Nlrp3 Inflammasome Signaling Regulates the Homing and Engraftment of Hematopoietic Stem Cells (HSPCs) by Enhancing Incorporation of CXCR4 Receptor into Membrane Lipid Rafts
Nlrp3 Inflammasome Signaling Regulates the Homing and Engraftment of Hematopoietic Stem Cells (HSPCs) by Enhancing Incorporation of CXCR4 Receptor into Membrane Lipid Rafts
复制标题
DOI：
10.1007/s12015-020-10005-w
复制
发表时间：
2020-07-13
影响因子：
4.8
通讯作者：
Ratajczak, Mariusz Z.
中科院分区：
文献类型：
--
作者：
Adamiak, Mateusz;Abdel-Latif, Ahmed;Ratajczak, Mariusz Z.
造血干祖细胞（HSPC）的快速有效归巢和植入对于移植的积极临床结果至关重要。我们发现，这一过程取决于Nlrp 3炎性体的激活，无论是在HSPC移植和受体骨髓（BM）微环境中的细胞。我们首次提供证据表明，移植细胞或宿主微环境中Nlrp 3炎性体的功能缺陷导致有缺陷的归巢和植入。在分子水平上，HSPC中Nlrp 3炎性体的功能缺陷导致其响应于主要BM归巢化学引诱物基质衍生因子1（SDF-1）和其他支持性化学引诱物（包括鞘氨醇-1-磷酸（S1 P）和细胞外腺苷三磷酸（eATP））的缺陷性迁移。我们报道Nlrp 3炎性小体的激活增加了eATP的自分泌释放，这促进了CXCR 4受体在迁移细胞的前沿表面并入膜脂筏。另一方面，在为移植而调节的BM中缺乏Nlrp 3炎性体表达导致SDF-1和SDF-1相关分子模式分子（DAMP）的表达降低，所述DAMP负责补体级联（ComC）的激活，这反过来促进HSPC的归巢和植入。
Fast and efficient homing and engraftment of hematopoietic stem progenitor cells (HSPCs) is crucial for positive clinical outcomes from transplantation. We found that this process depends on activation of the Nlrp3 inflammasome, both in the HSPCs to be transplanted and in the cells in the recipient bone marrow (BM) microenvironment. For the first time we provide evidence that functional deficiency in the Nlrp3 inflammasome in transplanted cells or in the host microenvironment leads to defective homing and engraftment. At the molecular level, functional deficiency of the Nlrp3 inflammasome in HSPCs leads to their defective migration in response to the major BM homing chemoattractant stromal-derived factor 1 (SDF-1) and to other supportive chemoattractants, including sphingosine-1-phosphate (S1P) and extracellular adenosine triphosphate (eATP). We report that activation of the Nlrp3 inflammasome increases autocrine release of eATP, which promotes incorporation of the CXCR4 receptor into membrane lipid rafts at the leading surface of migrating cells. On the other hand, a lack of Nlrp3 inflammasome expression in BM conditioned for transplantation leads to a decrease in expression of SDF-1 and danger-associated molecular pattern molecules (DAMPs), which are responsible for activation of the complement cascade (ComC), which in turn facilitates the homing and engraftment of HSPCs.