Circulating HMGB1 is elevated in veterans with Gulf War Illness and triggers the persistent pro-inflammatory microglia phenotype in male C57Bl/6J mice

Garza-Lombó, Carla; Thang, Morrent; Greve, Hendrik J.; Mumaw, Christen L.; Messenger, Evan J; Ahmed, Chandrama; Quinn, Emily; Sullivan, Kimberly; Block, Michelle L.

doi:10.1038/s41398-021-01517-1

Cited by 14 publications

(8 citation statements)

References 83 publications

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“…a higher AA-to-DHA ratio) had a higher risk of acute coronary syndrome than those with a high DHA/AA ratio, and this was significant for men in particular [ 53 ]. These differences in AA and DHA composition could reflect a generalized pro-inflammatory state in veterans with GWI, which would be consistent with reports of markers of chronic, low-grade inflammation being associated with GWI diagnosis [ 49 , 54 ]. Hence, future studies are needed that interrogate systems-level omic data along with biological parameters of inflammation to identify specific inflammatory pathways that are associated with GWI pathogenesis.…”

Section: Discussionsupporting

confidence: 88%

Sex-specific differences in plasma lipid profiles are associated with Gulf War Illness

et al. 2022

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Background Nearly 250,000 veterans from the 1990–1991 Gulf War have Gulf War Illness (GWI), a condition with heterogeneous pathobiology that remains difficult to diagnose. As such, availability of blood biomarkers that reflect the underlying biology of GWI would help clinicians provide appropriate care to ill veterans. In this study, we measured blood lipids to examine the influence of sex on the association between blood lipids and GWI diagnosis. Methods Plasma lipid extracts from GWI (n = 100) and control (n = 45) participants were subjected to reversed-phase nano-flow liquid chromatography-mass spectrometry analysis. Results An influence of sex and GWI case status on plasma neutral lipid and phospholipid species was observed. Among male participants, triglycerides, diglycerides, and phosphatidylcholines were increased while cholesterol esters were decreased in GWI cases compared to controls. In female participants, ceramides were increased in GWI cases compared to controls. Among male participants, unsaturated triglycerides, phosphatidylcholine and diglycerides were increased while unsaturated cholesterol esters were lower in GWI cases compared to controls. The ratio of arachidonic acid- to docosahexaenoic acid-containing triglyceride species was increased in female and male GWI cases as compared to their sex-matched controls. Conclusion Differential modulation of neutral lipids and ratios of arachidonic acid to docosahexaenoic acid in male veterans with GWI suggest metabolic dysfunction and inflammation. Increases in ceramides among female veterans with GWI also suggest activation of inflammatory pathways. Future research should characterize how these lipids and their associated pathways relate to GWI pathology to identify biomarkers of the disorder.

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Section: Discussionsupporting

confidence: 88%

Sex-specific differences in plasma lipid profiles are associated with Gulf War Illness

et al. 2022

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“…a higher AA-to-DHA ratio) had a higher risk of acute coronary syndrome than those with a high DHA/AA ratio, and this was signi cant for men in particular (50). These changes in AA and DHA composition could re ect a generalized proin ammatory state in veterans with GWI, which would be consistent with reports of markers of chroniclow grade in ammation being associated with GWI diagnosis (51,52).…”

Section: Discussionsupporting

confidence: 83%

Sex-Specific Differences In Plasma Lipid Profiles Are Associated With Gulf War Illness

