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IL-18R 介导体细胞静止和 MLKL 依赖性细胞死亡限制感染诱导性休克期间的造血。

IL-18R-mediated HSC quiescence and MLKL-dependent cell death limit hematopoiesis during infection-induced shock.

机构信息

The Department of Immunology and Infectious Disease, Albany Medical College, MC-151 47 New Scotland Avenue, Albany, NY 12208, USA.

The Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA.

出版信息

Stem Cell Reports. 2021 Dec 14;16(12):2887-2899. doi: 10.1016/j.stemcr.2021.10.011. Epub 2021 Nov 18.

DOI:10.1016/j.stemcr.2021.10.011
PMID:34798063
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8693653/
Abstract

Severe infection can dramatically alter blood production, but the mechanisms driving hematopoietic stem and progenitor cell (HSC/HSPC) loss have not been clearly defined. Using Ixodes ovatus Ehrlichia (IOE), a tick-borne pathogen that causes severe shock-like illness and bone marrow (BM) aplasia, type I and II interferons (IFNs) promoted loss of HSPCs via increased cell death and enforced quiescence. IFN-αβ were required for increased interleukin 18 (IL-18) expression during infection, correlating with ST-HSC loss. IL-18 deficiency prevented BM aplasia and increased HSC/HSPCs. IL-18R signaling was intrinsically required for ST-HSC quiescence, but not for HSPC cell death. To elucidate cell death mechanisms, MLKL- or gasdermin D-deficient mice were infected; whereas Mlkl mice exhibited protected HSC/HSPCs, no such protection was observed in Gsdmd mice during infection. MLKL deficiency intrinsically protected HSCs during infection and improved hematopoietic output upon recovery. These studies define MLKL and IL-18R signaling in HSC loss and suppressed hematopoietic function in shock-like infection.

摘要

严重感染会显著改变血液的生成，但导致造血干细胞和祖细胞（HSC/HSPC）丢失的机制尚未明确。利用伊氏锥虫埃立克体（IOE），一种导致严重类似休克的疾病和骨髓（BM）再生障碍的蜱传病原体，I 型和 II 型干扰素（IFNs）通过增加细胞死亡和强制静止来促进 HSPC 的丢失。IFN-αβ 在感染过程中增加白细胞介素 18（IL-18）的表达是必需的，这与 ST-HSC 的丢失相关。IL-18 缺陷可防止 BM 再生障碍和增加 HSC/HSPC。IL-18R 信号内在地需要 ST-HSC 静止，但不需要 HSPC 细胞死亡。为了阐明细胞死亡机制，用 MLKL 或 gasdermin D 缺陷型小鼠进行感染；尽管 Mlkl 小鼠表现出对 HSC/HSPC 的保护，但在感染期间 Gsdmd 小鼠没有观察到这种保护。MLKL 缺陷在感染期间内在地保护 HSCs，并在恢复时改善造血功能。这些研究定义了 MLKL 和 IL-18R 信号在 HSC 丢失中的作用，以及在类似休克的感染中抑制造血功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3456/8693653/346247ecc832/gr7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3456/8693653/346247ecc832/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3456/8693653/8c7995ce0c4a/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3456/8693653/969f5be1a3e8/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3456/8693653/0922e06b3c2f/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3456/8693653/adf07c45a983/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3456/8693653/c90ca04a4c99/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3456/8693653/420d35022ccc/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3456/8693653/40b096977ce8/gr6.jpg
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