tauopathies. SummaryNeuronal tau activates microglial NF-{kappa}B constitutively by secreting its inhibitor I{kappa}B. NF-{kappa}B activation in PS19Luc+ and hTauLuc+ mice peaks at 9- and 11-months of age, respectively. Neutralizing pTau with pT181-Q{beta} vaccine (targeting phosphorylated threonine 181 tau) alleviates NF-{kappa}B activity in tauopathy mice.

neuroscience↗

bioRxiv2024

Substance P receptor signaling contributes to host maladaptive responses during enteric bacterial infection.

Immune responses in the intestine are intricately balanced to prevent pathogen entry without inducing immunopathology. The nervous system is well-established to interface with the immune system to fine-tune immunity in various organ systems including the gastrointestinal tract. Specialized sensory neurons can detect bacteria, bacterial products, and the resulting inflammation, to coordinate the immune response in the gastrointestinal tract. These sensory neurons release peptide neurotransmitters such as Substance P (SP), to induce both neuronal signaling and localized responses in non-neuronal cells. With this in mind, we assessed the immunoregulatory roles of SP receptor signaling during enteric bacterial infection with the non-invasive pathogen Citrobacter rodentium. Pharmacological antagonism of the SP receptor significantly reduced bacterial burden and prevented colonic crypt hyperplasia. Mice with SP receptor signaling blockade had significantly reduced inflammation and recruitment of T-cells in the colon. Reduced colonic T-cell recruitment is due to reduced expression of adhesion molecules on colonic endothelial cells in SP receptor antagonist-treated mice. Using SP receptor T-cell conditional knockout mice, we further confirmed SP receptor signaling enhanced select aspects of T-cell responses. Our data demonstrates that SP receptor signaling can significantly reduce inflammation and prevent host-maladaptive responses without impinging upon host protection.

immunology↗

bioRxiv2022

WWOX P47T loss-of-function mutation induces epilepsy, progressive neuroinflammation, and cerebellar degeneration in mice phenocopying human SCAR12

WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12). This mutation affects the WW1 protein binding domain of WWOX, impairing its ability to interact with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T that phenocopies SCAR12. WwoxP47T/P47T mice displayed epilepsy, profound social behavior and cognition deficits, and poor motor coordination, and unlike KO models that survive only for 1 month, live beyond 1 year of age. These deficits progressed with age, and mice became practically immobile, suggesting severe cerebellar dysfunction. WwoxP47T/P47T mice exhibited signs of progressive neuroinflammation with elevated astro-microgliosis that increased with age. The cerebellar cortex displayed significantly reduced molecular and granular layer thickness and a strikingly reduced number of Purkinje cells with degenerated dendrites. Transcriptome profiling from various brain regions from these Wwox LoF mice highlighted widespread changes in neuronal and glial pathways, enrichment of bioprocesses related to neuroinflammation and severe cerebellar dysfunction, activation of pathways compatible with compensatory neurogenesis along with major suppression of gene networks associated with excitability, neuronal cell differentiation and brain development. Our results show significant pathobiological effects and potential mechanisms through which WWOX LoF leads to epilepsy, cerebellar neurodegeneration, neuroinflammation, and ataxia. Additionally, the mouse model described here will be a useful tool for the study of WWOX in common neurodegenerative conditions in which it has been identified as a novel risk factor.

neuroscience↗