Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA, United States.
Digital Technologies Research Centre, National Research Council Canada, Toronto, ON, Canada.
Front Immunol. 2020 Jul 29;11:1652. doi: 10.3389/fimmu.2020.01652. eCollection 2020.
Many diseases display unequal prevalence between sexes. The sex-specific immune response to both injury and persistent pain remains underexplored and would inform treatment paradigms. We utilized high-dimensional mass cytometry to perform a comprehensive analysis of phenotypic and functional immune system differences between male and female mice after orthopedic injury. Multivariate modeling of innate and adaptive immune cell responses after injury using an elastic net algorithm, a regularized regression method, revealed sex-specific divergence at 12 h and 7 days after injury with a stronger immune response to injury in females. At 12 h, females upregulated STAT3 signaling in neutrophils but downregulated STAT1 and STAT6 signals in T regulatory cells, suggesting a lack of engagement of immune suppression pathways by females. Furthermore, at 7 days females upregulated MAPK pathways (p38, ERK, NFkB) in CD4T memory cells, setting up a possible heightened immune memory of painful injury. Taken together, our findings provide the first comprehensive and functional analysis of sex-differences in the immune response to painful injury.
许多疾病在性别之间的发病率存在差异。对于损伤和持续性疼痛的性别特异性免疫反应仍未得到充分探索，这将为治疗模式提供信息。我们利用高维质谱流式细胞术对骨科损伤后雄性和雌性小鼠的表型和功能性免疫系统差异进行了全面分析。使用弹性网络算法（一种正则化回归方法）对损伤后固有和适应性免疫细胞反应进行多元建模，结果显示损伤后 12 小时和 7 天存在性别特异性差异，女性对损伤的免疫反应更强。在 12 小时时，雌性中性粒细胞中 STAT3 信号转导上调，但 T 调节细胞中 STAT1 和 STAT6 信号下调，表明女性未参与免疫抑制途径。此外，在 7 天时，雌性 CD4T 记忆细胞中 MAPK 途径（p38、ERK、NFkB）上调，为疼痛性损伤的可能增强免疫记忆奠定了基础。总之，我们的研究结果提供了对疼痛性损伤免疫反应中性别差异的首次全面和功能分析。
