IL-18R-mediated HSC quiescence and MLKL-dependent cell death limit hematopoiesis during infection-induced shock.
IL-18R-mediated HSC quiescence and MLKL-dependent cell death limit hematopoiesis during infection-induced shock.
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DOI：
10.1016/j.stemcr.2021.10.011
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发表时间：
2021-12-14
影响因子：
5.9
通讯作者：
MacNamara KC
中科院分区：
文献类型：
--
作者：
Howard JE;Smith JNP;Fredman G;MacNamara KC
严重感染可显著改变血液生成，但驱动造血干细胞和祖细胞（HSC/HSPC）损失的机制尚未明确定义。使用卵形硬蜱埃里希体（IOE），一种引起严重休克样疾病和骨髓（BM）发育不全的蜱传病原体，I型和II型干扰素（IFN）通过增加细胞死亡和强制静止促进HSPC的损失。IFN-αβ是感染期间白细胞介素18（IL-18）表达增加所必需的，与ST-HSC丢失相关。IL-18缺乏预防BM再生障碍性贫血并增加HSC/HSPC。IL-18 R信号传导是ST-HSC静止所固有的，但不是HSPC细胞死亡所固有的。为了阐明细胞死亡机制，感染了MLKL或gasdermin D缺陷小鼠;而Mlkl−/−小鼠表现出受保护的HSC/HSPC，在感染期间在Gsdmd−/−小鼠中没有观察到这种保护。MLKL缺陷在感染期间内在地保护HSC，并在恢复时改善造血输出。这些研究定义了休克样感染中HSC损失和造血功能抑制中的MLKL和IL-18 R信号传导。I型和II型IFN调节IL-18和IL-18 R在休克样感染中的表达IL-18产生有助于在休克样感染期间HSC/HSPC损失ST-HSC中的IL-18 R信号传导促进感染诱导的静止MLKL缺陷的HSC在感染期间受到保护MacNamara和同事定义了IL-18 R信号传导在严重休克样感染期间强制ST-HSC静止中的细胞自主作用。细胞死亡途径的分析表明，MLKL是严重感染期间HSC严重丧失的内在要求。在急性感染期间靶向IL-18 R和/或MLKL可以保护造血功能并改善患者结局。
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. Type I and II IFNs regulate expression of IL-18 and IL-18R in shock-like infection IL-18 production contributes to HSC/HSPC loss during shock-like infection IL-18R signaling in ST-HSCs promotes infection-induced quiescence MLKL-deficient HSCs are protected during infection MacNamara and colleagues define a cell-autonomous role for IL-18R signaling in enforcing quiescence of ST-HSCs during severe shock-like infection. Analysis of cell death pathways revealed that MLKL was intrinsically required for the profound loss of HSCs during severe infection. IL-18R and/or MLKL targeting during acute infection may preserve hematopoietic function and improve patient outcomes.
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影响因子：
16
作者：
Mandal P;Berger SB;Pillay S;Moriwaki K;Huang C;Guo H;Lich JD;Finger J;Kasparcova V;Votta B;Ouellette M;King BW;Wisnoski D;Lakdawala AS;DeMartino MP;Casillas LN;Haile PA;Sehon CA;Marquis RW;Upton J;Daley-Bauer LP;Roback L;Ramia N;Dovey CM;Carette JE;Chan FK;Bertin J;Gough PJ;Mocarski ES;Kaiser WJ
通讯作者：
Kaiser WJ
影响因子：
3.7
作者：
MacNamara KC;Jones M;Martin O;Winslow GM
通讯作者：
Winslow GM
影响因子：
13.6
作者：
Parikh, CR;Abraham, E;Edelstein, CL
通讯作者：
Edelstein, CL
影响因子：
64.5
作者：
Rickard, James A.;O'Donnell, Joanne A.;Silke, John
通讯作者：
Silke, John
影响因子：
3.8
作者：
Mariño, E;Cardier, JE
通讯作者：
Cardier, JE