Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.
Department of Immunology, Duke University Medical Center, Durham, NC, USA.
EMBO Rep. 2020 Nov 5;21(11):e50830. doi: 10.15252/embr.202050830. Epub 2020 Oct 30.
Inflammation associated with gram-negative bacterial infections is often instigated by the bacterial cell wall component lipopolysaccharide (LPS). LPS-induced inflammation and resulting life-threatening sepsis are mediated by the two distinct LPS receptors TLR4 and caspase-11 (caspase-4/-5 in humans). Whereas the regulation of TLR4 activation by extracellular and phago-endosomal LPS has been studied in great detail, auxiliary host factors that specifically modulate recognition of cytosolic LPS by caspase-11 are largely unknown. This study identifies autophagy-related and dynamin-related membrane remodeling proteins belonging to the family of Immunity-related GTPases M clade (IRGM) as negative regulators of caspase-11 activation in macrophages. Phagocytes lacking expression of mouse isoform Irgm2 aberrantly activate caspase-11-dependent inflammatory responses when exposed to extracellular LPS, bacterial outer membrane vesicles, or gram-negative bacteria. Consequently, Irgm2-deficient mice display increased susceptibility to caspase-11-mediated septic shock in vivo. This Irgm2 phenotype is partly reversed by the simultaneous genetic deletion of the two additional Irgm paralogs Irgm1 and Irgm3, indicating that dysregulated Irgm isoform expression disrupts intracellular LPS processing pathways that limit LPS availability for caspase-11 activation.
与革兰氏阴性细菌感染相关的炎症通常是由细菌细胞壁成分脂多糖（LPS）引发的。LPS 诱导的炎症和由此产生的危及生命的败血症是由两个不同的 LPS 受体 TLR4 和 caspase-11（人类中的 caspase-4/-5）介导的。虽然已经对细胞外和吞噬体 LPS 对 TLR4 激活的调节进行了详细研究，但专门调节胞质 LPS 被 caspase-11 识别的辅助宿主因子在很大程度上仍是未知的。本研究鉴定了自噬相关和动力蛋白相关的膜重塑蛋白，它们属于免疫相关 GTP 酶 M 族（IRGM）家族，是巨噬细胞中 caspase-11 激活的负调节剂。当吞噬细胞缺乏表达小鼠同种型 Irgm2 时，当暴露于细胞外 LPS、细菌外膜囊泡或革兰氏阴性细菌时，会异常激活 caspase-11 依赖性炎症反应。因此，Irgm2 缺陷小鼠在体内对 caspase-11 介导的败血症休克的易感性增加。这种 Irgm2 表型部分被另外两个 Irgm 同源物 Irgm1 和 Irgm3 的同时遗传缺失所逆转，表明失调的 Irgm 同工型表达破坏了限制 LPS 用于 caspase-11 激活的细胞内 LPS 处理途径。
