Neuroimmune priming and microglial exhaustion in aged Gulf War Illness mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE338196 | GEO | 2026/07/14
REPOSITORIES: GEO
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Project description:Gulf War Illness (GWI) affects up to one-third of 1990–1991 Gulf War veterans and is associated with chronic low-grade neuroinflammation, yet its cellular substrates remain unclear and targeted pharmacological therapies are still limited. By using bulk RNA-seq analyses of whole-brain in an established GWI mouse model, we uncovered a multi-lineage primed neuroimmune signature in aged GWI mice. Systemic lipopolysaccharide (LPS) elicited an amplified pro-inflammatory response in the brains of GWI mice compared to age-matched controls. Chronic cannabidiol (CBD) attenuated neuroimmune priming at baseline, and suppressed the parenchymal hyper-response, defining a therapeutic axis amenable to pharmacological intervention.
2026-07-14 | GSE338199 | GEO
Project description:Gulf War Illness (GWI) affects up to one-third of 1990–1991 Gulf War veterans and is associated with chronic low-grade neuroinflammation, yet its cellular substrates remain unclear and targeted pharmacological therapies are still limited. By using bulk RNA-seq analyses of FACS-purified microglia in an established GWI mouse model, we uncovered a multi-lineage primed neuroimmune signature in aged GWI mice. Systemic lipopolysaccharide (LPS) elicited an amplified pro-inflammatory response in the brains of GWI mice compared to age-matched controls, yet paradoxically, microglia were transcriptionally hyporesponsive to LPS, with inverted antigen presentation module score indicative of a microglial exhaustion phenotype. Chronic cannabidiol (CBD) attenuated neuroimmune priming at baseline, reshaping microglial translational and energetic states. Under immune-stimulated conditions, CBD partially restored GWI-associated deficits in microglial antigen presentation and oxidative phosphorylation, defining a therapeutic axis amenable to pharmacological intervention.
2026-07-14 | GSE338200 | GEO
Project description:This pilot study enrolled 9 GWI (Gulf War Illness) cases identified from the Department of Veterans Affairs GWI registry, and 11 sedentary control veterans who had not been deployed to the Persian Gulf and were matched to cases by sex, body mass index (BMI) and age.<br>We exposed GWI patients and matched controls to an exercise challenge to explore differences in immune cell function measured by classic immune assays and gene expression profiling.
2009-02-24 | E-MEXP-2069 | biostudies-arrayexpress
Project description:Of the nearly 1 million military personnel who participated in the 1990-1991 Gulf War, between 25% and 35% became ill with what now is referred to as Gulf War Illness (GWI), by the Department of Defense. Symptoms varied from gastrointestinal distress to lethargy, memory loss, inability to concentrate, depression, respiratory and reproductive problems. The symptoms have persisted for 30 years in those afflicted but the basis of the illness remains largely unknown. Nerve agents and other chemical exposures in theater have been implicated but the long-term effects of these acute exposures have left few if any identifiable signatures. The major aim of this study is to elucidate the possible genomic basis for the persistence, especially of the neurological and behavioral effects. To address this, we performed a whole genome epigenetic analysis of the proposed cause of GWI, viz., exposure to organophosphate neurotoxicants combined with high circulating glucocorticoids in two inbred mouse strains, C57BL/6J and DBA/2J. The animals received corticosterone in their drinking water (20mg%, w/v) for 7 days followed by injection of diisopropylfluorophosphate, a nerve agent surrogate (DFP, 4mg/kg, i.p.). Control mice were maintained under normal husbandry. Six weeks after DFP injection, the animals were euthanized and medial prefrontal cortex harvested for genomic methylation analysis by MBD-seq. We observed 67 differentially methylated genes, notably among them, Ttll7, Akr1c14, Slc44a4, and Rusc2, all related to different symptoms of GWI. Our results support proof of principle of genetic differences in the chronic effects of GWI-related exposures and may reveal why the disease has persisted in many of the now aging Gulf War veterans.
2023-06-01 | GSE225179 | GEO
Project description:Aims: In an effort to gain further insight into the underlying mechanisms tied to disease onset and progression of Gulf War Illness (GWI), our team evaluated GWI patient response to stress utilizing RNA-Seq. Main Methods: The protocol included blood collection before (baseline), during (peak of exercise, measured by VO2 max), and after exercise challenge (recovery – four hours post-exercise challenge). Peripheral blood mononuclear cell (PBMC) transcriptomics data were analyzed using DESeq2 and DEXseq software to understand why GWI patients process stressors differently from their healthy counterparts. Key findings: Our findings validate previously identified dysregulation of immune and inflammatory pathways among GWI patients as well as highlight novel immune and inflammatory markers of disease activity. These results provide a foundation for future research efforts in understanding GWI pathophysiology and creating targeted treatments. Significance: Gulf War Illness is a complex, chronic, and debilitating multi-system illness impacting 25%-30% of the U.S. troops deployed to the 1990-1991 Gulf War. The condition is characterized by medically unexplained fatigue and affects multiple organ systems. Because the underlying mechanisms are largely unknown, patients receive symptom-based treatment, rather than targeting fundamental biological processes. To the best of our knowledge, this is the first study that applies RNA-Seq to analyze the effect of GWI, and the response to stressors in GWI, on the transcriptomic changes in circulating immune cells.
