Li Zhiwei, Kanitz Ellen, Tuchscherer Margret, Tuchscherer Armin, Metges Cornelia C, Trakooljul Nares, Wimmers Klaus, Murani Eduard
Institute of Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.
Institute of Behavioural Physiology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.
Brain Behav Immun. 2020 Nov;90:174-183. doi: 10.1016/j.bbi.2020.08.009. Epub 2020 Aug 11.
Despite the crucial role of glucocorticoid receptor (GR) in proper immune responses, the effect of GR hypersensitivity on inflammation is rarely reported. To fill this knowledge gap, we exploited the natural gain-of-function substitution in the porcine glucocorticoid receptor (GR) and challenged pigs carrying normal or hypersensitive GR using 50 µg/kg lipopolysaccharide (LPS) following pretreatment with either saline or single bolus of 60 µg/kg dexamethasone (DEX). The GR substitution reduced baseline cortisol, adrenocorticotropic hormone (ACTH), and triglyceride concentration and granulocyte proportion whereas baseline platelet counts were elevated. Val-carriers, i.e. AlaVal as well as ValVal pigs, showed less LPS-induced cortisol rise but the cortisol fold change was similar in all genotypes. Differently, ACTH response to LPS was most significant in GR heterozygotes (AlaVal). LPS-induced disorders, including sickness behaviors, anorexia, thrombocytopenia, cytokine production, and metabolic alterations were more intense in Val-carriers. On the other hand, Val-carriers were more sensitive to DEX effect than wild types (AlaAla) during endotoxemia, but not under unchallenged conditions. This is the first report revealing aggravated responses to endotoxemia by GR gain-of-function. Together, these results imply that GR hypersensitivity is difficult to diagnose but may represent a risk factor for endotoxemia and sepsis.
尽管糖皮质激素受体（GR）在正常免疫反应中起着关键作用，但GR超敏反应对炎症的影响却鲜有报道。为填补这一知识空白，我们利用猪糖皮质激素受体（GR）的自然功能获得性替代，在用生理盐水或单次推注60μg/kg地塞米松（DEX）预处理后，用50μg/kg脂多糖（LPS）对携带正常或超敏GR的猪进行挑战。GR替代降低了基线皮质醇、促肾上腺皮质激素（ACTH）和甘油三酯浓度以及粒细胞比例，而基线血小板计数升高。Val携带者，即AlaVal以及ValVal猪，LPS诱导的皮质醇升高较少，但所有基因型的皮质醇变化倍数相似。不同的是，ACTH对LPS的反应在GR杂合子（AlaVal）中最为显著。LPS诱导的疾病，包括疾病行为、厌食、血小板减少、细胞因子产生和代谢改变，在Val携带者中更为严重。另一方面，在 endotoxemia期间，Val携带者比野生型（AlaAla）对DEX效应更敏感，但在未受挑战的条件下则不然。这是第一份揭示GR功能获得导致对内毒素血症反应加重的报告。总之，这些结果表明GR超敏反应难以诊断，但可能是内毒素血症和败血症的一个危险因素。
