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

• DOI: 10.1016/j.immuni.2021.07.002
• Publication Date: 2021-07-20T15:23:54Z
• Authors: Daniel Hofbauer; Dimitrios Mougiak...; 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 Giul...; Fabio Moda; Stefan Haskamp; Cindy Flamann; Martin Böttcher; Katrin Bitterer; Simon Völkl; Andreas Mackensen; Stefano Ricagno; Heiko Bruns
• Keywords: Inflammation; Mice, Knockout; Amyloid; 0303 health sciences; Interleukin-1beta; Interleukin-18; 610; tumor-associated macrophages; macrophages; multiple myeloma; inflammation; NLRP3; phagocytosis;; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Phagocytosis; NLR Family, Pyrin Domain-Containing 3 Protein; Tumor-Associated Macrophages; Tumor Microenvironment; Animals; Humans; Lysosomes; Multiple Myeloma; beta 2-Microglobulin; Cells, Cultured; inflammation; macrophages; multiple myeloma; NLRP3; phagocytosis; tumor-associated macrophages;; Signal Transduction

As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (β2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed β2m promotes β2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1β (IL-1β) and IL-18. This process depends on activation of the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficient mice lack efficient β2m-induced IL-1β production. Moreover, depletion or silencing of 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 osteolytic bone destruction normally promoted by β2m-induced inflammasome signaling. Our results provide mechanistic evidence for β2m's role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM.