Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
University of Michigan Medical School, Ann Arbor, MI, USA.
J Leukoc Biol. 2022 Mar;111(3):629-639. doi: 10.1002/JLB.3A0520-325RR. Epub 2021 Jul 14.
Macrophages possess mechanisms for reinforcing the integrity of their endolysosomes against damage. This property, termed inducible renitence, was previously observed in murine macrophages stimulated with LPS, peptidoglycan, IFNγ, or TNFα, which suggested roles for renitence in macrophage resistance to infection by membrane-damaging pathogens. This study analyzed additional inducers of macrophage differentiation for their ability to increase resistance to lysosomal damage by membrane-damaging particles. Renitence was evident in macrophages activated with LPS plus IFNγ, PGE , or adenosine, and in macrophages stimulated with IFN-β, but not in macrophages activated with IL-4 or IL-10. These responses indicated roles for macrophage subtypes specialized in host defense and suppression of immune responses, but not those involved in wound healing. Consistent with this pattern, renitence could be induced by stimulation with agonists for TLR, which required the signaling adaptors MyD88 and/or TRIF, and by infection with murine norovirus-1. Renitence induced by LPS was dependent on cytokine secretion by macrophages. However, no single secreted factor could explain all the induced responses. Renitence induced by the TLR3 agonist Poly(I:C) was mediated in part by the type I IFN response, but renitence induced by Pam3CSK4 (TLR2/1), LPS (TLR4), IFNγ, or TNFα was independent of type 1 IFN signaling. Thus, multiple pathways for inducing macrophage resistance to membrane damage exist and depend on the particular microbial stimulus sensed.
巨噬细胞拥有增强其内溶酶体完整性的机制，以防止损伤。这种特性被称为诱导抗性，先前在受到 LPS、肽聚糖、IFNγ 或 TNFα 刺激的鼠巨噬细胞中观察到，这表明抗性在巨噬细胞抵抗破坏膜的病原体感染方面具有作用。本研究分析了其他诱导巨噬细胞分化的因子，以研究它们是否能增强对抗破坏膜的颗粒引起的溶酶体损伤的抗性。在经 LPS 加 IFNγ、PGE 或腺苷激活的巨噬细胞中以及经 IFN-β 刺激的巨噬细胞中观察到诱导抗性，但在经 IL-4 或 IL-10 激活的巨噬细胞中未观察到。这些反应表明，在宿主防御和抑制免疫反应方面具有专门功能的巨噬细胞亚型具有作用，而在伤口愈合方面不具有作用。与此模式一致，TLR 的激动剂刺激可诱导诱导抗性，这需要信号适配器 MyD88 和/或 TRIF，并且可以通过感染鼠诺如病毒-1 来诱导。LPS 诱导的抗性依赖于巨噬细胞分泌的细胞因子。然而，没有一种分泌因子可以解释所有诱导的反应。TLR3 激动剂 Poly(I:C) 诱导的抗性部分由 I 型 IFN 反应介导，但 TLR2/1 激活剂 Pam3CSK4、LPS (TLR4)、IFNγ 或 TNFα 诱导的抗性不依赖于 I 型 IFN 信号。因此，存在多种诱导巨噬细胞抵抗膜损伤的途径，这取决于所感知的特定微生物刺激。
