Macrophage migration inhibitory factor promotes clearance of pneumococcal colonization.
Macrophage migration inhibitory factor promotes clearance of pneumococcal colonization.
复制标题
DOI：
10.4049/jimmunol.1400133
复制
发表时间：
2014-07-15
期刊：
影响因子：
--
通讯作者：
Weiser JN
中科院分区：
文献类型：
--
作者：
Das R;LaRose MI;Hergott CB;Leng L;Bucala R;Weiser JN
与巨噬细胞迁移抑制因子（MIF）表达降低相关的人类遗传多态性与社区获得性肺炎（CAP）的风险有关。由于肺炎链球菌是CAP的主要原因，而鼻腔携带是侵袭性疾病的前兆，我们在小鼠模型中探索了MIF在清除肺炎球菌定植中的作用。与野生型动物相比，Mif缺陷小鼠（Mif-/-）在无毒性（23F）和有毒性（6A）肺炎球菌血清型上的定植时间较长。肺炎球菌携带导致局部MIF表达上调和全身细胞因子升高。Mif-/-小鼠的延迟清除与上呼吸道灌洗中巨噬细胞数量减少以及单核细胞趋化蛋白-1 （MCP-1/CCL2）上调受损相关。我们发现，原代人单核细胞来源的巨噬细胞以及THP-1巨噬细胞在肺炎球菌感染后以溶肺素依赖的方式产生MIF。溶血素诱导的MIF产生需要巨噬细胞的成孔活性和p38-MAPK的磷酸化，在MIF缺乏的情况下，p38-MAPK的持续磷酸化被取消。肺炎溶素缺陷细菌的攻击显示MIF上调减少，鼻咽部巨噬细胞数量减少，清除效果较差。Mif-/-小鼠对肺炎球菌定植的抗体反应降低，清除继发载体的能力受损。最后，局部给药MIF能够恢复MIF -/-小鼠的细菌清除和巨噬细胞积累。我们的工作表明，MIF对肺炎球菌定植的先天和适应性免疫很重要，并且可能是肺炎球菌疾病易感性遗传差异的一个促成因素。
Human genetic polymorphisms associated with decreased expression of macrophage migration inhibitory factor (MIF) have been linked to the risk of community-acquired pneumonia (CAP). Since Streptococcus pneumoniae is the leading cause of CAP and nasal carriage a precursor to invasive disease, we explored the role of MIF in the clearance of pneumococcal colonization in a mouse model. MIF-deficient mice (Mif-/-) showed prolonged colonization with both avirulent (23F) and virulent (6A) pneumococcal serotypes compared, to wild-type animals. Pneumococcal carriage led to both local upregulation of MIF expression and systemic increase of the cytokine. Delayed clearance in the Mif-/- mice was correlated with reduced numbers of macrophages in upper respiratory tract lavages as well as impaired upregulation of monocyte chemotactic protein-1 (MCP-1/CCL2). We found that primary human monocyte derived macrophages as well as THP-1 macrophages produced MIF upon pneumococcal infection in a pneumolysin-dependent manner. Pneumolysin-induced MIF production required its pore-forming activity and phosphorylation of p38-MAPK in macrophages, with sustained p38-MAPK phosphorylation abrogated in the setting of MIF-deficiency. Challenge with pneumolysin-deficient bacteria demonstrated reduced MIF upregulation, decreased numbers of macrophages in the nasopharynx, and less effective clearance. Mif-/- mice also showed reduced antibody response to pneumococcal colonization and impaired ability to clear secondary carriage. Finally, local administration of MIF was able to restore bacterial clearance and macrophage accumulation in Mif-/- mice. Our work suggests that MIF is important for innate and adaptive immunity to pneumococcal colonization and could be a contributing factor in genetic differences in pneumococcal disease susceptibility.
登录
查看更多内容
影响因子：
3.1
作者：
BERRY, AM;YOTHER, J;PATON, JC
通讯作者：
PATON, JC
影响因子：
11.8
作者：
Albrich, W. C.;Madhi, S. A.;Klugman, K. P.
通讯作者：
Klugman, K. P.
DOI：
10.1073/pnas.56.1.72
发表时间：
1966-01-01
影响因子：
11.1
作者：
DAVID, JR
通讯作者：
DAVID, JR
DOI：
10.1073/pnas.95.19.11383
发表时间：
1998-09-15
影响因子：
11.1
作者：
Calandra, T;Spiegel, LA;Bucala, R
通讯作者：
Bucala, R
影响因子：
6.4
作者：
GRAY, BM;CONVERSE, GM;DILLON, HC
通讯作者：
DILLON, HC