Oberlin

Nkiliza

Parks

et al. 2021

Preprint

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Background: Nearly 250,000 veterans from the 1990-1991 Gulf War have Gulf War Illness (GWI), a condition with heterogeneous pathobiology that remains difficult to diagnose. As such, availability of blood biomarkers that reflect the underlying biology of GWI will help clinicians provide appropriate care to ill veterans. In this study, we measured blood lipids to examine the influence of sex on the association between blood lipids and GWI diagnosis. Methods: Plasma lipid extracts from GWI (n=100) and control (n = 45) participants were subjected to reversed-phase nano-flow liquid chromatography-mass spectrometry analysis. Results: An influence of sex and GWI case status on plasma neutral lipid and phospholipid species was observed. Among male participants, triglycerides, diglycerides, and phosphatidylcholines were increased while cholesterol esters were decreased in GWI compared to controls. In female participants, ceramides were increased in GWI cases compared to controls. Among male participants, unsaturated triglycerides, phosphatidylcholine and diglycerides were increased while unsaturated cholesterol esters were lower in GWI cases compared to controls. The ratio of arachidonic acid- to docosahexaenoic acid-containing triglyceride species was increased in female and male GWI cases as compared to their sex-matched controls. Conclusion: Differential modulation of neutral lipids and ratios of arachidonic acid to docosahexaenoic acid in male veterans with GWI suggest metabolic dysfunction and inflammation. Increases in ceramides among female veterans with GWI also suggest activation of inflammatory pathways. Future research should characterize how these lipids and their associated pathways relate to GWI pathology to identify biomarkers of the disorder.

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“…Senescence-induced pathological syncytia can trigger lymphopenia by cell-in-cell phenomena, elimination of viable lymphocytes, including NK cells, a frequent finding in ME/CFS [96][97][98]. In addition, as cellular senescence upregulates HMGB1, it may further predispose to fatiguing disorders [44,[47][48][49][99][100][101][102].…”

Section: Intestinal Barriermentioning

confidence: 99%

“…Indeed, accumulation of senescent cells has been associated with HMGB1 spillover into the extracellular space where it can act as an inflammagen and barrier disruptor [42][43][44][45][46]. Therefore, upregulated HMGB1, documented in ME/CFS, FM, and GWI, and COVID-19, directly links dysfunctional efferocytosis to chronic fatigue [47][48][49][50]. For example, gut HMGB1 disrupts the barrier tight junctions and is considered a biomarker of inflammatory bowel disease (IBD), a condition associated with both fatigue and increased GI tract permeability.…”

Section: Introductionmentioning

confidence: 99%

Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies

Sfera

Osorio

Hazan³

et al. 2022

Endocrines

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Similar to previous pandemics, COVID-19 has been succeeded by well-documented post-infectious sequelae, including chronic fatigue, cough, shortness of breath, myalgia, and concentration difficulties, which may last 5 to 12 weeks or longer after the acute phase of illness. Both the psychological stress of SARS-CoV-2 infection and being diagnosed with COVID-19 can upregulate cortisol, a stress hormone that disrupts the efferocytosis effectors, macrophages, and natural killer cells, leading to the excessive accumulation of senescent cells and disruption of biological barriers. This has been well-established in cancer patients who often experience unrelenting fatigue as well as gut and blood–brain barrier dysfunction upon treatment with senescence-inducing radiation or chemotherapy. In our previous research from 2020 and 2021, we linked COVID-19 to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via angiotensin II upregulation, premature endothelial senescence, intestinal barrier dysfunction, and microbial translocation from the gastrointestinal tract into the systemic circulation. In 2021 and 2022, these hypotheses were validated and SARS-CoV-2-induced cellular senescence as well as microbial translocation were documented in both acute SARS-CoV-2 infection, long COVID, and ME/CFS, connecting intestinal barrier dysfunction to disabling fatigue and specific infectious events. The purpose of this narrative review is to summarize what is currently known about host immune responses to translocated gut microbes and how these responses relate to fatiguing illnesses, including long COVID. To accomplish this goal, we examine the role of intestinal and blood–brain barriers in long COVID and other illnesses typified by chronic fatigue, with a special emphasis on commensal microbes functioning as viral reservoirs. Furthermore, we discuss the role of SARS-CoV-2/Mycoplasma coinfection in dysfunctional efferocytosis, emphasizing some potential novel treatment strategies, including the use of senotherapeutic drugs, HMGB1 inhibitors, Toll-like receptor 4 (TLR4) blockers, and membrane lipid replacement.

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Circulating HMGB1 is elevated in veterans with Gulf War Illness and triggers the persistent pro-inflammatory microglia phenotype in male C57Bl/6J mice

Cited by 14 publications

References 83 publications

Sex-specific differences in plasma lipid profiles are associated with Gulf War Illness

Sex-specific differences in plasma lipid profiles are associated with Gulf War Illness

Sex-Specific Differences In Plasma Lipid Profiles Are Associated With Gulf War Illness

Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies

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