The Innate Immune System and Inflammatory Priming: Potential Mechanistic Factors in Mood Disorders and Gulf War Illness

Trageser, Kyle J; Sebastian-Valverde, Maria; Naughton, Sean X.; Pasinetti, Giulio Maria

doi:10.3389/fpsyt.2020.00704

Cited by 17 publications

(14 citation statements)

References 113 publications

(128 reference statements)

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“…Amongst all of the generated networks, two cytokines, tumor necrosis factor (TNF) and interferon gamma (IFN-g), a kinase, PDPK1, and a phosphatase, PTEN, were observed across all of the time points and exposures (Tables 4 , 5 , and 6 ). Therefore, these time-independent common nodes are highly connected to the dataset, and may be shared links to the observed neuroinflammation with both of these AChEIs [ 2 , 19 , 42 ].…”

Section: Resultsmentioning

confidence: 99%

Differential phosphoprotein signaling in the cortex in mouse models of Gulf War Illness using corticosterone and acetylcholinesterase inhibitors

Penatzer

Miller

Prince

et al. 2021

Heliyon

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Veterans from the 1990-91 Gulf War were exposed to acetylcholinesterase inhibitors (AChEIs), and, following service, an estimated one-third began suffering from a medically unexplained, multi-symptom illness termed Gulf War Illness (GWI). Previous research has developed validated rodent models that include exposure to exogenous corticosterone (CORT) and AChEIs to simulate high stress and chemical exposures encountered in theater. This combination of exposures in mice resulted in a marked increase in neuroinflammation, which is a common symptom of veterans suffering from GWI. To further elucidate the mechanisms associated with these mouse models of GWI, an investigation into intracellular responses in the cortex were performed to characterize the early cellular signaling changes associated with this exposure-initiated neuroinflammation.Main methods: Adult male C57BL/6J mice were exposed to CORT in the drinking water (200 μg/mL) for 7 days followed by a single intraperitoneal injection of diisopropyl fluorophosphate (DFP; 4.0 mg/kg) or chlorpyrifos oxon (CPO; 8.0 mg/kg), on day 8 and euthanized 0.5, 2, and 24 h post-injection. Eleven post-translationally modified protein targets were measured using a multiplexed ELISA. Key findings: Phosphoprotein responses were found to be exposure specific following AChEI insult, with and without CORT. Specifically, CORT þ CPO exposure was found to sequentially activate several phosphoproteins involved in mitogen activated protein kinase signaling (p-MEK1/2, p-ERK1/2, and p-JNK). DFP alone similarly increased proteins in this pathway (p-RPS6, and p-JNK), but the addition of CORT ameliorated these affects. Significance: The results of this study provide insight into differentially activated pathways depending on AChEI in these GWI models.

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Section: Resultsmentioning

confidence: 99%

Differential phosphoprotein signaling in the cortex in mouse models of Gulf War Illness using corticosterone and acetylcholinesterase inhibitors

Penatzer

Miller

Prince

et al. 2021

Heliyon

View full text Add to dashboard Cite

show abstract

“…Evidence of a chronic inflammatory response has been reported in studies on GW veteran cohorts, where blood samples are taken and analyzed for biomarkers of inflammation. These studies have reported dysregulation of immune cells and other inflammatory markers such as C-reactive protein, Tau proteins, complement proteins, cytokines and chemokines [13,[65][66][67]. This may in part explain why patients with GWI report multiorgan disorders whose causes are difficult to pinpoint.…”

Section: Discussionmentioning

confidence: 99%

Gastrointestinal problems, mechanisms and possible therapeutic directions in Gulf war illness: a mini review

Kimono

2021

Military Med Res

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By its nature, Gulf war illness (GWI) is multisymptomatic and affects several organ systems in the body. Along with other symptoms, veterans who suffer from GWI commonly report chronic gastrointestinal issues such as constipation, pain, indigestion, etc. However, until recently, most attention has been focused on neurological disturbances such as cognitive impairments, chronic fatigue, and chronic pain among affected veterans. With such high prevalence of gastrointestinal problems among Gulf war (GW) veterans, it is surprising that there is little research to investigate the mechanisms behind these issues. This review summarizes all the available works on the mechanisms behind gastrointestinal problems in GWI that have been published to date in various databases. Generally, these studies, which were done in rodent models, in vitro and human cohorts propose that an altered microbiome, a reactive enteric nervous system or a leaky gut among other possible mechanisms are the major drivers of gastrointestinal problems reported in GWI. This review aims to draw attention to the gastrointestinal tract as an important player in GWI disease pathology and a potential therapeutic target.

