Neuroinflammatory gene expression changes in the brain in a rat model of Gulf War Illness – effects of rosiglitazone

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.海湾战争综合征（Gulf War Illness, GWI）是一类累及众多赴波斯湾战争部署退伍军人的多样化神经及全身症状群，但其病因尚未明确，治疗选择亦十分有限。罹患GWI的退伍军人曾暴露于多种致病因子，包括用于预防神经毒剂的溴吡斯的明（pyridostigmine bromide）、源自沙漠沙尘暴的鼻内脂多糖（lipopolysaccharide, LPS），以及作战相关的慢性不可预见性应激（chronic unpredictable stress, CUS）。本研究采用Clariom S芯片（Clariom S microarrays），探究了上述三种海湾战争相关暴露（GWE）对成年大鼠前额叶皮层（frontal cortex, FC）及外侧杏仁核（lateral amygdala, LA）基因表达的影响。研究结果显示，相较于未暴露对照组（n=3），GWE暴露组（n=2）的外侧杏仁核内共检测到138个差异表达转录簇（transcript clusters, TCs），前额叶皮层内则检测到38个差异表达转录簇（错误发现率<10%，False Discovery Rate, FDR）。上述转录簇包含与炎症反应相关的基因，如Fosb（pmin=1.02e-5）与Junb（pmin=1.13e-5）。基因本体分析（gene ontology analysis）发现，差异表达基因显著富集于"T细胞分化"（pmin=8.71e-5）、"有机磷应答"（pmin=1.74e-8）等多个功能类别。最后，本研究发现，作为过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor gamma, PPAR-γ）激动剂的罗格列酮（rosiglitazone）预防性给药，可缓解GWE诱导的基因表达改变：在外侧杏仁核中，115/138（83.3%）的转录簇的表达变化得到抑制（χ²=61.33, p=4.82e-15）。本研究结果表明，本研究所构建的GWI大鼠模型存在与神经炎症相关的基因表达异常，且部分此类分子层面的改变可通过罗格列酮预防性给药得到缓解。