Lung Epithelial Regnase-1 Dampens Local Immune Response but Does Not Worsen Susceptibility to Klebsiella pneumoniae.
Lung Epithelial Regnase-1 Dampens Local Immune Response but Does Not Worsen Susceptibility to Klebsiella pneumoniae.
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DOI：
10.4049/immunohorizons.2300082
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发表时间：
2024-01-01
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影响因子：
--
通讯作者：
Trevejo-Nuñez G
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文献类型：
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作者：
Lin B;Fan L;Jackson S;Matunis AR;Lou D;Chen K;Trevejo-Nuñez G
肺炎克雷伯氏菌（KP）是一种全球性的健康威胁，由于其多重耐药特征和治疗选择的有限性，导致显著的发病率和死亡率。为了消除KP肺部感染，宿主启动强烈的炎症反应。宿主减轻过度炎症的机制之一涉及RNA结合蛋白regnase-1（Reg 1，MCPIP 1或ZC 3 H12 A）。Reg 1有一个RNA结合域，可识别各种促炎转录物3′非翻译区的茎环结构，导致mRNA降解。然而，Reg 1对炎症的过度抑制导致次优的KP控制。非造血区室中的Reg 1缺陷赋予肺中对KP的抗性。鉴于肺上皮对KP耐药至关重要，我们假设肺上皮细胞中Reg 1的选择性缺失可能会增强促炎信号，从而更好地控制KP。我们对KP感染的野生型小鼠上皮细胞的转录组学分析显示，存在三种不同的肺泡2型细胞（AT 2）亚群（常规、炎症和循环），并在炎症AT 2细胞中富集Reg 1。我们有条件地删除肺AT 2细胞中的Reg 1（Δ Reg 1），与对照组相比，这放大了肺中的局部炎症反应并增加了巨噬细胞数量。然而，当Δ Reg 1小鼠经受KP感染时，与对照相比，细菌负荷或存活率没有显著差异。这些发现表明，在AT 2细胞中Reg 1缺失增强的局部炎症反应不足以控制KP感染。
Klebsiella pneumoniae (KP) presents a global health threat, leading to significant morbidity and mortality due to its multidrug-resistant profile and the limited availability of therapeutic options. To eliminate KP lung infection, the host initiates a robust inflammatory response. One of the host’s mechanisms for mitigating excessive inflammation involves the RNA-binding protein regnase-1 (Reg1, MCPIP1, or ZC3H12A). Reg1 has an RNA binding domain that recognizes stem-loop structures in the 3′ untranslated region of various proinflammatory transcripts, leading to mRNA decay. However, excessive suppression of inflammation by Reg1 results in suboptimal KP control. Reg1 deficiency within the nonhematopoietic compartment confers resistance to KP in the lung. Given that lung epithelium is crucial for KP resistance, we hypothesized that selective deletion of Reg1 in lung epithelial cells might enhance proinflammatory signals, leading to a better control of KP. Our transcriptomic analysis of epithelial cells in KP-infected wild-type mice revealed the presence of three distinct alveolar type 2 cell (AT2) subpopulations (conventional, inflammatory, and cycling) and enrichment of Reg1 in inflammatory AT2 cells. We conditionally deleted Reg1 in lung AT2 cells (ΔReg1), which amplified the local inflammatory response in the lung and increased macrophage cell numbers compared with controls. However, when ΔReg1 mice were subjected to KP infection, there were no significant differences in bacterial burden or survival compared with controls. These findings suggest that the local inflammatory response enhanced by Reg1 deletion in AT2 cells is insufficient to control KP infection.