IRAK-2 regulates IL-1-mediated pathogenic Th17 cell development in helminthic infection.
IRAK-2 regulates IL-1-mediated pathogenic Th17 cell development in helminthic infection.
复制标题
DOI：
10.1371/journal.ppat.1002272
复制
发表时间：
2011-10
期刊：
影响因子：
6.7
通讯作者：
Stadecker MJ
中科院分区：
文献类型：
--
作者：
Smith PM;Jacque B;Conner JR;Poltorak A;Stadecker MJ
Infection with the trematode parasite Schistosoma mansoni results in distinct heterogeneity of disease severity both in humans and in mice. In the experimental mouse model, severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation mediated by CD4 Th17 cells, whereas mild disease is associated with reduced hepatic inflammation in a Th2-skewed cytokine environment. Even though the host’s genetic background significantly impacts the clinical outcome of schistosomiasis, specific gene(s) that contribute to disease severity remain elusive. We investigated the schistosome infection in wild-derived mice, which possess a more diverse gene pool than classically inbred mouse strains and thus makes them more likely to reveal novel mechanisms of immune regulation. We now show that inbred wild-derived MOLF mice develop severe hepatic inflammation with high levels of IL-17. Congenic mice with a MOLF locus in chromosome 6, designated Why1, revealed high pathology and enabled the identification of Irak2 as the pathogenic gene. Although IRAK-2 is classically associated with TLR signaling, adoptive transfer of CD4 T cells revealed that IRAK-2 mediates pathology in a CD4 T cell specific manner by promoting Th17 cell development through enhancement of IL-1β-induced activation of transcription factors RORγt and BATF. The use of wild-derived mice unravels IRAK-2 as a novel regulator of IL-1-induced pathogenic Th17 cells in schistosomiasis, which likely has wide-ranging implications for other chronic inflammatory and autoimmune diseases. Schistosomes are trematode helminths that cause widespread disease in vertebrates and are responsible for over 200 million human infections worldwide. The species Schistosoma mansoni causes a hepatic granulomatous inflammatory and fibrosing reaction against tissue trapped parasite eggs that varies greatly in humans and among mouse strains, implying that the host’s genetic background plays a critical role in determining disease severity. Although exacerbated hepatic inflammation is known to be associated with an increase in CD4 Th17 cells, specific genes conducive to high pathology are unknown. In this study we used genetically diverse inbred wild-derived mice and found that their natural severe immunopathology and high IL-17 levels are regulated by the interleukin-1 (IL-1) receptor-associated kinase-like 2 (IRAK-2). We demonstrate that T cell intrinsic IRAK-2 affects disease severity by enhancing the development of Th17 cells, which results from an increased sensitivity to IL-1β induced activation of the lineage-specific transcription factors RORγt and BATF. Our findings thus identify IRAK-2 as a single regulator of pathogenic Th17 cell development in murine schistosomiasis and reveal a novel mechanism that is likely to operate in other chronic inflammatory and autoimmune diseases.
登录
查看更多内容
影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
DOI：
10.1073/pnas.0902745106
发表时间：
2009-04-28
影响因子：
11.1
作者：
Ben-Sasson, Shlomo Z.;Hu-Li, Jane;Paul, William E.
通讯作者：
Paul, William E.
影响因子：
5.4
作者：
Hernandez, HJ;Wang, Y;Stadecker, MJ
通讯作者：
Stadecker, MJ
影响因子：
4.8
作者：
Aggarwal, S;Ghilardi, N;Gurney, AL
通讯作者：
Gurney, AL