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“…Instead of the previously mentioned two functional statuses called the resting and activation statuses, microglia are now believed to be in a continuum status, ranging from resting state to full activation. The concepts of “microglia priming” have been proposed to explain the exaggerated immune responses when microglia receive a second insult [ 40 , 41 , 42 , 43 ]. In prime status, microglia could not be differentiated from the resting state by morphological analysis or even at transcriptional levels.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, these studies indicated that ELS could prime microglia, leading to exaggerated microglial immune responses in later life, which is responsible for various neurological disorders. The concepts of “microglia priming” and the “two-hit hypothesis” have guided work in the field of neuroimmunology over the last decade [ 40 , 41 , 42 , 43 ]. Microglia are highly plastic and could be pre-activated or ‘primed’ by an earlier inflammatory event, which leads to amplified responses to a second inflammatory insult, that is, “innate immune memory (IIM).” Our data indicated that NLRP3 signaling priming and activation was responsible for microglia priming and activation and bridged the linkage between ELS and drug addiction.…”

Section: Discussionmentioning

confidence: 99%

NLRP3 Inflammasome Is Involved in Cocaine-Mediated Potentiation on Behavioral Changes in CX3CR1-Deficient Mice

Guo

Chivero

Callen

et al. 2021

JPM

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Microglia, the primary immunocompetent cells of the brain, are suggested to play a role in the development of drug addiction. Previous studies have identified the microglia-derived pro-inflammatory factor IL1β can promote the progression of cocaine addiction. Additionally, the activation status of microglia and “two-hit hypothesis” have been proposed in the field of drug addiction to explain how early life stress (ELS) could significantly increase the incidence of drug addiction in later life. However, the mechanisms underlying microglia prime and full activation and their roles in drug addiction remain greatly unexplored. Here, we employed CX3CR1-GFP mice (CX3CR1 functional deficiency, CX3CR1−/−) to explore whether primed microglia could potentiate cocaine-mediated behavioral changes and the possible underlying mechanisms. CX3CR1−/− mice revealed higher hyperlocomotion activity and conditional place preference than wild-type (WT) mice did under cocaine administration. In parallel, CX3CR1−/− mice showed higher activity of NLR family pyrin domain-containing 3 (NLRP3) inflammasome than WT mice. Interestingly, CX3CR1 deficiency itself could prime NLRP3 signaling by increasing the expression of NLPR3 and affect lysosome biogenesis under basal conditions. Taken together, our findings demonstrated that the functional status of microglia could have an impact on cocaine-mediated reward effects, and NLRP3 inflammasome activity was associated with this phenomenon. This study was consistent with the two-hit hypothesis and provided solid evidence to support the involvement of microglia in drug addiction. Targeting the NLRP3 inflammasome may represent a novel therapeutic approach for ameliorating or blocking the development of drug addiction.

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The Innate Immune System and Inflammatory Priming: Potential Mechanistic Factors in Mood Disorders and Gulf War Illness

Cited by 17 publications

References 113 publications

Differential phosphoprotein signaling in the cortex in mouse models of Gulf War Illness using corticosterone and acetylcholinesterase inhibitors

Differential phosphoprotein signaling in the cortex in mouse models of Gulf War Illness using corticosterone and acetylcholinesterase inhibitors

Gastrointestinal problems, mechanisms and possible therapeutic directions in Gulf war illness: a mini review

NLRP3 Inflammasome Is Involved in Cocaine-Mediated Potentiation on Behavioral Changes in CX3CR1-Deficient Mice

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