德国埃尔兰根大学Heiko Bruns研究团队发现，β2-微球蛋白引发肿瘤相关巨噬细胞中NLRP3炎症体的激活，进而促进多发性骨髓瘤的进展。2021年7月20日，国际知名学术期刊《免疫》在线发表了这一成果。

研究人员发现β-2-微球蛋白（β2m）是启动骨髓瘤相关巨噬细胞（MAM）炎症的驱动因素。吞噬β2m的溶酶体积累促进了β2m淀粉样蛋白在MAM中的聚集，导致溶酶体破裂，最终产生活性白细胞介素-1β（IL-1β）和IL-18。这一过程取决于β2m聚集后NLRP3炎症体的激活，因为NLRP3缺陷的小鼠的巨噬细胞缺乏有效的β2m诱导的IL-1β生产。此外，在一个小鼠多发性骨髓瘤（MM）模型中，MM细胞中β2m的耗竭或沉默能废除炎症体的激活。

最后，研究人员证明，破坏NLRP3或IL-18会减少肿瘤生长和溶骨性骨质破坏，而这通常是由β2m诱导的炎症体信号所促进的。这些结果为β2m在MM发病过程中作为NLRP3炎症体激活剂的作用提供了机制上的证据。此外，抑制NLRP3代表了MM的一种潜在治疗方法。

据介绍，作为MM微环境的重要组成部分，促炎性巨噬细胞已成为疾病进展、骨质破坏和免疫损伤的关键推动者。

附：英文原文

Title: β2-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression

Author: Daniel Hofbauer, Dimitrios Mougiakakos, Luca Broggini, Mario Zaiss, Maike Büttner-Herold, Christian Bach, Bernd Spriewald, Frank Neumann, Savita Bisht, Jens Nolting, Robert Zeiser, Shaima’a Hamarsheh, Martin Eberhardt, Julio Vera, Cristina Visentin, Chiara Maria Giulia De Luca, Fabio Moda, Stefan Haskamp, Cindy Flamann, Martin Bttcher, Katrin Bitterer, Simon Vlkl, Andreas Mackensen, Stefano Ricagno, Heiko Bruns

Issue&Volume: 2021-07-20

Abstract: As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatorymacrophages have emerged as key promoters of disease progression, bone destruction,and immune impairment. We identify beta-2-microglobulin (β2m) as a driver in initiatinginflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosedβ2m promotes β2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimatelyproduction of active interleukin-1β (IL-1β) and IL-18. This process depends on activationof the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficientmice lack efficient β2m-induced IL-1β production. Moreover, depletion or silencingof β2m in MM cells abrogates inflammasome activation in a murine MM model. Finally,we demonstrate that disruption of NLRP3 or IL-18 diminishes tumor growth and osteolyticbone destruction normally promoted by β2m-induced inflammasome signaling. Our resultsprovide mechanistic evidence for β2m’s role as an NLRP3 inflammasome activator duringMM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeuticapproach in MM.

DOI: 10.1016/j.immuni.2021.07.002

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00264-8