The Tyrosine Kinase Btk Regulates the Macrophage Response to Listeria monocytogenes Infection

In this study we investigated the role of Bruton's tyrosine kinase (Btk) in the immune response to the Gram-positive intracellular bacterium Listeria monocytogenes (Lm). In response to Lm infection, Btk was activated in bone marrow-derived macrophages (BMMs) and Btk−/− BMMs showed enhanced TNF-α, IL-6 and IL-12p40 secretion, while type I interferons were produced at levels similar to wild-type (wt) BMMs. Although Btk-deficient BMMs displayed reduced phagocytosis of E. coli fragments, there was no difference between wt and Btk−/− BMMs in the uptake of Lm upon infection. Moreover, there was no difference in the response to heat-killed Lm between wt and Btk−/− BMMs, suggesting a role for Btk in signaling pathways that are induced by intracellular Lm. Finally, Btk−/− mice displayed enhanced resistance and an increased mean survival time upon Lm infection in comparison to wt mice. This correlated with elevated IFN-γ and IL-12p70 serum levels in Btk−/− mice at day 1 after infection. Taken together, our data suggest an important regulatory role for Btk in macrophages during Lm infection.本研究探讨了布鲁顿酪氨酸激酶（Bruton's tyrosine kinase，Btk）在针对革兰氏阳性胞内致病菌单核细胞增生李斯特菌（Listeria monocytogenes，Lm）的免疫应答中的作用。受Lm感染刺激后，Btk在骨髓来源巨噬细胞（bone marrow-derived macrophages，BMMs）中被激活；Btk基因敲除（Btk−/−）的BMMs其肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）及白细胞介素12p40（IL-12p40）的分泌水平显著升高，而I型干扰素的产生水平与野生型（wild-type，wt）BMMs无明显差异。尽管Btk缺陷型BMMs对大肠杆菌（E. coli）片段的吞噬作用减弱，但在Lm感染后的病菌摄取能力与野生型BMMs并无差异。此外，野生型与Btk−/− BMMs对热灭活Lm的应答水平无显著差异，这提示Btk参与了胞内Lm诱导的信号传导通路。与野生型小鼠相比，Btk−/−小鼠在Lm感染后展现出更强的抗感染抵抗力与更长的平均存活时间，这与感染后第1天Btk−/−小鼠血清中干扰素-γ（IFN-γ）及白细胞介素12p70（IL-12p70）水平升高显著相关。综上，本研究数据表明，Btk在巨噬细胞应对Lm感染的过程中发挥着重要的调控作用。