Reese Oliver

Introduction: Gulf War Illness (GWI) is a chronic, multisymptom illness that affects 30-40% of the 700,000 veterans that served in the first Gulf War.^1,2 Primary symptoms of Gulf War Illness include cognitive and mood decline, chronic fatigue, musculoskeletal pain, and gastrointestinal dysfunction.^1,2,3,4 It is thought that the pathophysiology of GWI is thought to be persistent neuroinflammation due to exposure to multiple chemicals including permethrin, DEET, and pyridostigmine bromide.^1,2The ubiquitously expressed nuclear protein High Mobility Group Box -1 (HMGB1) protein is thought to be the likely mediator of the persistent neuroinflammation underlying GWI, through its ability to activate the classical complement pathway, upregulate pro-inflammatory cytokines, and alter the transcriptional profile of microglia^1,2Glycyrrhizen, a direct HMGB1 antagonist, has shown promise as a therapeutic for GWI. Methods: Model rats were exposed to GWI chemicals and restraint stress, then performed multiple behavioral tests.^1,2Afterwards, blood, tissue, and cerebral cortex samples were collected from both model and control rats.^1,2,3,4Blood samples were also collected from eighty veterans diagnosed with GWI.²Samples were analyzed via ELISA and immunofluorescence for levels of complement pathway proteins C1q and terminal membrane attack complex (TccC5b-9), and proinflammatory cytokines such as TNFa, IL-6, IL-1b.^1,2 RT-PCR was used to analyze the transcriptional profile of HMGB1 activated microglia.² Subarachnoid hemorrhages were induced in model rats, who were then immediately administered Glycyrrhizin. Serum samples were collected and analyzed via ELISA and immunofluorescence for the concentrations of HMGB1 and proinflammatory cytokines.⁶ Results: The serums of both model animals and GWI veterans were found to have elevated levels of circulating HMGB1 compared to controls.^1,2 Model rats were found to have elevated serum levels of complement proteins and proinflammatory cytokines.^1,2 Analyzed microglia were found to exhibit a unique transcriptional profile that showed upregulation of proinflammatory genes, six of which that were induced directly by HMGB1.²  Model rats showed decreased cognitive function on multiple behavioral tests.¹ Rats treated with Glycyrrhizin showed reduced levels of circulating HMGB1 and proinflammatory cytokines.⁶ Conclusions: HMGB1 is implicated as the key mediator of the persistent neuroinflammation underlying Gulf War Illness as increased levels of HMGb1 have been exhibited in both model animals and veterans diagnosed with GWI. HMGB1 promotes neuroinflammation and neurodegeneration through activating the classical complement pathway, upregulating proinflammatory cytokines, and altering the transcriptional profile of microglia. This neuroinflammation and neurodegeneration leads to the cognitive decline, chronic fatigue, and musculoskeltal pain experienced by Gulf War Illness patients. Further research into therapeutics is needed, but HMGB1 antagonist Glycyrrhizin has shown promise as a medical treatment for Gulf War Illness.

1. ^{Madhu, L. N., Attaluri, S., Kodali, M., Shuai, B., Upadhya, R., Gitai, D., & Shetty, A. K. (2019). Neuroinflammation in Gulf War Illness is linked with HMGB1 and complement activation, which can be discerned from brain-derived extracellular vesicles in the blood. Brain Behav Immun, 81, 430-443. https://doi.org/10.1016/j.bbi.2019.06.040}
2. ^{Garza-Lombo, C., Thang, M., Greve, H. J., Mumaw, C. L., Messenger, E. J., Ahmed, C., Quinn, E., Sullivan, K., & Block, M. L. (2021). Circulating HMGB1 is elevated in veterans with Gulf War Illness and triggers the persistent pro-inflammatory microglia phenotype in male C57Bl/6J mice. Transl Psychiatry, 11(1), 390. https://doi.org/10.1038/s41398-021-01517-1}
3. ^{Lacagnina, M. J., Li, J., Lorca, S., Rice, K. C., Sullivan, K., O’Callaghan, J. P., & Grace, P. M. (2021). A role for neuroimmune signaling in a rat model of Gulf War Illness-related pain. Brain Behav Immun, 91, 418-428. https://doi.org/10.1016/j.bbi.2020.10.022}
4. ^{Seth, R. K., Maqsood, R., Mondal, A., Bose, D., Kimono, D., Holland, L. A., Janulewicz Lloyd, P., Klimas, N., Horner, R. D., Sullivan, K., Lim, E. S., & Chatterjee, S. (2019). Gut DNA Virome Diversity and Its Association with Host Bacteria Regulate Inflammatory Phenotype and Neuronal Immunotoxicity in Experimental Gulf War Illness. Viruses, 11(10). https://doi.org/10.3390/v11100968}
5. ^{Kodali, M., Hattiangady, B., Shetty, G. A., Bates, A., Shuai, B., & Shetty, A. K. (2018). Curcumin treatment leads to better cognitive and mood function in a model of Gulf War Illness with enhanced neurogenesis, and alleviation of inflammation and mitochondrial dysfunction in the hippocampus. Brain Behav Immun, 69, 499-514. https://doi.org/10.1016/j.bbi.2018.01.009}
6. ^{Ieong, C., Sun, H., Wang, Q., & Ma, J. (2018). Glycyrrhizin suppresses the expressions of HMGB1 and ameliorates inflammative effect after acute subarachnoid hemorrhage in rat model. J Clin Neurosci, 47, 278-284. https://doi.org/10.1016/j.jocn.2017.10.034}