Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Cell Rep. 2024 Feb 27;43(2):113795. doi: 10.1016/j.celrep.2024.113795. Epub 2024 Feb 15.
Activation of endosomal Toll-like receptor (TLR) 7, TLR9, and TLR11/12 is a key event in the resistance against the parasite Toxoplasma gondii. Endosomal TLR engagement leads to expression of interleukin (IL)-12 via the myddosome, a protein complex containing MyD88 and IL-1 receptor-associated kinase (IRAK) 4 in addition to IRAK1 or IRAK2. In murine macrophages, IRAK2 is essential for IL-12 production via endosomal TLRs but, surprisingly, Irak2 mice are only slightly susceptible to T. gondii infection, similar to Irak1 mice. Here, we report that upon T. gondii infection IL-12 production by different cell populations requires either IRAK1 or IRAK2, with conventional dendritic cells (DCs) requiring IRAK1 and monocyte-derived DCs (MO-DCs) requiring IRAK2. In both populations, we identify interferon regulatory factor 5 as the main transcription factor driving the myddosome-dependent IL-12 production during T. gondii infection. Consistent with a redundant role of DCs and MO-DCs, mutations that affect IL-12 production in both cell populations show high susceptibility to infection in vivo.
内体 Toll 样受体 (TLR) 7、TLR9 和 TLR11/12 的激活是抵抗寄生虫刚地弓形虫的关键事件。内体 TLR 的结合导致白细胞介素 (IL)-12 的表达，通过 MyD88 和包含 IRAK4 的 MyD88 相关激酶 (IRAK) 的复合物，除了 IRAK1 或 IRAK2。在小鼠巨噬细胞中，IRAK2 对于通过内体 TLR 产生 IL-12 是必不可少的，但令人惊讶的是，Irak2 小鼠对 T. gondii 感染的敏感性仅略低于 Irak1 小鼠。在这里，我们报告说，在 T. gondii 感染后，不同细胞群的 IL-12 产生需要 IRAK1 或 IRAK2，常规树突状细胞 (DCs) 需要 IRAK1，单核细胞衍生的 DCs (MO-DCs) 需要 IRAK2。在这两种细胞群中，我们确定干扰素调节因子 5 是驱动 T. gondii 感染期间 MyD88 依赖性 IL-12 产生的主要转录因子。与 DC 和 MO-DCs 的冗余作用一致，影响这两种细胞群中 IL-12 产生的突变在体内表现出高易感性。
