Biology subjects

Sun, E. W.

Publications and source records attributed to Sun, E. W..

3 recordsLinked to original sources

bioRxiv2026

Chronic NLRP3 inflammasome activation drives neutrophil brain entry and interactions with microglia

NOD-like receptor family pyrin domain-containing 3 (NLRP3) is a cytosolic regulator of an inflammasome-mediated innate immune response. In the central nervous system (CNS), NLRP3 inflammasome activation has been implicated in multiple neurodegenerative diseases, yet the mechanisms by which it contributes to disease remain unclear. Here, we investigated the CNS effects of chronic NLRP3 activation using a humanized NLRP3 gain-of-function mouse model (hNLRP3D305N). Bulk brain analyses confirmed constitutive inflammasome activation, widespread cytokine induction, and the increased presence of blood-associated proteins suggestive of dysfunction at CNS border sites and the blood-brain barrier (BBB). Furthermore, cerebrospinal fluid (CSF) neurofilament light chain levels were elevated, indicating neuronal damage. Single-cell RNA-sequencing of CD45+ immune cells in the brain demonstrated that microglia adopt distinct reactive states and that peripheral immune cells infiltrate the CNS, with neutrophils emerging as the predominant infiltrating immune cell type. This finding was confirmed by untargeted bulk brain and CSF proteomics that also suggest neutrophil reactivity. Immunohistochemistry further revealed regional neutrophil entry into the brain parenchyma, concurrent with reactive microglia and engulfment of neutrophils, suggesting functional microglia-neutrophil interactions. Collectively, these findings establish a direct pathogenic role for the NLRP3 inflammasome in the CNS independent of other neurodegeneration-related disease pathologies.

neuroscience↗

bioRxiv2025

CNS-penetrant NLRP3 inhibitor achieves durable weight loss and reverses hypothalamic inflammation in diet-induced obesity

The NLRP3 inflammasome is a key mediator of innate immunity that integrates inflammatory and metabolic stress signals. Increased and/or chronic activation of this critical pathway has been implicated in obesity, with hypothalamic neuroinflammation linked to dysregulation of energy balance. TN-783 is an investigational, CNS-penetrant, small-molecule NLRP3 inhibitor that potently suppressed inflammasome activation across multiple in vitro assays. In diet-induced obese (DIO) mice, only TN-783, and not the peripherally restricted NLRP3 inhibitor TN-101, produced progressive and sustained weight loss, underscoring the requirement for central target engagement. Weight loss was driven by a persistent reduction in food intake across both acute and chronic phases, without altering energy expenditure. This effect was further characterized by selective reduction of fat mass, with minimal impact on lean tissues. Mechanistically, NLRP3 inhibition attenuated DIO-induced hypothalamic neuroinflammation and partially reversed obesity-associated molecular changes based on transcriptomic and proteomic profiling of the hypothalamus. Beyond monotherapy, TN-783 enhanced the effects of the GLP-1 receptor agonist semaglutide by amplifying weight loss, reinitiating weight loss after semaglutide effect had plateaued, and maintaining the weight loss benefit after semaglutide withdrawal. Discontinuation of TN-783 resulted in reversal of both weight and feeding effects, indicating that its therapeutic activity requires ongoing target engagement rather than permanent remodeling of metabolic pathways. Collectively, these observations support central NLRP3 inhibition as a distinct and promising approach for obesity treatment, offering robust induction and sustained maintenance of weight loss while preserving reversibility.

neuroscience↗

bioRxiv2024

Lysosomes cell autonomously regulate myeloid cell states and immune responses

Myeloid cells maintain tissue homeostasis via the recognition, engulfment, and lysosomal clearance of dying cells and cellular debris, which is often accompanied by changes from homeostatic to reactive states. While a role for phagocytic receptors in gating these transitions has been described1,2, less is known about if and how lysosomes can contribute to transcriptional and functional plasticity. To determine how lysosomal health impacts myeloid cell states, we evaluated microglia and macrophages deficient for progranulin (encoded by Grn), a lysosomal protein with pleiotropic functions whose loss is associated with several neurodegenerative diseases3-8. Single-cell RNA-sequencing of the aged mouse brain identified a Grn knockout (KO)-specific microglial subpopulation marked by high GPNMB expression that displays hallmarks of lysosomal dysfunction, including lipofuscin accumulation. Epigenetic analysis of aged microglia revealed MITF/TFE transcription factors as key mediators of the transcriptional states associated with Grn deficiency. In addition to identifying a core myeloid cell transcriptional response to diverse lysosomal stressors, targeted perturbations of various lysosomal properties in vitro uncovered a cell autonomous, TREM2- independent, response to lysosomal deacidification (via v-ATPase or VPS34 loss of function) that overlaps with Grn KO microglia phenotypes, including the induction of a lysosomal gene program, increased proliferation, and secretion of pro-inflammatory cytokines. Compound loss-of-function approaches established GPNMB upregulation upon lysosomal stress is required for the compensatory response to enhance lysosomal function via promoting acidification. Finally, pharmacological endolysosomal reacidification through sodium/proton exchanger inhibition partially rescued Grn KO microglia phenotypes. Overall, these data establish a fundamental link between lysosomal health and myeloid cell epigenetic, transcriptional, and functional states observed in neurodegeneration models.

neuroscience↗