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 (GRAla610Val) 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 GRAla610Val 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 GRAla610Val 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.

中文翻译：

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导致糖皮质激素受体超敏反应的天然 Ala610Val 替代会加重内毒素血症的后果

尽管糖皮质激素受体 (GR) 在适当的免疫反应中起着至关重要的作用，但很少报道 GR 超敏反应对炎症的影响。为了填补这一知识空白，我们利用猪糖皮质激素受体 (GRAla610Val) 中的自然获得功能替代，并在用盐水或单次推注60 µg/kg 地塞米松 (DEX)。GRAla610Val 替代降低了基线皮质醇、促肾上腺皮质激素 (ACTH) 和甘油三酯浓度和粒细胞比例，而基线血小板计数升高。Val 携带者，即 AlaVal 和 ValVal 猪，表现出较少的 LPS 诱导的皮质醇升高，但所有基因型的皮质醇倍数变化相似。不同的是，在 GRAla610Val 杂合子 (AlaVal) 中，ACTH 对 LPS 的反应最为显着。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 携带者中更为强烈。另一方面，Val 携带者在内毒素血症期间比野生型 (AlaAla) 对 DEX 效应更敏感，但在不受挑战的条件下则不然。这是第一份揭示 GR 功能获得对内毒素血症反应加重的报告。总之，这些结果意味着 GR 超敏反应难以诊断，但可能是内毒素血症和败血症的危险因素。另一方面，Val 携带者在内毒素血症期间比野生型 (AlaAla) 对 DEX 效应更敏感，但在不受挑战的条件下则不然。这是第一份揭示 GR 功能获得对内毒素血症反应加重的报告。总之，这些结果意味着 GR 超敏反应难以诊断，但可能是内毒素血症和败血症的危险因素。另一方面，Val 携带者在内毒素血症期间比野生型 (AlaAla) 对 DEX 效应更敏感，但在不受挑战的条件下则不然。这是第一份揭示 GR 功能获得对内毒素血症反应加重的报告。总之，这些结果意味着 GR 超敏反应难以诊断，但可能是内毒素血症和败血症的危险因素。