Department of Microbiology, University of Chicago, Illinois.
Department of Molecular Microbiology, Washington University in St Louis, Missouri.
J Infect Dis. 2024 Aug 16;230(2):336-345. doi: 10.1093/infdis/jiae060.
Early innate immune responses play an important role in determining the protective outcome of Mycobacterium tuberculosis (Mtb) infection. Nuclear factor κB (NF-κB) signaling in immune cells regulates the expression of key downstream effector molecules that mount early antimycobacterial responses. Using conditional knockout mice, we studied the effect of abrogation of NF-κB signaling in different myeloid cell types and its impact on Mtb infection. Our results show that the absence of IKK2-mediated signaling in all myeloid cells resulted in increased susceptibility to Mtb infection. In contrast, the absence of IKK2-mediated signaling in CD11c+ myeloid cells induced early proinflammatory cytokine responses, enhanced the recruitment of myeloid cells, and mediated early resistance to Mtb. Abrogation of IKK2 in MRP8-expressing neutrophils did not affect disease pathology or Mtb control. Thus, we describe an early immunoregulatory role for NF-κB signaling in CD11c-expressing phagocytes and a later protective role for NF-κB in LysM-expressing cells during Mtb infection.
早期固有免疫反应在决定结核分枝杆菌（Mtb）感染的保护结果方面起着重要作用。免疫细胞中的核因子κB（NF-κB）信号转导调节表达关键下游效应分子，从而引发早期抗分枝杆菌反应。使用条件性敲除小鼠，我们研究了不同髓样细胞中 NF-κB 信号转导的缺失及其对 Mtb 感染的影响。我们的结果表明，所有髓样细胞中 IKK2 介导的信号转导缺失导致对 Mtb 感染的易感性增加。相比之下，CD11c+髓样细胞中 IKK2 介导的信号转导缺失诱导早期促炎细胞因子反应，增强髓样细胞募集，并介导早期对 Mtb 的抗性。MRP8 表达的中性粒细胞中 IKK2 的缺失不影响疾病病理学或 Mtb 控制。因此，我们描述了 NF-κB 信号在表达 CD11c 的吞噬细胞中的早期免疫调节作用，以及在 Mtb 感染期间 LysM 表达细胞中的 NF-κB 的后期保护作用。
