Spight Donn, Trapnell Bruce, Zhao Bin, Berclaz Pierre, Shanley Thomas P
Department of Surgery, University of Cincinnati, Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
Shock. 2008 Oct;30(4):434-42. doi: 10.1097/SHK.0b013e3181673543.
Granulocyte-macrophage-colony-stimulating factor (GM-CSF) plays a critical role in innate immunity by stimulating the differentiation of tissue macrophages via the transcription factor PU.1. Previous studies showed that GMCSF-deficient(GM-CSF-/-) mice had susceptibility to and impaired clearance of group B streptococcal bacteria by macrophages. For these studies, we hypothesized that GM-CSF-/- mice have increased susceptibility to peritonitis caused by immune dysfunction of peritoneal macrophages. We examined the role of peritoneal macrophages in pathogen clearance, cytokine responses, and survival in a murine cecal ligation and puncture (CLP) model of peritonitis/sepsis. Surprisingly, CLP minimally affected survival in GM-CSF-/- mice while markedly reducing survival in wild-type mice. This was not explained by differences in the composition of microbial flora, rates of bacterial peritonitis, or sepsis, all of which were similar in GM-CSF-/- and wild-type mice. However, survival correlated with peritoneal and serum TNF-alpha and IL-6 levels that were significantly lower in GM-CSF-/- than in control mice. After peritoneal LPS instillation, GM-CSF-/- mice also had improved survival and reduced TNF-alpha and IL-6 responses. In vitro studies demonstrated reduced secretion of TNF-alpha and IL-6 by peritoneal macrophages isolated from sham GM-CSF-/- mice as compared with macrophages from sham control mice. Peritoneal instillation of GM-CSF-/-/PU.1+ macrophages, but not GM-CSF-/-/PU.1+ macrophages into GM-CSF-/- mice conferred susceptibility to death after CLP or peritoneal LPS exposure. These results demonstrate that GM-CSFY/PU.1-dependent peritoneal macrophage responses are a critical determinant of survival after experimentally induced peritonitis/sepsis or exposure to LPS and have implications for therapies to treat such infections.
粒细胞-巨噬细胞集落刺激因子（GM-CSF）通过转录因子PU.1刺激组织巨噬细胞的分化，在固有免疫中发挥关键作用。先前的研究表明，GM-CSF缺陷（GM-CSF-/-）小鼠对B族链球菌易感，且巨噬细胞对其清除能力受损。在这些研究中，我们假设GM-CSF-/-小鼠对由腹膜巨噬细胞免疫功能障碍引起的腹膜炎易感性增加。我们在小鼠盲肠结扎和穿刺（CLP）腹膜炎/脓毒症模型中研究了腹膜巨噬细胞在病原体清除、细胞因子反应和生存中的作用。令人惊讶的是，CLP对GM-CSF-/-小鼠的生存影响极小，而对野生型小鼠的生存则有显著降低。这不能用微生物菌群组成、细菌性腹膜炎或脓毒症发生率的差异来解释，所有这些在GM-CSF-/-和野生型小鼠中都是相似的。然而，生存与腹膜和血清TNF-α及IL-6水平相关，GM-CSF-/-小鼠中的这些水平显著低于对照小鼠。腹膜内注入LPS后，GM-CSF-/-小鼠的生存也得到改善，TNF-α和IL-6反应降低。体外研究表明，与假手术对照小鼠的巨噬细胞相比，从假手术GM-CSF-/-小鼠分离的腹膜巨噬细胞分泌TNF-α和IL-6减少。将GM-CSF-/-/PU.1+巨噬细胞而非GM-CSF-/-/PU.1-巨噬细胞腹膜内注入GM-CSF-/-小鼠，会使其在CLP或腹膜内暴露于LPS后易死亡。这些结果表明，GM-CSF/PU.1依赖的腹膜巨噬细胞反应是实验性诱导的腹膜炎/脓毒症或暴露于LPS后生存的关键决定因素，对治疗此类感染的疗法具有启示意义。
