IRAK4 activity controls immune responses to intracellular bacteria Listeria monocytogenes and Mycobacterium smegmatis.
IRAK4 activity controls immune responses to intracellular bacteria Listeria monocytogenes and Mycobacterium smegmatis.
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DOI：
10.1002/jlb.2a1117-449r
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发表时间：
2018-10
影响因子：
5.5
通讯作者：
Medvedev AE
中科院分区：
文献类型：
--
作者：
Pattabiraman G;Murphy M;Agliano F;Karlinsey K;Medvedev AE
白细胞介素1受体相关激酶(IRAK)4是Toll样受体(TLR)通路的中心酶。这项研究验证了一种假设，即IRAK4激酶活性是调节细胞内细菌感染期间先天免疫的先决条件。为此，我们分析了表达野生型IRAK4或其激酶失活K213M突变体(IRAK4KI)的小鼠获得的巨噬细胞在感染单核细胞增生性李斯特菌或耻垢分枝杆菌时的反应。与表达激酶充足的IRAK4的巨噬细胞对细胞因子的强烈诱导不同，IRAK4KI巨噬细胞在感染单增李斯特菌或耻垢分枝杆菌时，其肿瘤坏死因子α、IL-6、IL-1β和C-C基序趋化因子配体5的表达减少。细菌感染IRAK4KI巨噬细胞导致IRAK1、丝裂原活化蛋白激酶(MAPKs)和核因子(NF)-κB的激活减弱，诱导型一氧化氮合酶(NO)的诱导和NO的分泌减弱，但导致微生物负荷增加。与野生型动物相比，全身感染耻垢分枝杆菌或单核细胞增多性乳杆菌的IRAK4KI小鼠，血清IL-6和CXC基序配体-1水平降低，但脾和肝脏的细菌负荷增加。因此，IRAK4激酶活性的丧失是细胞内单核细胞增生性乳杆菌或耻垢分枝杆菌感染过程中缺乏细胞因子和杀微菌反应的基础，这是通过IRAK1、MAPKs和NF-κB的活性受损而导致的，但增加了细菌负荷，与NO的诱导减少相关。
Interleukin (IL)-1 receptor-associated kinase (IRAK) 4 is a central enzyme of the Toll-like receptor (TLR) pathways. This study tested the hypothesis that IRAK4 kinase activity is prerequisite for regulating innate immunity during infections with intracellular bacteria. To this end, we analyzed responses of macrophages obtained from mice expressing wild-type IRAK4 or its kinase-inactive K213M mutant (IRAK4KI) upon infection with intracellular bacteria Listeria monocytogenes or Mycobacterium smegmatis. In contrast to robust induction of cytokines by macrophages expressing kinase-sufficient IRAK4, IRAK4KI macrophages expressed decreased tumor necrosis factor-α, IL-6, IL-1β, and C-C motif chemokine ligand 5 upon infection with L. monocytogenes or M. smegmatis. Bacterial infection of IRAK4KI macrophages led to attenuated activation of IRAK1, mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB, impaired induction of inducible nitric oxide (NO) synthase mRNA and secretion of NO, but resulted in elevated microbial burdens. Compared to wild-type animals, systemic infection of IRAK4KI mice with M. smegmatis or L. monocytogenes resulted in decreased levels of serum IL-6 and CXC motif ligand-1 but increased bacterial burdens in the spleen and liver. Thus, a loss of IRAK4 kinase activity underlies deficient cytokine and microbicidal responses during infection with intracellular bacteria L. monocytogenes or M. smegmatis via impaired activation of IRAK1, MAPKs, and NF-κB but increases bacterial burdens, correlating with decreased induction of NO.