Alipour Misagh, Lou Yuefei, Zimmerman Daniel, Bording-Jorgensen Michael W, Sergi Consolato, Liu Julia J, Wine Eytan
Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada ; Centre of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR), University of Alberta, Edmonton, Alberta, Canada.
PLoS One. 2013 Dec 2;8(12):e80656. doi: 10.1371/journal.pone.0080656. eCollection 2013.
Microbial sensing plays essential roles in the innate immune response to pathogens. In particular, NLRP3 forms a multiprotein inflammasome complex responsible for the maturation of interleukin (IL)-1β. Our aim was to delineate the role of the NLRP3 inflammasome in macrophages, and the contribution of IL-1β to the host defense against Citrobacter rodentium acute infection in mice. Nlrp3(-/-) and background C57BL/6 (WT) mice were infected by orogastric gavage, received IL-1β (0.5 µg/mouse; ip) on 0, 2, and 4 days post-infection (DPI), and assessed on 6 and 10 DPI. Infected Nlrp3(-/-) mice developed severe colitis; IL-1β treatments reduced colonization, abrogated dissemination of bacteria to mesenteric lymph nodes, and protected epithelial integrity of infected Nlrp3(-/-) mice. In contrast, IL-1β treatments of WT mice had an opposite effect with increased penetration of bacteria and barrier disruption. Microscopy showed reduced damage in Nlrp3(-/-) mice, and increased severity of disease in WT mice with IL-1β treatments, in particular on 10 DPI. Secretion of some pro-inflammatory plasma cytokines was dissipated in Nlrp3(-/-) compared to WT mice. IL-1β treatments elevated macrophage infiltration into infected crypts in Nlrp3(-/-) mice, suggesting that IL-1β may improve macrophage function, as exogenous administration of IL-1β increased phagocytosis of C. rodentium by peritoneal Nlrp3(-/-) macrophages in vitro. As well, the exogenous administration of IL-1β to WT peritoneal macrophages damaged the epithelial barrier of C. rodentium-infected polarized CMT-93 cells. Treatment of Nlrp3(-/-) mice with IL-1β seems to confer protection against C. rodentium infection by reducing colonization, protecting epithelial integrity, and improving macrophage activity, while extraneous IL-1β appeared to be detrimental to WT mice. Together, these findings highlight the importance of balanced cytokine responses as IL-1β improved bacterial clearance in Nlrp3(-/-) mice but increased tissue damage when given to WT mice.
微生物感知在对病原体的先天免疫反应中起着至关重要的作用。特别是，NLRP3形成一种多蛋白炎性小体复合物，负责白细胞介素（IL）-1β的成熟。我们的目的是阐明NLRP3炎性小体在巨噬细胞中的作用，以及IL-1β对小鼠抵抗鼠柠檬酸杆菌急性感染的宿主防御的贡献。通过经口灌胃感染Nlrp3(-/-)和背景C57BL/6（野生型，WT）小鼠，在感染后（DPI）第0、2和4天给予IL-1β（0.5μg/小鼠；腹腔注射），并在第6和10天进行评估。感染的Nlrp3(-/-)小鼠发生了严重的结肠炎；IL-1β治疗减少了细菌定植，消除了细菌向肠系膜淋巴结的扩散，并保护了感染的Nlrp3(-/-)小鼠的上皮完整性。相反，IL-1β治疗WT小鼠产生了相反的效果，细菌穿透增加且屏障破坏。显微镜检查显示Nlrp3(-/-)小鼠的损伤减少，而接受IL-1β治疗的WT小鼠疾病严重程度增加，尤其是在第10天DPI时。与WT小鼠相比，Nlrp3(-/-)小鼠中一些促炎血浆细胞因子的分泌减少。IL-1β治疗增加了Nlrp3(-/-)小鼠感染隐窝中的巨噬细胞浸润，这表明IL-1β可能改善巨噬细胞功能，因为体外给予IL-1β增加了腹膜Nlrp3(-/-)巨噬细胞对鼠柠檬酸杆菌的吞噬作用。同样，向WT腹膜巨噬细胞外源性给予IL-1β破坏了鼠柠檬酸杆菌感染的极化CMT-93细胞的上皮屏障。用IL-1β治疗Nlrp3(-/-)小鼠似乎通过减少定植、保护上皮完整性和改善巨噬细胞活性来提供针对鼠柠檬酸杆菌感染的保护，而外源性IL-1β似乎对WT小鼠有害。总之，这些发现突出了平衡细胞因子反应的重要性，因为IL-1β改善了Nlrp3(-/-)小鼠的细菌清除，但给予WT小鼠时增加了组织损伤。
