Sadatomo Ai, Inoue Yoshiyuki, Ito Homare, Karasawa Tadayoshi, Kimura Hiroaki, Watanabe Sachiko, Mizushina Yoshiko, Nakamura Jun, Kamata Ryo, Kasahara Tadashi, Horie Hisanaga, Sata Naohiro, Takahashi Masafumi
Division of Inflammation Research, Center for Molecular Medicine, Jichi Medical University, Tochigi 329-0498, Japan; and.
Department of Surgery, Jichi Medical University, Tochigi 329-0498, Japan.
J Immunol. 2017 Nov 1;199(9):3306-3315. doi: 10.4049/jimmunol.1700717. Epub 2017 Oct 2.
Accumulating evidence suggests that IL-1β plays a pivotal role in the pathophysiology of hepatic ischemia-reperfusion (I/R) injury; however, the mechanism by which I/R triggers IL-1β production in the liver remains unclear. Recent data have shown that neutrophils contribute to hepatic I/R injury independently of the inflammasomes regulating IL-1β maturation. Thus, we investigated the role of neutrophils in IL-1β maturation and tissue injury in a murine model of hepatic I/R. IL-1β was released from the I/R liver and its deficiency reduced reactive oxygen species generation, apoptosis, and inflammatory responses, such as inflammatory cell infiltration and cytokine expression, thereby resulting in reduced tissue injury. Depletion of either macrophages or neutrophils also attenuated IL-1β release and hepatic I/R injury. In vitro experiments revealed that neutrophil-derived proteinases process pro-IL-1β derived from macrophages into its mature form independently of caspase-1. Furthermore, pharmacological inhibition of serine proteases attenuated IL-1β release and hepatic I/R injury in vivo. Taken together, the interaction between neutrophils and macrophages promotes IL-1β maturation and causes IL-1β-driven inflammation in the I/R liver. Both neutrophils and macrophages are indispensable in this process. These findings suggest that neutrophil-macrophage interaction is a therapeutic target for hepatic I/R injury and may also provide new insights into the inflammasome-independent mechanism of IL-1β maturation in the liver.
越来越多的证据表明，白细胞介素-1β（IL-1β）在肝脏缺血再灌注（I/R）损伤的病理生理学中起关键作用；然而，I/R触发肝脏中IL-1β产生的机制仍不清楚。最近的数据表明，中性粒细胞独立于调节IL-1β成熟的炎性小体而导致肝脏I/R损伤。因此，我们在小鼠肝脏I/R模型中研究了中性粒细胞在IL-1β成熟和组织损伤中的作用。IL-1β从I/R肝脏中释放出来，其缺乏减少了活性氧的产生、细胞凋亡以及炎症反应，如炎症细胞浸润和细胞因子表达，从而减轻了组织损伤。巨噬细胞或中性粒细胞的消耗也减弱了IL-1β的释放和肝脏I/R损伤。体外实验表明，中性粒细胞衍生的蛋白酶将巨噬细胞衍生的前体IL-1β加工成成熟形式，这一过程独立于半胱天冬酶-1。此外，丝氨酸蛋白酶的药理学抑制在体内减弱了IL-1β的释放和肝脏I/R损伤。综上所述，中性粒细胞与巨噬细胞之间的相互作用促进了IL-1β的成熟，并在I/R肝脏中引发了IL-1β驱动的炎症。中性粒细胞和巨噬细胞在这一过程中都是不可或缺的。这些发现表明，中性粒细胞-巨噬细胞相互作用是肝脏I/R损伤的治疗靶点，也可能为肝脏中IL-1β成熟的炎性小体非依赖机制提供新的见解。
