Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
Department of Nuclear Medicine and PET Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
Cell Death Dis. 2022 Jul 7;13(7):587. doi: 10.1038/s41419-022-05048-5.
Soluble glucose regulated protein 78 (sGRP78) has long been suggested as a mediator resolution of inflammation. We previously reported that sGRP78 induced the rapid endocytosis of TLR4 with defective TLR4 signaling. To elucidate the underlying mechanisms, in this study, we investigated how sGRP78 influenced the behavior and trafficking of TLR4 in myeloid cells. It was found that sGRP78 promoted LPS endocytosis with monomeric TLR4. This internalized monomeric TLR4 formed complexes with p62-LC3, and was degraded in autolysosomes. Furthermore, the sGRP78-enhanced autophagy-dependent TLR4 degradation caused apoptosis and ferroptosis in myeloid cells, contributing to the sGRP78-mediated resolution of inflammation. These reports establish innovative mechanisms for endotoxin clearance and immune regulation by TLR4 degradation, linking innate immunity with multiple ancient processes, including autophagy, apoptosis, and ferroptosis, together through a shared resolution-associated molecular pattern (RAMP)-sGRP78.
可溶性葡萄糖调节蛋白 78（sGRP78）长期以来一直被认为是炎症缓解的介质。我们之前报道过，sGRP78 诱导 TLR4 的快速内吞作用，导致 TLR4 信号转导缺陷。为了阐明潜在的机制，在本研究中，我们研究了 sGRP78 如何影响髓样细胞中 TLR4 的行为和运输。结果发现，sGRP78 促进 LPS 与单体 TLR4 的内吞作用。这种内化的单体 TLR4 与 p62-LC3 形成复合物，并在自噬溶酶体中降解。此外，sGRP78 增强的自噬依赖性 TLR4 降解导致髓样细胞凋亡和铁死亡，这有助于 sGRP78 介导的炎症缓解。这些研究结果为 TLR4 降解通过内毒素清除和免疫调节建立了创新的机制，通过共享的与炎症缓解相关的分子模式（RAMP）-sGRP78 将先天免疫与包括自噬、凋亡和铁死亡在内的多种古老过程联系在一起。
