Biology subjects

Guldberg, S. M.

Publications and source records attributed to Guldberg, S. M..

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

GPR34 regulates microglia state and loss-of-function rescues TREM2 metabolic dysfunction

Microglia are implicated in modifying neurodegenerative disease risk in the central nervous system (CNS). GPR34 is a microglia-enriched G-protein coupled receptor that detects cytotoxic lipids upregulated in Alzheimers Disease (AD). Since dysregulated lipid metabolism occurs in disease, we hypothesized GPR34 could act with other lipid sensors, such as TREM2, to regulate microglial function. Here, we report that GPR34 knockout (KO) rescues dysregulated cholesterol metabolism in TREM2 KO iPSC-derived microglia (iMG) and alone promotes fatty acid catabolism without the proton leak observed in TREM2 KO. Loss of GPR34 downregulated ERK signaling, while its agonism promoted interaction with and activation of ERK. In healthy and amyloid mouse models, Gpr34 KO accelerated the conversion of homeostatic microglia to disease-associated microglia (DAM) states. Additionally, in Gpr34 KO amyloid mouse brain, the frequency of large plaques was increased compared to WT, indicating that Gpr34 KO microglia may promote amyloid aggregation. Overall, our data suggest GPR34 as a therapeutic target for modulating microglial function to slow AD progression.

neuroscience↗

bioRxiv2022

T cell-instructed inflammation drives immune checkpoint inhibitor therapy resistance

Resistance to immune checkpoint inhibitors (ICIs) is common, even in tumors with T cell infiltration. We thus investigated consequences of ICI-induced T cell infiltration in the microenvironment of resistant tumors. T cells increased in ICI-resistant tumors following treatment as did neutrophils, in contrast to ICI-responsive tumors. Resistant tumors were distinguished by high expression of IL-1 Receptor 1 (IL1R1), enabling a synergistic response to IL-1 and TNF to induce G-CSF, CXCL1, and CXCL2 via NF-{kappa}B signaling, supporting neutrophils. Perturbation of this inflammatory resistance circuit sensitized tumors to ICIs. Paradoxically, T cells drove this resistance circuit via TNF both in vitro and in vivo. Evidence of this inflammatory resistance circuit and its impact also translated to human cancers. These data support a novel mechanism of ICI resistance, wherein treatment-induced T cell activity can drive resistance in tumors responsive to IL-1 and TNF, with important therapeutic implications. Statement of SignificanceAlthough T cell-infiltrated cancers are frequently resistant to immune checkpoint inhibitor therapies, mechanisms of resistance beyond T cell exhaustion remain unclear. Here, we reveal the functional significance of tumor- infiltrating T cells in resistant tumors, which surprisingly instruct immunosuppressive inflammation in mouse and human cancers responsive to IL-1 and TNF.

immunology↗