Department of Surgery, Rutgers-New Jersey Medical School, Newark, New Jersey.
Shock. 2022 Aug 1;58(2):179-188. doi: 10.1097/SHK.0000000000001966. Epub 2022 Aug 3.
Sex-related outcome differences in trauma remain controversial. The mechanisms causing sex-biased outcomes are likely to have hormonal and genetic components, in which X-linked genetic polymorphisms may play distinct roles because of X-linked inheritance, hemizygosity in males, and X chromosome mosaicism in females. The study aimed to elucidate the contribution of biological sex and the common X-linked IRAK1 haplotype to posttrauma clinical complications, inflammatory cytokine and chemokine production, and polymorphonuclear cell and monocyte activation. Postinjury clinical outcome was tested in 1507 trauma patients (1,110 males, 397 females) after stratification by sex or the variant IRAK1 haplotype. Males showed a three- to fivefold greater frequency of posttrauma sepsis, but similar mortality compared to females. Stratification by the variant IRAK1 haplotype revealed increased pneumonia and urinary tract infection in Wild type (WT) versus variant IRAK1 males, whereas increased respiratory failures in variant versus WT females. Cytokine/chemokine profiles were tested in whole blood from a subset of patients (n = 81) and healthy controls (n = 51), which indicated sex-related differences in ex vivo lipopolysaccharide responsiveness manifesting in a 1.5- to 2-fold increased production rate of tumor necrosis factor α, interleukin-1β (IL-1β), IL-10, Macrophage Inflammatory Protein-1 Alpha, and MIP1β in WT male compared to WT female trauma patients. Variant IRAK1 decreased IL-6, IL-8, and interferon gamma-induced protein 10 production in male trauma subjects compared to WT, whereas cytokine/chemokine responses were similar in variant IRAK1 and WT female trauma subjects. Trauma-induced and lipopolysaccharide-stimulated polymorphonuclear cell and monocyte activation determined by using a set of cluster of differentiation markers and flow cytometry were not influenced by sex or variant IRAK1. These findings suggest that variant IRAK1 is a potential contributor to sex-based outcome differences, but its immunomodulatory impacts are modulated by biological sex.
创伤相关的性别结局差异仍然存在争议。导致性别偏向结果的机制可能具有激素和遗传成分，其中 X 连锁遗传多态性可能由于 X 连锁遗传、男性的半合子状态和女性的 X 染色体嵌合性而发挥独特的作用。本研究旨在阐明生物学性别和常见的 X 连锁 IRAK1 单倍型对创伤后临床并发症、炎症细胞因子和趋化因子产生以及多形核细胞和单核细胞激活的贡献。在按性别或变体 IRAK1 单倍型分层的 1507 名创伤患者（1110 名男性，397 名女性）中测试了损伤后临床结局。与女性相比，男性创伤后脓毒症的发生频率高出三到五倍，但死亡率相似。按变体 IRAK1 单倍型分层显示，野生型（WT）男性的肺炎和尿路感染发生率增加，而变体男性的呼吸衰竭发生率增加；变体女性的肺炎和尿路感染发生率增加，而变体女性的呼吸衰竭发生率增加。从一组患者（n=81）和健康对照者（n=51）的全血中检测细胞因子/趋化因子谱，表明体外脂多糖反应存在性别相关差异，表现为 WT 男性比 WT 女性创伤患者产生肿瘤坏死因子-α、白细胞介素-1β（IL-1β）、IL-10、巨噬细胞炎症蛋白-1α和 MIP1β的速率增加 1.5 至 2 倍。与 WT 相比，变体 IRAK1 降低了男性创伤患者的 IL-6、IL-8 和干扰素γ诱导蛋白 10 的产生，而变体 IRAK1 和 WT 女性创伤患者的细胞因子/趋化因子反应相似。通过使用一组分化群标记物和流式细胞术确定的创伤诱导和脂多糖刺激的多形核细胞和单核细胞激活不受性别或变体 IRAK1 的影响。这些发现表明变体 IRAK1 是性别相关结局差异的潜在贡献者，但它的免疫调节作用受生物学性别调节。
