Niu Shuo, Bian Zhen, Tremblay Alexandra, Luo Youqun, Kidder Koby, Mansour Ahmed, Zen Ke, Liu Yuan
Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA 30302.
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854; and.
J Immunol. 2016 Oct 15;197(8):3293-3301. doi: 10.4049/jimmunol.1502494. Epub 2016 Sep 12.
Chronic diseases are often associated with altered inflammatory response, leading to increased host vulnerability to new inflammatory challenges. Employing streptozotocin (STZ)-induced diabetes as a model, we further investigate mechanisms leading to enhanced neutrophil (polymorphonuclear leukocytes [PMN]) responses under hyperglycemia and compare them with those under chronic colitis. We show that, different from colitis under which the PMN response is significantly potentiated, the existence of a proinflammatory state associated with broad increases in macrophages in various organs plays a dominant role in promoting the PMN inflammatory response in diabetic mice. Studies of PMN infiltration during zymosan-induced peritonitis reveal that hyperglycemia enhances PMN recruitment not through inducing a high level of IL-17, which is the case in colitis, but through increasing F4/80 macrophages in the peritoneal cavity, resulting in elevations of IL-6, IL-1β, TNF-α, and CXCL1 production. Insulin reversal of hyperglycemia, but not the neutralization of IL-17, reduces peritoneal macrophage numbers and ameliorates PMN infiltration during peritonitis. Significantly increased macrophages are also observed in the liver, kidneys, and intestines under hyperglycemia, and they are attributable to exacerbated nephropathy and colitis when inflammatory conditions are induced by doxorubicin and dextran sulfate sodium, respectively. Furthermore, analyses of monocyte production and macrophage proliferation in tissues suggest that significant monocytosis of inflammatory F4/80Gr-1 monocytes from the spleen and macrophage proliferation in situ synergistically contribute to the increased macrophage population under hyperglycemia. In conclusion, our results demonstrate that STZ-induced hyperglycemic mice develop a systemic proinflammatory state mediated by broad infiltration of macrophages.
慢性疾病常与炎症反应改变相关，导致宿主对新的炎症刺激的易感性增加。我们以链脲佐菌素（STZ）诱导的糖尿病为模型，进一步研究高血糖状态下导致中性粒细胞（多形核白细胞[PMN]）反应增强的机制，并将其与慢性结肠炎状态下的机制进行比较。我们发现，与PMN反应显著增强的结肠炎不同，糖尿病小鼠体内存在一种与各器官巨噬细胞广泛增加相关的促炎状态，这在促进PMN炎症反应中起主导作用。对酵母聚糖诱导的腹膜炎期间PMN浸润的研究表明，高血糖增强PMN募集并非通过诱导高水平的IL-17（结肠炎的情况），而是通过增加腹腔内的F4/80巨噬细胞，导致IL-6、IL-1β、TNF-α和CXCL1产生增加。高血糖的胰岛素逆转而非IL-17的中和可减少腹膜炎期间腹腔巨噬细胞数量并改善PMN浸润。在高血糖状态下，肝脏、肾脏和肠道中也观察到巨噬细胞显著增加，当分别用阿霉素和葡聚糖硫酸钠诱导炎症时，它们分别导致肾病和结肠炎加重。此外，对组织中单核细胞产生和巨噬细胞增殖的分析表明，脾脏中炎性F4/80Gr-1单核细胞的显著单核细胞增多和原位巨噬细胞增殖协同促成了高血糖状态下巨噬细胞数量的增加。总之，我们的结果表明，STZ诱导的高血糖小鼠发展出一种由巨噬细胞广泛浸润介导的全身性促炎状态。
