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. 2022 Apr 21:13:723923.
doi: 10.3389/fneur.2022.723923. eCollection 2022.

Elevations in Tumor Necrosis Factor Alpha and Interleukin 6 From Neuronal-Derived Extracellular Vesicles in Repeated Low-Level Blast Exposed Personnel

Katie A Edwards  1   2 , Jacqueline J Leete  1 , Ethan G Smith  1 , Alycia Quick  3 , Claire M Modica  4 , Eric M Wassermann  5 , Elena Polejaeva  6 , Kristine C Dell  7 , Matthew LoPresti  8 , Peter Walker  9 , Meghan O'Brien  10 , Chen Lai  1 , Bao-Xi Qu  1   2 , Christina Devoto  1   2 , Walter Carr  8   11 , James R Stone  10 , Stephen T Ahlers  12 , Jessica M Gill  1   13
Affiliations

Elevations in Tumor Necrosis Factor Alpha and Interleukin 6 From Neuronal-Derived Extracellular Vesicles in Repeated Low-Level Blast Exposed Personnel

Katie A Edwards et al. Front Neurol. .

Abstract

Objective: The purpose of this pilot study was to determine if military service members with histories of hundreds to thousands of low-level blast exposures (i. e., experienced breachers) had different levels of serum and neuronal-derived extracellular vesicle (EV) concentrations of interleukin (IL)-6, IL-10, and tumor necrosis factor alpha (TNFα), compared to matched controls, and if these biomarkers related to neurobehavioral symptoms.

Methods: Participants were experienced breachers (n = 20) and matched controls without blast exposures (n = 14). Neuronal-derived EVs were isolated from serum and identified with mouse anti-human CD171. Serum and neuronal-derived EVs were analyzed for IL-6, IL-10, and TNFα using an ultra-sensitive assay.

Results: Serum TNFα concentrations were decreased in breachers when compared to control concentrations (p < 0.01). There were no differences in serum concentrations of IL-6, IL-10, or the IL-6/IL-10 ratio between breachers and controls (p's > 0.01). In neuronal-derived EVs, TNFα and IL-6 levels were increased in breachers compared to controls (p's < 0.01), and IL-10 levels were decreased in the breacher group compared to controls (p < 0.01). In breachers the IL-6/IL-10 ratio in neuronal-derived EVs was higher compared to controls, which correlated with higher total Rivermead Post-concussion Questionnaire (RPQ) scores (p's < 0.05).

Conclusions: These findings suggest that exposure of personnel to high numbers of low-level blast over a career may result in enduring central inflammation that is associated with chronic neurological symptoms. The data also suggest that peripheral markers of inflammation are not necessarily adequate surrogates for central neuroinflammation.

Keywords: blast; breacher; extracellular vesicles; military; neuroinflammation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Reviewer MM declared a past coauthorship/collaboration with one of the authors JG.

Figures

Figure 1
Figure 1
Serum levels of pro-inflammatory cytokine TNFα decreased in breachers. (A) Serum TNFα is decreased in breachers as compared to unexposed controls, (B) No change in serum IL-6 in breachers as compared to unexposed controls, (C) No change in serum IL-10 between groups, (D) No change in the IL-6/IL-10 ratio between groups. Significant p-values are represented as: ***p < 0.001.
Figure 2
Figure 2
Neuronal-derived EV cytokines propagate a pro-inflammatory environment in the brain. (A,B) EVs derived from neurons contain elevated levels of pro-inflammatory cytokines TNFα and IL-6 in experienced breachers when compared to unexposed controls. In addition, (C) anti-inflammatory cytokine IL-10 is decreased in this population. (D) The ratio of pro/anti-inflammatory cytokines IL-6/IL-10 is higher in experienced breachers. Significant p-values are represented as: **p < 0.01, ***p < 0.001.
Figure 3
Figure 3
IL-6/IL-10 ratios correlate with late postconcussive symptoms. (A) Serum ratios of IL-6/IL-10 (r = 0.526, p = 0.025) and (B) EV ratios of IL-6/IL-10 correlate with total RPQ score (r = 0.585, p = 0.022). (C) Serum ratios of IL-6/IL-10 (r = 0.515, p = 0.029) and (D) EV ratios of IL-6/IL-10 correlate with RPQ-13 scores (r = 0.580, p = 0.023), the portion of the exam related to late postconcussive symptoms. Graphs include line of best fit.
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References

    1. Carr W, Stone JR, Walilko T, Young LA, Snook TL, Paggi ME, et al. . Repeated low-level blast exposure: a descriptive human subjects study. Mil Med. (2016) 181(Suppl. 5):28–39. 10.7205/MILMED-D-15-00137 - DOI - PubMed
    1. Carr W, Polejaeva E, Grome A, Crandall B, LaValle C, Eonta SE, et al. . Relation of repeated low-level blast exposure with symptomology similar to concussion. J Head Trauma Rehabil. (2015) 30:47–55. 10.1097/HTR.0000000000000064 - DOI - PubMed
    1. Gill J, Motamedi V, Osier N, Dell K, Arcurio L, Carr W, et al. . Moderate blast exposure results in increased IL-6 and TNFα in peripheral blood. Brain Behav Immun. (2017) 65:90–4. 10.1016/j.bbi.2017.02.015 - DOI - PMC - PubMed
    1. Devoto C, Arcurio L, Fetta J, Ley M, Rodney T, Kanefsky R, et al. . Inflammation relates to chronic behavioral and neurological symptoms in military personnel with traumatic brain injuries. Cell Transplant. (2017) 26:1169–77. 10.1177/0963689717714098 - DOI - PMC - PubMed
    1. Edwards KA, Motamedi V, Osier ND, Kim H-S, Yun S, Cho Y-E, et al. . A moderate blast exposure results in dysregulated gene network activity related to cell death, survival, structure, and metabolism. Front Neurol. (2020) 11:91. 10.3389/fneur.2020.00091 - DOI - PMC - PubMed