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.

中文翻译：

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Nlrp3 炎性体信号传导通过增强 CXCR4 受体与膜脂筏的结合来调节造血干细胞 (HSPC) 的归巢和植入。

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。我们发现这个过程依赖于 Nlrp3 炎性体的激活，无论是在要移植的 HSPC 中还是在受体骨髓 (BM) 微环境中的细胞中。我们首次提供证据表明移植细胞或宿主微环境中 Nlrp3 炎性体的功能缺陷会导致归巢和植入缺陷。在分子水平上，HSPCs 中 Nlrp3 炎性体的功能缺陷导致它们响应主要的 BM 归巢趋化因子基质衍生因子 1 (SDF-1) 和其他支持性趋化因子，包括 1-磷酸鞘氨醇 (S1P) 的迁移缺陷) 和细胞外三磷酸腺苷 (eATP)。我们报告说，Nlrp3 炎性体的激活会增加 eATP 的自分泌释放，从而促进 CXCR4 受体结合到迁移细胞前表面的膜脂筏中。另一方面，BM 中缺乏 Nlrp3 炎性小体表达会导致 SDF-1 和危险相关分子模式分子 (DAMPs) 的表达减少，这些分子模式分子 (DAMPs) 负责激活补体级联反应 (ComC)，这反过来又促进了 HSPC 的归巢和植入。