Department of Anesthesiology, The University of Texas Medical Branch, Galveston, 77555-0591, USA.
Am J Respir Crit Care Med. 2012 Feb 1;185(3):291-300. doi: 10.1164/rccm.201108-1560OC. Epub 2011 Dec 1.
Lymphocytes have been shown to facilitate systemic inflammation and physiologic dysfunction in experimental models of severe sepsis. Our previous studies show that natural killer (NK) cells migrate into the peritoneal cavity during intraabdominal sepsis, but the trafficking of NKT and T lymphocytes has not been determined. The factors that regulate lymphocyte trafficking during sepsis are currently unknown.
To ascertain the importance of CXC chemokine receptor 3 (CXCR3) as a regulator of lymphocyte trafficking during sepsis and determine the contribution of CXCR3-mediated lymphocyte trafficking to the pathogenesis of septic shock.
Lymphocyte trafficking was evaluated in control and CXCR3-deficient mice using flow cytometry during sepsis caused by cecal ligation and puncture (CLP). Survival, core temperature, cytokine production, and bacterial clearance were measured as pathobiological endpoints.
This study shows that concentrations of the CXCR3 ligands CXCL9 (monokine induced by interferon γ, MIG) and CXCL10 (interferon γ-induced protein 10, IP-10) increase in plasma and the peritoneal cavity after CLP, peak at 8 hours after infection, and are higher in the peritoneal cavity than in plasma. The numbers of CXCR3(+) NK cells progressively decreased in spleen after CLP with a concomitant increase within the peritoneal cavity, a pattern that was ablated in CXCR3-deficient mice. CXCR3-dependent recruitment of T cells was also evident at 16 hours after CLP. Treatment of mice with anti-CXCR3 significantly attenuated CLP-induced hypothermia, decreased systemic cytokine production, and improved survival.
CXCR3 regulates NK- and T-cell trafficking during sepsis and blockade of CXCR3 attenuates the pathogenesis of septic shock.
淋巴细胞已被证实可促进实验性严重脓毒症模型中的全身炎症和生理功能障碍。我们之前的研究表明，自然杀伤 (NK) 细胞在腹腔内感染期间迁移到腹腔，但 NKT 和 T 淋巴细胞的迁移尚未确定。目前尚不清楚调节脓毒症期间淋巴细胞迁移的因素。
确定 CXC 趋化因子受体 3 (CXCR3) 作为脓毒症期间淋巴细胞迁移的调节剂的重要性，并确定 CXCR3 介导的淋巴细胞迁移对感染性休克发病机制的贡献。
使用流式细胞术在盲肠结扎和穿孔 (CLP) 引起的脓毒症期间评估对照和 CXCR3 缺陷小鼠中的淋巴细胞迁移。将存活率、核心体温、细胞因子产生和细菌清除作为病理生物学终点进行测量。
本研究表明，在 CLP 后，CXCR3 配体 CXCL9（干扰素 γ 诱导的单核细胞趋化蛋白 1，MIG）和 CXCL10（干扰素 γ 诱导的蛋白 10，IP-10）的浓度在血浆和腹腔中增加，在感染后 8 小时达到峰值，并且在腹腔中比在血浆中更高。在 CLP 后，CXCR3(+)NK 细胞在脾脏中的数量逐渐减少，同时在腹腔中增加，这种模式在 CXCR3 缺陷小鼠中被消除。在 CLP 后 16 小时，也可以明显观察到 CXCR3 依赖性 T 细胞的募集。用抗-CXCR3 治疗显著减轻 CLP 引起的体温过低、降低全身细胞因子产生并提高存活率。
CXCR3 调节脓毒症期间 NK 和 T 细胞的迁移，阻断 CXCR3 可减轻感染性休克的发病机制。
