Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia, USA.
Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, China.
JCI Insight. 2020 May 21;5(10):133365. doi: 10.1172/jci.insight.133365.
NOD-like receptor 12 (NLRP12) is a member of the nucleotide-binding domain and leucine-rich repeat containing receptor inflammasome family that plays a central role in innate immunity. We previously showed that DNA damage upregulated NLRP12 in hematopoietic stem cells (HSCs) of mice deficient in the DNA repair gene Fanca. However, the role of NLRP12 in HSC maintenance is not known. Here, we show that persistent DNA damage-induced NLRP12 improves HSC function in both mouse and human models of DNA repair deficiency and aging. Specifically, treatment of Fanca-/- mice with the DNA cross-linker mitomycin C or ionizing radiation induces NLRP12 upregulation in phenotypic HSCs. NLRP12 expression is specifically induced by persistent DNA damage. Functionally, knockdown of NLRP12 exacerbates the repopulation defect of Fanca-/- HSCs. Persistent DNA damage-induced NLRP12 was also observed in the HSCs from aged mice, and depletion of NLRP12 in these aged HSCs compromised their self-renewal and hematopoietic recovery. Consistently, overexpression of NLRP12 substantially improved the long-term repopulating function of Fanca-/- and aged HSCs. Finally, persistent DNA damage-induced NLRP12 maintains the function of HSCs from patients with FA or aged donors. These results reveal a potentially novel role of NLRP12 in HSC maintenance and suggest that NLRP12 targeting has therapeutic potential in DNA repair disorders and aging.
核苷酸结合域和富含亮氨酸重复受体炎症小体家族中的 NOD 样受体 12（NLRP12）是先天免疫的核心成员。我们之前表明，在缺乏 DNA 修复基因 Fanca 的小鼠造血干细胞（HSCs）中，DNA 损伤会上调 NLRP12。然而，NLRP12 在 HSC 维持中的作用尚不清楚。在这里，我们表明，持续的 DNA 损伤诱导的 NLRP12 改善了 DNA 修复缺陷和衰老的小鼠和人类模型中的 HSC 功能。具体而言，用 DNA 交联剂丝裂霉素 C 或电离辐射处理 Fanca-/- 小鼠可诱导表型 HSCs 中 NLRP12 的上调。NLRP12 的表达是由持续的 DNA 损伤特异性诱导的。功能上，NLRP12 的敲低会加剧 Fanca-/- HSCs 的重编程缺陷。在老年小鼠的 HSCs 中也观察到持续的 DNA 损伤诱导的 NLRP12，并且这些衰老的 HSCs 中 NLRP12 的耗竭会损害它们的自我更新和造血恢复。一致地，NLRP12 的过表达大大改善了 Fanca-/- 和衰老 HSCs 的长期重编程功能。最后，持续的 DNA 损伤诱导的 NLRP12 维持 FA 患者或老年供体的 HSCs 功能。这些结果揭示了 NLRP12 在 HSC 维持中的潜在新作用，并表明 NLRP12 靶向在 DNA 修复障碍和衰老中有治疗潜力。