2021-08-15 | GSE168409 | GEO
Project description:Gulf War Illness (GWI) is a complex condition affecting Veterans, and its underlying neuropathological mechanisms remain unclear. Patient-derived induced pluripotent stem cells (iPSCs) offer a platform to model the disease in vitro. Objective: To map transcriptomic landscapes and infer single-cell gene regulatory networks (scGRNs) in iPSC-derived neurons from symptomatic and non-symptomatic Gulf War Veterans to identify genes and pathways implicated in GWI pathophysiology and predisposition. Design, Setting, and Participants: This study utilized iPSCs generated from symptomatic GWI Veterans and non-symptomatic GWI Veteran controls. Neurons were differentiated from these iPSCs for analysis. Main Outcomes and Measures: Single-cell RNA sequencing (scRNAseq) was used to generate transcriptomic data. Machine learning algorithms were applied to infer and compare scGRNs between the symptomatic and non-symptomatic groups, identifying key regulatory differences. Results: Analysis of scRNAseq data revealed significant differences in gene expression profiles between neurons derived from symptomatic and non-symptomatic Veterans. scGRN inference identified distinct regulatory modules associated with GWI symptom status. Key transcription factors driving these differences were identified, along with target genes involved in neuroinflammatory responses, synaptic signaling, and stress response pathways. These findings point towards specific molecular dysregulations contributing to GWI neuropathology. Conclusions and Relevance: This study demonstrates the utility of iPSC-derived neurons coupled with single-cell transcriptomics and computational network inference for investigating GWI. The identified differences in scGRNs provide novel insights into the molecular underpinnings of the illness and highlight potential targets for future diagnostic and therapeutic strategies.
2026-01-01 | GSE303735 | GEO
Project description:Background Gulf War Illness (GWI) is a severely debilitating condition with chronic symptoms affecting up to 30% of the veterans deployed to the 1990-91 Persian Gulf War. The symptoms associated with GWI include fatigue, musculoskeletal/joint pain and disturbances of multiple organ systems. The mechanisms of GWI are unknown, although the symptoms suggest that GWI is most likely caused by a combination of genetic predisposition and it’s interaction with environmental factors such as exposure to toxic chemicals. Objectives This research project aims to assess how sex differences in individuals with GWI impact their response to stress, specifically through an exercise challenge. Additionally, it highlights the importance of considering sex differences in the diagnosis and treatment of GWI. Methods We utilized RNA-seq to examine the differential gene expression (GE) in peripheral blood mononuclear cells of 24 female GWI patients, 20 male GWI patients, and 40 healthy controls (HC) who were matched in for sex, age, and BMI. We evaluated the gene expression changes at three time points: T0 (baseline), T1 (at maximal exertion), and T2 (4 hours into recovery after T1). To ensure consistency, we excluded genes located on the sex chromosomes and performed separate analyses for men and women. Our focus was to compare the response to exercise within each group (GWI patients and HC) between different time points. Results In the male GWI cohort, pathways associated with immune system process, particularly IL-12, and natural killer cell cytotoxicity were activated during exercise. The female GWI patients exhibited less significant changes in gene expression than men. During the recovery period, male GWI patients demonstrated distinct alterations in the regulation of innate immune responses. On the other hand, female GWI patients showed significant changes in genes related to regulation of intracellular signal transduction. These functional pathways and differentially expressed genes identified in this project provide valuable insights into the sex-specific pathophysiology of GWI. Conclusion The identification of sex-specific biomarkers and therapeutic targets in GWI holds great potential for understanding the distinct onset and progression of this disease in different sexes.
2025-04-30 | GSE286345 | GEO
Project description:Gulf War Illness (GWI) is a diverse set of neurologic and systemic symptoms affecting many veterans deployed in the Persian Gulf War, but its etiology is unknown and treatment options are limited. Veterans with GWI were exposed to a variety of agents, including pyridostigmine bromide, used as prophylaxis against nerve agents, intranasal lipopolysaccharide (LPS) from desert sandstorms, and chronic unpredictable stress (CUS) from combat. Here, we investigated the gene expression effects of these three Gulf War-related exposures (GWE) in adult rat frontal cortex (FC) and lateral amygdala (LA) using Clariom S microarrays. We found 138 transcript clusters (TCs) in LA and 38 TCs in FC differentially expressed between the group with GWE (n=2) compared to naïve controls (n=3, FDR <10%). These TCs included genes involved in inflammation such as Fosb (pmin=1.02e-5) and Junb (pmin=1.13e-5). Gene ontology analysis found enrichment of differentially expressed genes in “T cell differentiation” (pmin=8.71e-5) and “response to organophosphorus” (pmin=1.74e-8), among other categories. Lastly, we found that prophylactic treatment with rosiglitazone, a PPAR- agonist, reduced gene expression changes associated with GWE (in LA: 115/138 [83.3%] TCs with reduced changes, χ2=61.33, p=4.82e-15). These results suggest our rat model of GWI is associated with gene expression changes related to neuroinflammation and that some of these molecular changes may be mitigated by rosiglitazone prophylaxis.
2021-06-01 | GSE165221 | GEO
Project description:Immune transcriptomic changes in Australian Gulf War Veterans
2025-12-10 | GSE305935 | GEO
Project description:Gulf War Illness (GWI) is a chronic multisymptom disorder associated with prior stress and toxicant exposures. Adult male C57BL/6J mice were exposed to corticosterone (CORT) and diisopropyl fluorophosphate (DFP), followed by repeated intermittent CORT and a later immune challenge with lipopolysaccharide (LPS) or saline. RNA-seq was performed in hippocampus and frontal cortex collected 6 h, 12 h, and 24 h after challenge to define transcriptional responses associated with persistent neuroimmune priming in this mouse model of GWI.
2026-03-27 | GSE325692 | GEO